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1. Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author: Kast, Karin, John, Esther M, Hopper, John L, Andrieu, Nadine, Noguès, Catherine, Mouret-Fourme, Emmanuelle, Lasset, Christine, Fricker, Jean-Pierre, Berthet, Pascaline, Mari, Véronique, Salle, Lucie, Schmidt, Marjanka K, Ausems, Margreet GEM, Garcia, Encarnacion B Gomez, van de Beek, Irma, Wevers, Marijke R, Evans, D Gareth, Tischkowitz, Marc, Lalloo, Fiona, Cook, Jackie, Izatt, Louise, Tripathi, Vishakha, Snape, Katie, Musgrave, Hannah, Sharif, Saba, Murray, Jennie, EMBRACE Collaborators, Colonna, Sarah V, Andrulis, Irene L, Daly, Mary B, Southey, Melissa C, de la Hoya, Miguel, Osorio, Ana, Foretova, Lenka, Berkova, Dita, Gerdes, Anne-Marie, Olah, Edith, Jakubowska, Anna, Singer, Christian F, Tan, Yen, Augustinsson, Annelie, Rantala, Johanna, Simard, Jacques, Schmutzler, Rita K, Milne, Roger L, Phillips, Kelly-Anne, Terry, Mary Beth, Goldgar, David, van Leeuwen, Flora E, Mooij, Thea M, Antoniou, Antonis C, Easton, Douglas F, Rookus, Matti A, Engel, Christoph, Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Adult, BRCA2 Protein, Risk, Heterozygote, BRCA1 Protein, Genes, BRCA2, Humans, Female, Breast Neoplasms, Genetic Predisposition to Disease, Weight Gain, Body Mass Index, Retrospective Studies
Abstract: INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.
Published: 2023
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2. HOPE (SOLTI-1903) breast cancer study: real-world, patient-centric, clinical practice study to assess the impact of genomic data on next treatment decision-choice in patients with locally advanced or metastatic breast cancer

Author: Olivera-Salguero, Rubén, Seguí, Elia, Cejalvo, Juan Miguel, Oliveira, Mafalda, Tolosa, Pablo, Vidal, Maria, Malumbres, Marcos, Gavilá, Joaquín, Saura, Cristina, Pernas, Sonia, López, Rafael, Margelí, Mireia, Balmaña, Judith, Muñoz, Montserrat, Blancas, Isabel, Boni, Valentina, Ciruelos, Eva, Galve, Elena, Perelló, Antonia, Sánchez-Bayona, Rodrigo, de la Cruz, Susana, de la Hoya, Miguel, Galván, Patricia, Sanfeliu, Esther, Gonzalez-Farre, Blanca, Sirenko, Valeria, Blanch-Torras, Aura, Canes, Jordi, Masanas, Helena, Olmos, Rosa, Forns, Margarita, Prat, Aleix, Casas, Ana, and Pascual, Tomás
Subjects: Targeted therapy, Patient-centric trials, Cancer Research, Oncology, Molecular advisory board, Genomic data, Molecular tumor board, Metastatic breast cancer
Abstract: Background: Metastatic breast cancer (mBC) causes nearly all BC-related deaths. Next-generation sequencing (NGS) technologies allow for the application of personalized medicine using targeted therapies that could improve patients’ outcomes. However, NGS is not routinely used in the clinical practice and its cost induces access-inequity among patients. We hypothesized that promoting active patient participation in the management of their disease offering access to NGS testing and to the subsequent medical interpretation and recommendations provided by a multidisciplinary molecular advisory board (MAB) could contribute to progressively overcome this challenge. We designed HOPE (SOLTI-1903) breast cancer trial, a study where patients voluntarily lead their inclusion through a digital tool (DT). The main objectives of HOPE study are to empower mBC patients, gather real-world data on the use of molecular information in the management of mBC and to generate evidence to assess the clinical utility for healthcare systems. Trial design: After self-registration through the DT, the study team validates eligibility criteria and assists patients with mBC in the subsequent steps. Patients get access to the information sheet and sign the informed consent form through an advanced digital signature. Afterwards, they provide the most recent (preferably) metastatic archival tumor sample for DNA-sequencing and a blood sample obtained at the time of disease progression for ctDNA analysis. Paired results are reviewed by the MAB, considering patient’s medical history. The MAB provides a further interpretation of molecular results and potential treatment recommendations, including ongoing clinical trials and further (germline) genetic testing. Participants self-document their treatment and disease evolution for the next 2 years. Patients are encouraged to involve their physicians in the study. HOPE also includes a patient empowerment program with educational workshops and videos about mBC and precision medicine in oncology. The primary endpoint of the study was to describe the feasibility of a patient-centric precision oncology program in mBC patients when a comprehensive genomic profile is available to decide on a subsequent line of treatment., Novartis and the non-profit organizations: Asociación Cáncer de Mama Metastásico and Fundación Actitud frente al Cáncer. F1CDx, initiative: Saray (Asociación Navarra de cáncer de mama); Federación Española de Cáncer de Mama (FECMA, Asociación Vive, ni una estrella más and Manualitats Solidàries Cerdanyola. Pfizer, HOPE Run initiative whose benefits were invested in this trial
Published: 2023

3. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Author: Hakkaart, Christopher, Pearson, John F, Marquart, Louise, Dennis, Joe, Wiggins, George AR, Barnes, Daniel R, Robinson, Bridget A, Mace, Peter D, Aittomäki, Kristiina, Andrulis, Irene L, Arun, Banu K, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Belhadj, Sami, Berger, Lieke, Blok, Marinus J, Boonen, Susanne E, Borde, Julika, Bradbury, Angela R, Brunet, Joan, Buys, Saundra S, Caligo, Maria A, Campbell, Ian, Chung, Wendy K, Claes, Kathleen BM, GEMO Study Collaborators, EMBRACE Collaborators, Collonge-Rame, Marie-Agnès, Cook, Jackie, Cosgrove, Casey, Couch, Fergus J, Daly, Mary B, Dandiker, Sita, Davidson, Rosemarie, De La Hoya, Miguel, De Putter, Robin, Delnatte, Capucine, Dhawan, Mallika, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Donaldson, Alan, Eason, Jacqueline, Easton, Douglas F, Ehrencrona, Hans, Engel, Christoph, Evans, D Gareth, Faust, Ulrike, Feliubadaló, Lidia, Fostira, Florentia, Friedman, Eitan, Frone, Megan, Frost, Debra, Garber, Judy, Gayther, Simon A, Gehrig, Andrea, Gesta, Paul, Godwin, Andrew K, Goldgar, David E, Greene, Mark H, Hahnen, Eric, Hake, Christopher R, Hamann, Ute, Hansen, Thomas VO, Hauke, Jan, Hentschel, Julia, Herold, Natalie, Honisch, Ellen, Hulick, Peter J, Imyanitov, Evgeny N, SWE-BRCA Investigators, KConFab Investigators, HEBON Investigators, Isaacs, Claudine, Izatt, Louise, Izquierdo, Angel, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, John, Esther M, Joseph, Vijai, Karlan, Beth Y, Kemp, Zoe, Kirk, Judy, Konstantopoulou, Irene, Koudijs, Marco, Kwong, Ava, Laitman, Yael, Lalloo, Fiona, Lasset, Christine, Lautrup, Charlotte, Lazaro, Conxi, Legrand, Clémentine, Leslie, Goska, Lesueur, Fabienne, Mai, Phuong L, Manoukian, Siranoush, Mari, Véronique, Martens, John WM, McGuffog, Lesley, Mebirouk, Noura, Meindl, Alfons, Miller, Austin, Montagna, Marco, Moserle, Lidia, Mouret-Fourme, Emmanuelle, Musgrave, Hannah, Nambot, Sophie, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nguyen-Dumont, Tu, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Osorio, Ana, Ott, Claus-Eric, Park, Sue K, Parsons, Michael T, Pedersen, Inge Sokilde, Peixoto, Ana, Perez-Segura, Pedro, Peterlongo, Paolo, Pocza, Timea, Radice, Paolo, Ramser, Juliane, Rantala, Johanna, Rodriguez, Gustavo C, Rønlund, Karina, Rosenberg, Efraim H, Rossing, Maria, Schmutzler, Rita K, Shah, Payal D, Sharif, Saba, Sharma, Priyanka, Side, Lucy E, Simard, Jacques, Singer, Christian F, Snape, Katie, Steinemann, Doris, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R, Teo, Soo Hwang, Thomassen, Mads, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Trainer, Alison H, Tripathi, Vishakha, Tung, Nadine, Van Engelen, Klaartje, Van Rensburg, Elizabeth J, Vega, Ana, Viel, Alessandra, Walker, Lisa, Weitzel, Jeffrey N, Wevers, Marike R, Chenevix-Trench, Georgia, Spurdle, Amanda B, Antoniou, Antonis C, Walker, Logan C, Pearson, John F [0000-0001-5607-4517], Dennis, Joe [0000-0003-4591-1214], Barnes, Daniel R [0000-0002-3781-7570], Mace, Peter D [0000-0003-2175-9537], Andrulis, Irene L [0000-0002-4226-6435], Azzollini, Jacopo [0000-0002-9364-9778], Blok, Marinus J [0000-0002-7935-5933], Brunet, Joan [0000-0003-1945-3512], Campbell, Ian [0000-0002-7773-4155], Chung, Wendy K [0000-0003-3438-5685], Claes, Kathleen BM [0000-0003-0841-7372], Dandiker, Sita [0000-0003-3837-7690], de la Hoya, Miguel [0000-0002-8113-1410], de Putter, Robin [0000-0001-9410-8941], Easton, Douglas F [0000-0003-2444-3247], Ehrencrona, Hans [0000-0002-5589-3622], Feliubadaló, Lidia [0000-0002-1736-0112], Gayther, Simon A [0000-0001-7937-5443], Gesta, Paul [0000-0002-4410-8668], Godwin, Andrew K [0000-0002-3987-9580], Greene, Mark H [0000-0003-1852-9239], Hauke, Jan [0000-0001-8236-4075], Hulick, Peter J [0000-0001-8397-4078], Isaacs, Claudine [0000-0002-9646-1260], Izatt, Louise [0000-0003-1258-4843], Izquierdo, Angel [0000-0003-2004-3246], Jakubowska, Anna [0000-0002-5650-0501], James, Paul A [0000-0002-4361-4657], Joseph, Vijai [0000-0002-7933-151X], Karlan, Beth Y [0000-0002-9451-2933], Konstantopoulou, Irene [0000-0002-0470-0309], Lazaro, Conxi [0000-0002-7198-5906], Leslie, Goska [0000-0001-5756-6222], Lesueur, Fabienne [0000-0001-7404-4549], Martens, John WM [0000-0002-3428-3366], Miller, Austin [0000-0001-9739-8462], Nambot, Sophie [0000-0002-9630-5049], Nathanson, Katherine L [0000-0002-6740-0901], Neuhausen, Susan L [0000-0001-5053-0390], Nevanlinna, Heli [0000-0002-0916-2976], Yie, Joanne Ngeow Yuen [0000-0003-1558-3627], Nikitina-Zake, Liene [0000-0003-2491-5187], Olopade, Olufunmilayo I [0000-0002-9936-1599], Osorio, Ana [0000-0001-8124-3984], Ott, Claus-Eric [0000-0003-3627-3791], Park, Sue K [0000-0001-5002-9707], Parsons, Michael T [0000-0003-3242-8477], Pedersen, Inge Sokilde [0000-0002-9902-8040], Peterlongo, Paolo [0000-0001-6951-6855], Radice, Paolo [0000-0001-6298-4111], Rosenberg, Efraim H [0000-0002-3859-6941], Simard, Jacques [0000-0001-6906-3390], Steinemann, Doris [0000-0001-8797-0816], Sutter, Christian [0000-0003-4051-5888], Tan, Yen Yen [0000-0003-1063-5352], Teixeira, Manuel R [0000-0002-4896-5982], Teo, Soo Hwang [0000-0002-0444-590X], Tischkowitz, Marc [0000-0002-7880-0628], Toland, Amanda E [0000-0002-0271-1792], Tripathi, Vishakha [0000-0001-8118-8364], van Rensburg, Elizabeth J [0000-0003-2077-230X], Vega, Ana [0000-0002-7416-5137], Viel, Alessandra [0000-0003-2804-0840], Weitzel, Jeffrey N [0000-0001-6714-092X], Wevers, Marike R [0000-0001-8008-6008], Spurdle, Amanda B [0000-0003-1337-7897], Walker, Logan C [0000-0003-0018-3719], and Apollo - University of Cambridge Repository
Subjects: Heterozygote, DNA Copy Number Variations, 45/43, 45/22, 13/107, 45/23, 13/106, Breast Neoplasms, 13, 14, 13/44, 631/67/68, 38/89, Humans, Genetic Predisposition to Disease, RNA, Messenger, 45/90, 38/109, 64, BRCA2 Protein, 45, BRCA1 Protein, article, 45/77, 692/4028/67, 38/35, 14/63, Female
Abstract: The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers., C12292/A20861 PPRPGM-Nov20\100002
Published: 2022
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4. Additional file 3 of Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author: Kast, Karin, John, Esther M., Hopper, John L., Andrieu, Nadine, Noguès, Catherine, Mouret-Fourme, Emmanuelle, Lasset, Christine, Fricker, Jean-Pierre, Berthet, Pascaline, Mari, Véronique, Salle, Lucie, Schmidt, Marjanka K., Ausems, Margreet G. E. M., Garcia, Encarnacion B. Gomez, van de Beek, Irma, Wevers, Marijke R., Evans, D. Gareth, Tischkowitz, Marc, Lalloo, Fiona, Cook, Jackie, Izatt, Louise, Tripathi, Vishakha, Snape, Katie, Musgrave, Hannah, Sharif, Saba, Murray, Jennie, Colonna, Sarah V., Andrulis, Irene L., Daly, Mary B., Southey, Melissa C., de la Hoya, Miguel, Osorio, Ana, Foretova, Lenka, Berkova, Dita, Gerdes, Anne-Marie, Olah, Edith, Jakubowska, Anna, Singer, Christian F., Tan, Yen, Augustinsson, Annelie, Rantala, Johanna, Simard, Jacques, Schmutzler, Rita K., Milne, Roger L., Phillips, Kelly-Anne, Terry, Mary Beth, Goldgar, David, van Leeuwen, Flora E., Mooij, Thea M., Antoniou, Antonis C., Easton, Douglas F., Rookus, Matti A., and Engel, Christoph
Abstract: Additional file 3: Table S3. Retrospective analysis of height, body mass index, weight change and breast cancer risk, by menopausal status.
Published: 2023
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5. Additional file 1 of Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author: Kast, Karin, John, Esther M., Hopper, John L., Andrieu, Nadine, Noguès, Catherine, Mouret-Fourme, Emmanuelle, Lasset, Christine, Fricker, Jean-Pierre, Berthet, Pascaline, Mari, Véronique, Salle, Lucie, Schmidt, Marjanka K., Ausems, Margreet G. E. M., Garcia, Encarnacion B. Gomez, van de Beek, Irma, Wevers, Marijke R., Evans, D. Gareth, Tischkowitz, Marc, Lalloo, Fiona, Cook, Jackie, Izatt, Louise, Tripathi, Vishakha, Snape, Katie, Musgrave, Hannah, Sharif, Saba, Murray, Jennie, Colonna, Sarah V., Andrulis, Irene L., Daly, Mary B., Southey, Melissa C., de la Hoya, Miguel, Osorio, Ana, Foretova, Lenka, Berkova, Dita, Gerdes, Anne-Marie, Olah, Edith, Jakubowska, Anna, Singer, Christian F., Tan, Yen, Augustinsson, Annelie, Rantala, Johanna, Simard, Jacques, Schmutzler, Rita K., Milne, Roger L., Phillips, Kelly-Anne, Terry, Mary Beth, Goldgar, David, van Leeuwen, Flora E., Mooij, Thea M., Antoniou, Antonis C., Easton, Douglas F., Rookus, Matti A., and Engel, Christoph
Abstract: Additional file 1: Table S1. Overview of the studies contributing to the retrospective and prospective analyses.
Published: 2023
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6. Additional file 5 of Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author: Kast, Karin, John, Esther M., Hopper, John L., Andrieu, Nadine, Noguès, Catherine, Mouret-Fourme, Emmanuelle, Lasset, Christine, Fricker, Jean-Pierre, Berthet, Pascaline, Mari, Véronique, Salle, Lucie, Schmidt, Marjanka K., Ausems, Margreet G. E. M., Garcia, Encarnacion B. Gomez, van de Beek, Irma, Wevers, Marijke R., Evans, D. Gareth, Tischkowitz, Marc, Lalloo, Fiona, Cook, Jackie, Izatt, Louise, Tripathi, Vishakha, Snape, Katie, Musgrave, Hannah, Sharif, Saba, Murray, Jennie, Colonna, Sarah V., Andrulis, Irene L., Daly, Mary B., Southey, Melissa C., de la Hoya, Miguel, Osorio, Ana, Foretova, Lenka, Berkova, Dita, Gerdes, Anne-Marie, Olah, Edith, Jakubowska, Anna, Singer, Christian F., Tan, Yen, Augustinsson, Annelie, Rantala, Johanna, Simard, Jacques, Schmutzler, Rita K., Milne, Roger L., Phillips, Kelly-Anne, Terry, Mary Beth, Goldgar, David, van Leeuwen, Flora E., Mooij, Thea M., Antoniou, Antonis C., Easton, Douglas F., Rookus, Matti A., and Engel, Christoph
Abstract: Additional file 5: Table S5. Weight versus body mass index and breast cancer risk in BRCA1 and BRCA2 variant carriers, by menopausal status.
Published: 2023
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7. Additional file 2 of Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author: Kast, Karin, John, Esther M., Hopper, John L., Andrieu, Nadine, Noguès, Catherine, Mouret-Fourme, Emmanuelle, Lasset, Christine, Fricker, Jean-Pierre, Berthet, Pascaline, Mari, Véronique, Salle, Lucie, Schmidt, Marjanka K., Ausems, Margreet G. E. M., Garcia, Encarnacion B. Gomez, van de Beek, Irma, Wevers, Marijke R., Evans, D. Gareth, Tischkowitz, Marc, Lalloo, Fiona, Cook, Jackie, Izatt, Louise, Tripathi, Vishakha, Snape, Katie, Musgrave, Hannah, Sharif, Saba, Murray, Jennie, Colonna, Sarah V., Andrulis, Irene L., Daly, Mary B., Southey, Melissa C., de la Hoya, Miguel, Osorio, Ana, Foretova, Lenka, Berkova, Dita, Gerdes, Anne-Marie, Olah, Edith, Jakubowska, Anna, Singer, Christian F., Tan, Yen, Augustinsson, Annelie, Rantala, Johanna, Simard, Jacques, Schmutzler, Rita K., Milne, Roger L., Phillips, Kelly-Anne, Terry, Mary Beth, Goldgar, David, van Leeuwen, Flora E., Mooij, Thea M., Antoniou, Antonis C., Easton, Douglas F., Rookus, Matti A., and Engel, Christoph
Abstract: Additional file 2: Table S2. Retrospective and prospective analysis of height in quintiles and breast cancer risk, by menopausal status.
Published: 2023
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8. Additional file 4 of Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Author: Kast, Karin, John, Esther M., Hopper, John L., Andrieu, Nadine, Noguès, Catherine, Mouret-Fourme, Emmanuelle, Lasset, Christine, Fricker, Jean-Pierre, Berthet, Pascaline, Mari, Véronique, Salle, Lucie, Schmidt, Marjanka K., Ausems, Margreet G. E. M., Garcia, Encarnacion B. Gomez, van de Beek, Irma, Wevers, Marijke R., Evans, D. Gareth, Tischkowitz, Marc, Lalloo, Fiona, Cook, Jackie, Izatt, Louise, Tripathi, Vishakha, Snape, Katie, Musgrave, Hannah, Sharif, Saba, Murray, Jennie, Colonna, Sarah V., Andrulis, Irene L., Daly, Mary B., Southey, Melissa C., de la Hoya, Miguel, Osorio, Ana, Foretova, Lenka, Berkova, Dita, Gerdes, Anne-Marie, Olah, Edith, Jakubowska, Anna, Singer, Christian F., Tan, Yen, Augustinsson, Annelie, Rantala, Johanna, Simard, Jacques, Schmutzler, Rita K., Milne, Roger L., Phillips, Kelly-Anne, Terry, Mary Beth, Goldgar, David, van Leeuwen, Flora E., Mooij, Thea M., Antoniou, Antonis C., Easton, Douglas F., Rookus, Matti A., and Engel, Christoph
Abstract: Additional file 4: Table S4. Prospective analysis of associations between height, body mass index, weight change and breast cancer risk, by menopausal status.
Published: 2023
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9. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Author: Barnes, Daniel R, Silvestri, Valentina, Leslie, Goska, McGuffog, Lesley, Dennis, Joe, Yang, Xin, Adlard, Julian, Agnarsson, Bjarni A, Ahmed, Munaza, Aittomäki, Kristiina, Andrulis, Irene L, Arason, Adalgeir, Arnold, Norbert, Auber, Bernd, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Barwell, Julian, Belotti, Muriel, Benitez, Javier, Berthet, Pascaline, Boonen, Susanne E, Borg, Åke, Bozsik, Aniko, Brady, Angela F, Brennan, Paul, Brewer, Carole, Brunet, Joan, Bucalo, Agostino, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Cassingham, Hayley, Christensen, Lise Lotte, Cini, Giulia, Claes, Kathleen BM, GEMO Study Collaborators, EMBRACE Collaborators, Cook, Jackie, Coppa, Anna, Cortesi, Laura, Damante, Giuseppe, Darder, Esther, Davidson, Rosemarie, de la Hoya, Miguel, De Leeneer, Kim, de Putter, Robin, Del Valle, Jesús, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Donaldson, Alan, Eason, Jacqueline, Eeles, Ros, Engel, Christoph, Evans, D Gareth, Feliubadaló, Lidia, Fostira, Florentia, Frone, Megan, Frost, Debra, Gallagher, David, Gehrig, Andrea, Giraud, Sophie, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, Greene, Mark H, Gregory, Helen, Gross, Eva, Hahnen, Eric, Hamann, Ute, Hansen, Thomas VO, Hanson, Helen, Hentschel, Julia, Horvath, Judit, KConFab Investigators, HEBON Investigators, Izatt, Louise, Izquierdo, Angel, James, Paul A, Janavicius, Ramunas, Jensen, Uffe Birk, Johannsson, Oskar Th, John, Esther M, Kramer, Gero, Kroeldrup, Lone, Kruse, Torben A, Lautrup, Charlotte, Lazaro, Conxi, Lesueur, Fabienne, Lopez-Fernández, Adria, Mai, Phuong L, Manoukian, Siranoush, Matrai, Zoltan, Matricardi, Laura, Maxwell, Kara N, Mebirouk, Noura, Meindl, Alfons, Montagna, Marco, Monteiro, Alvaro N, Morrison, Patrick J, Muranen, Taru A, Murray, Alex, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Nguyen-Dumont, Tu, Niederacher, Dieter, Olah, Edith, Olopade, Olufunmilayo I, Palli, Domenico, Parsons, Michael T, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Peterlongo, Paolo, Petersen, Annabeth H, Pinto, Pedro, Porteous, Mary E, Pottinger, Caroline, Pujana, Miquel Angel, Radice, Paolo, Ramser, Juliane, Rantala, Johanna, Robson, Mark, Rogers, Mark T, Rønlund, Karina, Rump, Andreas, Sánchez de Abajo, Ana María, Shah, Payal D, Sharif, Saba, Side, Lucy E, Singer, Christian F, Stadler, Zsofia, Steele, Linda, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R, Teulé, Alex, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tommasi, Stefania, Toss, Angela, Trainer, Alison H, Tripathi, Vishakha, Valentini, Virginia, van Asperen, Christi J, Venturelli, Marta, Viel, Alessandra, Vijai, Joseph, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Whaite, Anna, Zanna, Ines, Offit, Kenneth, Thomassen, Mads, Couch, Fergus J, Schmutzler, Rita K, Simard, Jacques, Easton, Douglas F, Chenevix-Trench, Georgia, Antoniou, Antonis C, Ottini, Laura, Consortium of Investigators of Modifiers of BRCA1 and BRCA2, Barnes, Daniel R [0000-0002-3781-7570], Silvestri, Valentina [0000-0003-0712-9379], Leslie, Goska [0000-0001-5756-6222], Dennis, Joe [0000-0003-4591-1214], Yang, Xin [0000-0003-0037-3790], Adlard, Julian [0000-0002-1693-0435], Agnarsson, Bjarni A [0000-0001-7721-9965], Andrulis, Irene L [0000-0002-4226-6435], Arason, Adalgeir [0000-0003-0480-886X], Arnold, Norbert [0000-0003-4523-8808], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Barkardottir, Rosa B [0000-0003-0629-2772], Barrowdale, Daniel [0000-0003-1661-3939], Benitez, Javier [0000-0002-0923-7202], Boonen, Susanne E [0000-0002-7824-2080], Bozsik, Aniko [0000-0001-5410-9173], Brennan, Paul [0000-0003-1128-6254], Brunet, Joan [0000-0003-1945-3512], Bucalo, Agostino [0000-0003-3475-1067], Caligo, Maria A [0000-0003-0589-1829], Campbell, Ian [0000-0002-7773-4155], Cassingham, Hayley [0000-0001-9922-2321], Cini, Giulia [0000-0002-8696-8922], Claes, Kathleen BM [0000-0003-0841-7372], Coppa, Anna [0000-0001-9758-5444], Cortesi, Laura [0000-0001-8950-8561], Darder, Esther [0000-0002-7764-1397], de la Hoya, Miguel [0000-0002-8113-1410], de Putter, Robin [0000-0001-9410-8941], Del Valle, Jesús [0000-0003-3607-7045], Domchek, Susan M [0000-0002-5914-7272], Donaldson, Alan [0000-0001-9193-4172], Eason, Jacqueline [0000-0002-8711-8671], Engel, Christoph [0000-0002-7247-282X], Fostira, Florentia [0000-0003-2751-2332], Frone, Megan [0000-0001-8273-8866], Glendon, Gord [0000-0001-8630-6673], Godwin, Andrew K [0000-0002-3987-9580], Greene, Mark H [0000-0003-1852-9239], Hahnen, Eric [0000-0003-2448-7872], Hanson, Helen [0000-0002-3303-8713], Izatt, Louise [0000-0003-1258-4843], Izquierdo, Angel [0000-0003-2004-3246], James, Paul A [0000-0002-4361-4657], John, Esther M [0000-0003-3259-8003], Kroeldrup, Lone [0000-0003-3623-6536], Kruse, Torben A [0000-0002-2460-6483], Lazaro, Conxi [0000-0002-7198-5906], Lesueur, Fabienne [0000-0001-7404-4549], Matrai, Zoltan [0000-0001-8160-7100], Montagna, Marco [0000-0002-4929-2150], Monteiro, Alvaro N [0000-0002-8448-4801], Morrison, Patrick J [0000-0002-2823-1762], Muranen, Taru A [0000-0002-5895-1808], Nathanson, Katherine L [0000-0002-6740-0901], Neuhausen, Susan L [0000-0001-5053-0390], Nevanlinna, Heli [0000-0002-0916-2976], Nguyen-Dumont, Tu [0000-0002-6217-0182], Niederacher, Dieter [0000-0001-6231-9226], Palli, Domenico [0000-0002-5558-2437], Parsons, Michael T [0000-0003-3242-8477], Perez-Segura, Pedro [0000-0001-5049-7199], Peterlongo, Paolo [0000-0001-6951-6855], Pinto, Pedro [0000-0001-6289-5792], Pottinger, Caroline [0000-0003-4233-882X], Radice, Paolo [0000-0001-6298-4111], Robson, Mark [0000-0002-3109-1692], Rump, Andreas [0000-0001-7116-6364], Sharif, Saba [0000-0002-9564-4890], Steele, Linda [0000-0003-3628-2022], Stoppa-Lyonnet, Dominique [0000-0002-5438-8309], Teixeira, Manuel R [0000-0002-4896-5982], Thull, Darcy L [0000-0001-7999-2804], Tischkowitz, Marc [0000-0002-7880-0628], Toland, Amanda E [0000-0002-0271-1792], Tommasi, Stefania [0000-0002-2157-2978], Toss, Angela [0000-0002-1854-6701], Tripathi, Vishakha [0000-0001-8118-8364], Valentini, Virginia [0000-0003-3393-7185], van Asperen, Christi J [0000-0002-1436-7650], Venturelli, Marta [0000-0003-0658-8004], Viel, Alessandra [0000-0003-2804-0840], Vijai, Joseph [0000-0002-7933-151X], Whaite, Anna [0000-0003-4485-0341], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F [0000-0003-2444-3247], Chenevix-Trench, Georgia [0000-0002-1878-2587], Ottini, Laura [0000-0001-8030-0449], and Apollo - University of Cambridge Repository
Subjects: Aged, 80 and over, BRCA2 Protein, Male, Heterozygote, BRCA1 Protein, Prostatic Neoplasms, Breast Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Mutation, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases
Abstract: BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.
Published: 2022

10. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Author: Li, Shuai, Silvestri, Valentina, Leslie, Goska, Rebbeck, Timothy R, Neuhausen, Susan L, Hopper, John L, Nielsen, Henriette Roed, Lee, Andrew, Yang, Xin, McGuffog, Lesley, Parsons, Michael T, Andrulis, Irene L, Arnold, Norbert, Belotti, Muriel, Borg, Åke, Buecher, Bruno, Buys, Saundra S, Caputo, Sandrine M, Chung, Wendy K, Colas, Chrystelle, Colonna, Sarah V, Cook, Jackie, Daly, Mary B, de la Hoya, Miguel, de Pauw, Antoine, Delhomelle, Hélène, Eason, Jacqueline, Engel, Christoph, Evans, D Gareth, Faust, Ulrike, Fehm, Tanja N, Fostira, Florentia, Fountzilas, George, Frone, Megan, Garcia-Barberan, Vanesa, Garre, Pilar, Gauthier-Villars, Marion, Gehrig, Andrea, Glendon, Gord, Goldgar, David E, Golmard, Lisa, Greene, Mark H, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hassan, Tiara, Hentschel, Julia, Horvath, Judit, Izatt, Louise, Janavicius, Ramunas, Jiao, Yue, John, Esther M, Karlan, Beth Y, Kim, Sung-Won, Konstantopoulou, Irene, Kwong, Ava, Laugé, Anthony, Lee, Jong Won, Lesueur, Fabienne, Mebirouk, Noura, Meindl, Alfons, Mouret-Fourme, Emmanuelle, Musgrave, Hannah, Ngeow Yuen Yie, Joanne, Niederacher, Dieter, Park, Sue K, Pedersen, Inge Sokilde, Ramser, Juliane, Ramus, Susan J, Rantala, Johanna, Rashid, Muhammad U, Reichl, Florian, Ritter, Julia, Rump, Andreas, Santamariña, Marta, Saule, Claire, Schmidt, Gunnar, Schmutzler, Rita K, Senter, Leigha, Shariff, Saba, Singer, Christian F, Southey, Melissa C, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen, Teo, Soo Hwang, Terry, Mary Beth, Thomassen, Mads, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Vega, Ana, Wagner, Sebastian A, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weber, Bernhard HF, Yannoukakos, Drakoulis, Spurdle, Amanda B, Easton, Douglas F, and Chenevix-Trench, Georgia
Subjects: Male, Risk, Urologic Diseases, Heterozygote, Aging, Clinical Sciences, Oncology and Carcinogenesis, Breast Neoplasms, Rare Diseases, Breast Cancer, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Aetiology, Cancer, Ovarian Neoplasms, BRCA2 Protein, BRCA1 Protein, Prevention, Infant, Newborn, Ovarian Cancer, Pancreatic Neoplasms, Mutation, Female, Digestive Diseases
Abstract: PurposeTo provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management.MethodsWe used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.ResultsBRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.ConclusionIn addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.
Published: 2022

11. Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author: Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V., Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen, Colonna, Sarah, Lesueur, Fabienne, Mebirouk, Noura, Engel, Christoph, Schmutzler, Rita K., Davies, Eleanor, Eccles, Diana M., Evans, D. Gareth, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eliassen, Heather A., Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Høgdall, Estrid, Høgdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Chenevix-Trench, Georgia, van der Hout, Annemieke H., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th., John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I., Olson, Sara H., Olsson, Håkan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamariña, Marta, Soucy, Penny, Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., Terry, Mary Beth, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Titus, Linda, Trabert, Britton, Travis, Ruth, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., Van Nieuwenhuysen, Els, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Webb, Penelope M., Weinberg, Clarice R., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Lawrenson, Kate, deFazio, Anna, Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie M., Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Gayther, Simon A., Pharoah, Paul D. P., Claes, Kathleen B. M., Thomassen, Mads, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Torres, Diana, Tung, Nadine, van Rensburg, Elizabeth J., Vega, Ana, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Zavaglia, Katia M., Zorn, Kristin K., Sellers, Thomas A., Antoniou, Antonis C., Kleibl, Zdenek, Easton, Douglas, DeFazio, Anna, Cunningham, Julie, GEMO Study Collaborators, [missing], GC-HBOC Study Collaborators, [missing], EMBRACE Collaborators, [missing], OPAL Study Group, [missing], AOCS Group, [missing], KConFab Investigators, [missing], HEBON Investigators, [missing], The OCAC Consortium, [missing], The CIMBA Consortium, [missing], Clinicum, Department of Pathology, HUSLAB, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, Faculteit Medische Wetenschappen/UMCG, Institut Català de la Salut, [Dareng EO, Barnes DR, Yang X] University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Cambridge, UK. [Tyrer JP] University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge, UK. [Jones MR] Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [Aben KKH] Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands. [Balmaña J] Hereditary cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Ovarian Cancer Action, and National Institute for Health Research
Subjects: Male, Biochemistry & Molecular Biology, OCAC Consortium, Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], Breast Neoplasms, Ovaris - Càncer - Aspectes genètics, Carcinoma, Ovarian Epithelial, SUSCEPTIBILITY, Polymorphism, Single Nucleotide, GEMO Study Collaborators, Risk Factors, OPAL Study Group, Other subheadings::Other subheadings::/genetics [Other subheadings], Medicine and Health Sciences, Genetics, Ovaris - Càncer - Propensió, Humans, Genetic Predisposition to Disease, Prospective Studies, EMBRACE Collaborators, GC-HBOC Study Collaborators, Genetics (clinical), HEBON Investigators, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], Medicinsk genetik, Ovarian Neoplasms, Genetics & Heredity, 0604 Genetics, Science & Technology, Otros calificadores::Otros calificadores::/genética [Otros calificadores], 1184 Genetics, developmental biology, physiology, Neoplasms::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms::Carcinoma, Ovarian Epithelial [DISEASES], 1103 Clinical Sciences, Bayes Theorem, AOCS Group, neoplasias::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas::carcinoma epitelial de ovario [ENFERMEDADES], Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Carcinoma, Ovarian Epithelial/genetics, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], CIMBA Consortium, 1182 Biochemistry, cell and molecular biology, Female, KConFab Investigators, Ovarian Neoplasms/epidemiology, Medical Genetics, Life Sciences & Biomedicine
Abstract: Clinical genetics; Genetic markers; Risk factors Genética clínica; Marcadores genéticos; Factores de riesgo Genètica clínica; Marcadors genètics; Factors de risc Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022

12. Additional file 1 of Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Author: Dorling, Leila, Carvalho, Sara, Allen, Jamie, Parsons, Michael T., Fortuno, Cristina, González-Neira, Anna, Heijl, Stephan M., Adank, Muriel A., Ahearn, Thomas U., Andrulis, Irene L., Auvinen, Päivi, Becher, Heiko, Beckmann, Matthias W., Behrens, Sabine, Bermisheva, Marina, Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Bremer, Michael, Briceno, Ignacio, Camp, Nicola J., Campbell, Archie, Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chenevix-Trench, Georgia, Collée, J. Margriet, Czene, Kamila, Dennis, Joe, Dörk, Thilo, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Giles, Graham G., Glendon, Gord, Guénel, Pascal, Gündert, Melanie, Hadjisavvas, Andreas, Hahnen, Eric, Hall, Per, Hamann, Ute, Harkness, Elaine F., Hartman, Mikael, Hogervorst, Frans B. L., Hollestelle, Antoinette, Hoppe, Reiner, Howell, Anthony, Jakubowska, Anna, Jung, Audrey, Khusnutdinova, Elza, Kim, Sung-Won, Ko, Yon-Dschun, Kristensen, Vessela N., Lakeman, Inge M. M., Li, Jingmei, Lindblom, Annika, Loizidou, Maria A., Lophatananon, Artitaya, Lubiński, Jan, Luccarini, Craig, Madsen, Michael J., Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mavroudis, Dimitrios, Milne, Roger L., Mohd Taib, Nur Aishah, Muir, Kenneth, Nevanlinna, Heli, Newman, William G., Oosterwijk, Jan C., Park, Sue K., Peterlongo, Paolo, Radice, Paolo, Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Shah, Mitul, Sim, Xueling, Southey, Melissa C., Surowy, Harald, Suvanto, Maija, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, van Asperen, Christi J., Waltes, Regina, Wang, Qin, Yang, Xiaohong R., Pharoah, Paul D. P., Schmidt, Marjanka K., Benitez, Javier, Vroling, Bas, Dunning, Alison M., Teo, Soo Hwang, Kvist, Anders, de la Hoya, Miguel, Devilee, Peter, Spurdle, Amanda B., Vreeswijk, Maaike P. G., and Easton, Douglas F.
Subjects: Data_FILES
Abstract: Additional file 1.
Published: 2022
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13. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author: Barnes, Daniel R, Rookus, Matti A, McGuffog, Lesley, Leslie, Goska, Mooij, Thea M, Dennis, Joe, Mavaddat, Nasim, Adlard, Julian, Ahmed, Munaza, Aittomäki, Kristiina, Andrieu, Nadine, Andrulis, Irene L, Arnold, Norbert, Arun, Banu K, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Benitez, Javier, Berthet, Pascaline, Białkowska, Katarzyna, Blanco, Amie M, Blok, Marinus J, Bonanni, Bernardo, Boonen, Susanne E, Borg, Åke, Bozsik, Aniko, Bradbury, Angela R, Brennan, Paul, Brewer, Carole, Brunet, Joan, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Christensen, Lise Lotte, Chung, Wendy K, Claes, Kathleen BM, Colas, Chrystelle, GEMO Study Collaborators, EMBRACE Collaborators, Collonge-Rame, Marie-Agnès, Cook, Jackie, Daly, Mary B, Davidson, Rosemarie, de la Hoya, Miguel, de Putter, Robin, Delnatte, Capucine, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Dorfling, Cecilia M, Dumont, Martine, Eeles, Ros, Ejlertsen, Bent, Engel, Christoph, Evans, D Gareth, Faivre, Laurence, Foretova, Lenka, Fostira, Florentia, Friedlander, Michael, Friedman, Eitan, Frost, Debra, Ganz, Patricia A, Garber, Judy, Gehrig, Andrea, Gerdes, Anne-Marie, Gesta, Paul, Giraud, Sophie, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gschwantler-Kaulich, Daphne, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hentschel, Julia, Hogervorst, Frans BL, Hooning, Maartje J, Horvath, Judit, Hu, Chunling, Hulick, Peter J, Imyanitov, Evgeny N, kConFab Investigators, HEBON Investigators, GENEPSO Investigators, Isaacs, Claudine, Izatt, Louise, Izquierdo, Angel, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, John, Esther M, Joseph, Vijai, Karlan, Beth Y, Kast, Karin, and Koudijs, Marco
Subjects: Heterozygote, endocrine system diseases, Clinical Sciences, Breast Neoplasms, PRS, GEMO Study Collaborators, Rare Diseases, breast cancer, Clinical Research, Risk Factors, BRCA1/2, Ovarian Epithelial, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Prospective Studies, Aetiology, EMBRACE Collaborators, Cancer, HEBON Investigators, Retrospective Studies, Ovarian Neoplasms, BRCA2 Protein, Genetics & Heredity, Consortium of Investigators of Modifiers of BRCA and BRCA2, BRCA1 Protein, Prevention, Carcinoma, BRCA1, GENEPSO Investigators, ovarian cancer, Mutation, kConFab Investigators, Female
Abstract: PurposeWe assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.MethodsRetrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.ResultsThe ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar.ConclusionPopulation-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
Published: 2020

14. Haplotype analysis of the internationally distributed BRCA1 c.3331_3334delCAAG founder mutation reveals a common ancestral origin in Iberia

Author: Tuazon, Anna Marie De Asis, Lott, Paul, Bohórquez, Mabel, Benavides, Jennyfer, Ramirez, Carolina, Criollo, Angel, Estrada-Florez, Ana, Mateus, Gilbert, Velez, Alejandro, Carmona, Jenny, Olaya, Justo, Garcia, Elisha, Polanco-Echeverry, Guadalupe, Stultz, Jacob, Alvarez, Carolina, Tapia, Teresa, Ashton-Prolla, Patricia, Brazilian Familial Cancer Network, Vega, Ana, Lazaro, Conxi, Tornero, Eva, Martinez-Bouzas, Cristina, Infante, Mar, De La Hoya, Miguel, Diez, Orland, Browning, Brian L, COLUMBUS Consortium, Rannala, Bruce, Teixeira, Manuel R, Carvallo, Pilar, Echeverry, Magdalena, Carvajal-Carmona, Luis G, Institut Català de la Salut, [De Asis Tuazon AM, Lott P] Genome Center, University of California Davis, Davis, CA, USA. [Bohórquez M, Benavides J, Ramirez C, Criollo A] Universidad del Tolima, Ibague, Colombia. [Diez O] Grupo de Cáncer Hereditario, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, University of California, Davis, Colciencias (Colombia), Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), Hospital de Clínicas de Porto Alegre, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Generalitat de Catalunya, and National Institutes of Health (US)
Subjects: Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [DISEASES], Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Càncer d'ovari, Càncer - Aspectes genètics, Identity by descent, 0302 clinical medicine, Breast cancer, Mama - Càncer, Mutation Carrier, Haplotype, Chile, Cancer, Genetics, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], 0303 health sciences, BRCA1 Protein, Single Nucleotide, c.3331_3334delCAAG, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Founder Effect, Chromosome 17 (human), 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Female, Brazil, Research Article, COLUMBUS Consortium, Human, Brazilian Familial Cancer Network, Oncology and Carcinogenesis, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Colombia, lcsh:RC254-282, Polymorphism, Single Nucleotide, Chromosomes, Càncer de mama, afecciones patológicas, signos y síntomas::procesos patológicos::atributos de la enfermedad::susceptibilidad a enfermedades::predisposición genética a la enfermedad [ENFERMEDADES], 03 medical and health sciences, Rare Diseases, Ovarian cancer, SNP, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Polymorphism, Founder mutation, Germ-Line Mutation, 030304 developmental biology, Portugal, BRCA1 c.3331_3334delCAAG, Pair 17, Human Genome, Multiple Hispanic, BRCA1, Haplotypes, Spain, Africa, Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract: © The Author(s)., [Background]: The BRCA1 c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluate BRCA1 c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry. [Methods]: BC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity around BRCA1 c.3331_3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surrounding BRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia., [Results]: The haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was ~ 100 generations in Iberia and that it was introduced to South America early during the European colonization period., [Conclusions]: Our results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening., AMDEA was supported with graduate Fellowships from UC Davis T32 Biotechnology Program. MB, ME, and LGC-C received funding from GSK Oncology and from “Oficina de Desarrollo a la Docencia de la Universidad del Tolima, Convocatoria 2010”. AC and AEF received funding from the Colciencias program “Becas Doctorales Nacionales, Convocatorias 528-2011 and 647-2015”. JB received funding from the Colciencias program “Formación de Capital Humano de Alto Nivel para el Departamento de Tolima- 2016, convocatoria 755”. BRCA1/2 genotyping of the Brazilian patients was performed in part with grants from CNPq (408313/2016-1), FAPERGS and Fundo de Incentivo a Pesquisa (FIPE) do Hospital de Clínicas de Porto Alegre, Brazil. AV received funding from CIBERER (grant ER17P1AC7112/2017). PC received funding from FONDEF grant #CA12I10152. CL was Supported by the Carlos III National Health Institute funded by FEDER funds—a way to build Europe—[PI19/00553; PI16/00563; PI16/01898; SAF2015-68016-R and CIBERONC]; the Government of Catalonia [Pla estratègic de recerca i innovació en salut (PERIS_MedPerCan and URDCat projects), 2017SGR1282 and 2017SGR496]. BR received funding from the National Institutes of Health (R01GM123306).
Published: 2020

15. Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

Author: Silvestri, Valentina, Leslie, Goska, Barnes, Daniel R, CIMBA Group, Agnarsson, Bjarni A, Aittomäki, Kristiina, Alducci, Elisa, Andrulis, Irene L, Barkardottir, Rosa B, Barroso, Alicia, Barrowdale, Daniel, Benitez, Javier, Bonanni, Bernardo, Borg, Ake, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Capalbo, Carlo, Campbell, Ian, Chung, Wendy K, Claes, Kathleen BM, Colonna, Sarah V, Cortesi, Laura, Couch, Fergus J, De La Hoya, Miguel, Diez, Orland, Ding, Yuan Chun, Domchek, Susan, Easton, Douglas F, Ejlertsen, Bent, Engel, Christoph, Evans, D Gareth, Feliubadalò, Lidia, Foretova, Lenka, Fostira, Florentia, Géczi, Lajos, Gerdes, Anne-Marie, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, Hahnen, Eric, Hogervorst, Frans BL, Hopper, John L, Hulick, Peter J, Isaacs, Claudine, Izquierdo, Angel, James, Paul A, Janavicius, Ramunas, Jensen, Uffe Birk, John, Esther M, Joseph, Vijai, Konstantopoulou, Irene, Kurian, Allison W, Kwong, Ava, Landucci, Elisabetta, Lesueur, Fabienne, Loud, Jennifer T, Machackova, Eva, Mai, Phuong L, Majidzadeh-A, Keivan, Manoukian, Siranoush, Montagna, Marco, Moserle, Lidia, Mulligan, Anna Marie, Nathanson, Katherine L, Nevanlinna, Heli, Ngeow, Joanne, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Osorio, Ana, Papi, Laura, Park, Sue K, Pedersen, Inge Sokilde, Perez-Segura, Pedro, Petersen, Annabeth H, Pinto, Pedro, Porfirio, Berardino, Pujana, Miquel Angel, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad U, Rosenzweig, Barak, Rossing, Maria, Santamariña, Marta, Schmutzler, Rita K, Senter, Leigha, Simard, Jacques, Singer, Christian F, Solano, Angela R, Southey, Melissa C, Steele, Linda, Steinsnyder, Zoe, Stoppa-Lyonnet, Dominique, Tan, Yen Yen, Teixeira, Manuel R, Teo, Soo H, Terry, Mary Beth, Thomassen, Mads, Toland, Amanda E, Torres-Esquius, Sara, Tung, Nadine, Van Asperen, Christi J, Vega, Ana, Viel, Alessandra, Vierstraete, Jeroen, Wappenschmidt, Barbara, Weitzel, Jeffrey N, Wieme, Greet, Yoon, Sook-Yee, Zorn, Kristin K, McGuffog, Lesley, Parsons, Michael T, Hamann, Ute, Greene, Mark H, Kirk, Judy A, Neuhausen, Susan L, Rebbeck, Timothy R, Tischkowitz, Marc, Chenevix-Trench, Georgia, Antoniou, Antonis C, Friedman, Eitan, Ottini, Laura, Leslie, Goska [0000-0001-5756-6222], Barnes, Daniel [0000-0002-3781-7570], Easton, Douglas [0000-0003-2444-3247], Tischkowitz, Marc [0000-0002-7880-0628], Antoniou, Antonis [0000-0001-9223-3116], and Apollo - University of Cambridge Repository
Subjects: Adult, Aged, 80 and over, BRCA2 Protein, Male, endocrine system diseases, Adolescent, BRCA1 Protein, Middle Aged, Young Adult, Phenotype, Neoplasms, Humans, skin and connective tissue diseases, Germ-Line Mutation, Aged, Retrospective Studies
Abstract: IMPORTANCE: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. OBJECTIVE: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. MAIN OUTCOMES AND MEASURES: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. RESULTS: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier. CONCLUSIONS AND RELEVANCE: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.
Published: 2020
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16. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Author: Rebbeck, Timothy R, Friebel, Tara M, Friedman, Eitan, Hamann, Ute, Huo, Dezheng, Kwong, Ava, Olah, Edith, Olopade, Olufunmilayo I, Solano, Angela R, Teo, Soo-Hwang, Thomassen, Mads, Weitzel, Jeffrey N, Chan, TL, Couch, Fergus J, Goldgar, David E, Kruse, Torben A, Palmero, Edenir Inêz, Park, Sue Kyung, Torres, Diana, van Rensburg, Elizabeth J, McGuffog, Lesley, Parsons, Michael T, Leslie, Goska, Aalfs, Cora M, Abugattas, Julio, Adlard, Julian, Agata, Simona, Aittomäki, Kristiina, Andrews, Lesley, Andrulis, Irene L, Arason, Adalgeir, Arnold, Norbert, Arun, Banu K, Asseryanis, Ella, Auerbach, Leo, Azzollini, Jacopo, Balmaña, Judith, Barile, Monica, Barkardottir, Rosa B, Barrowdale, Daniel, Benitez, Javier, Berger, Andreas, Berger, Raanan, Blanco, Amie M, Blazer, Kathleen R, Blok, Marinus J, Bonadona, Valérie, Bonanni, Bernardo, Bradbury, Angela R, Brewer, Carole, Buecher, Bruno, Buys, Saundra S, Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A, Campbell, Ian, Caputo, Sandrine M, Chiquette, Jocelyne, Chung, Wendy K, Claes, Kathleen BM, Collée, J Margriet, Cook, Jackie, Davidson, Rosemarie, de la Hoya, Miguel, De Leeneer, Kim, de Pauw, Antoine, Delnatte, Capucine, Diez, Orland, Ding, Yuan Chun, Ditsch, Nina, Domchek, Susan M, Dorfling, Cecilia M, Velazquez, Carolina, Dworniczak, Bernd, Eason, Jacqueline, Easton, Douglas F, Eeles, Ros, Ehrencrona, Hans, Ejlertsen, Bent, EMBRACE, Engel, Christoph, Engert, Stefanie, Evans, D Gareth, Faivre, Laurence, Feliubadaló, Lidia, Ferrer, Sandra Fert, Foretova, Lenka, Fowler, Jeffrey, Frost, Debra, Galvão, Henrique CR, Ganz, Patricia A, Garber, Judy, Gauthier-Villars, Marion, Gehrig, Andrea, GEMO Study Collaborators, Gerdes, Anne-Marie, Gesta, Paul, Giannini, Giuseppe, Giraud, Sophie, and Glendon, Gord
Subjects: Internationality, endocrine system diseases, Clinical Sciences, geography, EMBRACE, GEMO Study Collaborators, Databases, breast cancer, Genetic, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Family, Aetiology, skin and connective tissue diseases, HEBON, Cancer, BRCA2 Protein, Genetics & Heredity, BRCA1 Protein, BRCA1, BRCA2, ovarian cancer, Mutation, ethnicity
Abstract: The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
Published: 2018

17. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Author: Rebbeck, Timothy R, Friebel, Tara M, Mitra, Nandita, Wan, Fei, Chen, Stephanie, Andrulis, Irene L, Apostolou, Paraskevi, Arnold, Norbert, Arun, Banu K, Barrowdale, Daniel, Benitez, Javier, Berger, Raanan, Berthet, Pascaline, Borg, Ake, Buys, Saundra S, Caldes, Trinidad, Carter, Jonathan, Chiquette, Jocelyne, Claes, Kathleen BM, Couch, Fergus J, Cybulski, Cezary, Daly, Mary B, de la Hoya, Miguel, Diez, Orland, Domchek, Susan M, Nathanson, Katherine L, Durda, Katarzyna, Ellis, Steve, EMBRACE, Evans, D Gareth, Foretova, Lenka, Friedman, Eitan, Frost, Debra, Ganz, Patricia A, Garber, Judy, Glendon, Gord, Godwin, Andrew K, Greene, Mark H, Gronwald, Jacek, Hahnen, Eric, Hallberg, Emily, Hamann, Ute, Hansen, Thomas VO, HEBON, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, Janavicius, Ramunas, Jaworska-Bieniek, Katarzyna, John, Esther M, Karlan, Beth Y, Kaufman, Bella, Investigators, KConFab, Kwong, Ava, Laitman, Yael, Lasset, Christine, Lazaro, Conxi, Lester, Jenny, Loman, Niklas, Lubinski, Jan, Manoukian, Siranoush, Mitchell, Gillian, Montagna, Marco, Neuhausen, Susan L, Nevanlinna, Heli, Niederacher, Dieter, Nussbaum, Robert L, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Park, Sue Kyung, Piedmonte, Marion, Radice, Paolo, Rappaport-Fuerhauser, Christine, Rookus, Matti A, Seynaeve, Caroline, Simard, Jacques, Singer, Christian F, Soucy, Penny, Southey, Melissa, Stoppa-Lyonnet, Dominique, Sukiennicki, Grzegorz, Szabo, Csilla I, Tancredi, Mariella, Teixeira, Manuel R, Teo, Soo-Hwang, Terry, Mary Beth, Thomassen, Mads, Tihomirova, Laima, Tischkowitz, Marc, Toland, Amanda Ewart, Toloczko-Grabarek, Aleksandra, Tung, Nadine, van Rensburg, Elizabeth J, Villano, Danylo, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weitzel, Jeffrey N, Zidan, Jamal, and Zorn, Kristin K
Subjects: Heterozygote, endocrine system diseases, Hereditary breast and ovarian cancer, Oncology and Carcinogenesis, Loss of Heterozygosity, Breast Neoplasms, EMBRACE, Promoter Regions, Genetic, Clinical Research, Breast Cancer, Humans, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Aetiology, skin and connective tissue diseases, HEBON, Germ-Line Mutation, Alleles, Cancer, Exons, BRCA1, BRCA2, Phenotype, Genes, Population Surveillance, Female, Transheterozygosity
Abstract: BackgroundMost BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood.MethodsFrom 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3%). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.ResultsThe majority of TH (45.2%) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5years younger in TH than in SH2 (p
Published: 2016

18. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Author: Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2, Hollestelle, Antoinette, van der Baan, Frederieke H, Berchuck, Andrew, Johnatty, Sharon E, Aben, Katja K, Agnarsson, Bjarni A, Aittomäki, Kristiina, Alducci, Elisa, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Antoniou, Antonis C, Apicella, Carmel, Arndt, Volker, Arnold, Norbert, Arun, Banu K, Arver, Brita, Ashworth, Alan, Australian Ovarian Cancer Study Group, Baglietto, Laura, Balleine, Rosemary, Bandera, Elisa V, Barrowdale, Daniel, Bean, Yukie T, Beckmann, Lars, Beckmann, Matthias W, Benitez, Javier, Berger, Andreas, Berger, Raanan, Beuselinck, Benoit, Bisogna, Maria, Bjorge, Line, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Anders, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Brand, Judith S, Brauch, Hiltrud, Breast Cancer Family Register, Brenner, Hermann, Brinton, Louise, Brooks-Wilson, Angela, Bruinsma, Fiona, Brunet, Joan, Brüning, Thomas, Budzilowska, Agnieszka, Bunker, Clareann H, Burwinkel, Barbara, Butzow, Ralf, Buys, Saundra S, Caligo, Maria A, Campbell, Ian, Carter, Jonathan, Chang-Claude, Jenny, Chanock, Stephen J, Claes, Kathleen BM, Collée, J Margriet, Cook, Linda S, Couch, Fergus J, Cox, Angela, Cramer, Daniel, Cross, Simon S, Cunningham, Julie M, Cybulski, Cezary, Czene, Kamila, Damiola, Francesca, Dansonka-Mieszkowska, Agnieszka, Darabi, Hatef, de la Hoya, Miguel, deFazio, Anna, Dennis, Joseph, Devilee, Peter, Dicks, Ed M, Diez, Orland, Doherty, Jennifer A, Domchek, Susan M, Dorfling, Cecilia M, Dörk, Thilo, Silva, Isabel Dos Santos, du Bois, Andreas, Dumont, Martine, Dunning, Alison M, Duran, Mercedes, Easton, Douglas F, Eccles, Diana, Edwards, Robert P, Ehrencrona, Hans, Ejlertsen, Bent, Ekici, Arif B, Ellis, Steve D, EMBRACE, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Feliubadalo, Lidia, Figueroa, Jonine, and Flesch-Janys, Dieter
Subjects: Australian Ovarian Cancer Study Group, endocrine system diseases, Ovarian Cancer Association Consortium, Clinical Trials and Supportive Activities, Oncology and Carcinogenesis, Breast Neoplasms, EMBRACE, GEMO Study Collaborators, Proto-Oncogene Proteins p21(ras), Paediatrics and Reproductive Medicine, Breast cancer, Rare Diseases, Ovarian cancer, Clinical Research, Neoplasms, Ovarian Epithelial, Genetics, Humans, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Aetiology, skin and connective tissue diseases, HEBON, Cancer, Ovarian Neoplasms, Clinical outcome, Prevention, Carcinoma, Glandular and Epithelial, SWE-BRCA, KRAS variant, and Consortium of Modifiers of BRCA1 and BRCA2, Breast Cancer Association Consortium, Genetic association, Female, KConFab Investigators, GENICA Network, Breast Cancer Family Register
Abstract: ObjectiveClinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.MethodsCentralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers).ResultsWe found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations.Conclusionsrs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
Published: 2016

19. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author: Couch, Fergus J, Kuchenbaecker, Karoline B, Michailidou, Kyriaki, Mendoza-Fandino, Gustavo A, Nord, Silje, Lilyquist, Janna, Olswold, Curtis, Hallberg, Emily, Agata, Simona, Ahsan, Habibul, Aittomäki, Kristiina, Ambrosone, Christine, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Arun, Banu K, Arver, Brita, Barile, Monica, Barkardottir, Rosa B, Barrowdale, Daniel, Beckmann, Lars, Beckmann, Matthias W, Benitez, Javier, Blank, Stephanie V, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Buys, Saundra S, Caldes, Trinidad, Caligo, Maria A, Canzian, Federico, Carpenter, Jane, Chang-Claude, Jenny, Chanock, Stephen J, Chung, Wendy K, Claes, Kathleen BM, Cox, Angela, Cross, Simon S, Cunningham, Julie M, Czene, Kamila, Daly, Mary B, Damiola, Francesca, Darabi, Hatef, de la Hoya, Miguel, Devilee, Peter, Diez, Orland, Ding, Yuan C, Dolcetti, Riccardo, Domchek, Susan M, Dorfling, Cecilia M, Dos-Santos-Silva, Isabel, Dumont, Martine, Dunning, Alison M, Eccles, Diana M, Ehrencrona, Hans, Ekici, Arif B, Eliassen, Heather, Ellis, Steve, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Försti, Asta, Fostira, Florentia, Foulkes, William D, Friebel, Tara, Friedman, Eitan, Frost, Debra, Gabrielson, Marike, Gammon, Marilie D, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, Gaudet, Mia M, Gayther, Simon A, Gerdes, Anne-Marie, Ghoussaini, Maya, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Gunter, Marc, Haeberle, Lothar, Haiman, Christopher A, Hamann, Ute, Hansen, Thomas VO, Hart, Steven, Healey, Sue, Heikkinen, Tuomas, Henderson, Brian E, and Herzog, Josef
Subjects: Heterozygote, Genotype, Breast Neoplasms, Chromosomes, Cyclophilins, Risk Factors, Receptors, Breast Cancer, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Aetiology, Polymorphism, skin and connective tissue diseases, Cancer, tRNA Methyltransferases, BRCA1 Protein, Prevention, Human Genome, Single Nucleotide, Estrogen, Pair 2, Mutation, Female, Human, Genome-Wide Association Study
Abstract: Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P
Published: 2016

20. Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Author: Kuchenbaecker, Karoline B, Ramus, Susan J, Tyrer, Jonathan, Lee, Andrew, Shen, Howard C, Beesley, Jonathan, Lawrenson, Kate, McGuffog, Lesley, Healey, Sue, Lee, Janet M, Spindler, Tassja J, Lin, Yvonne G, Pejovic, Tanja, Bean, Yukie, Li, Qiyuan, Coetzee, Simon, Hazelett, Dennis, Miron, Alexander, Southey, Melissa, Terry, Mary Beth, Goldgar, David E, Buys, Saundra S, Janavicius, Ramunas, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Neuhausen, Susan L, Ding, Yuan Chun, Hansen, Thomas VO, Jønson, Lars, Gerdes, Anne-Marie, Ejlertsen, Bent, Barrowdale, Daniel, Dennis, Joe, Benitez, Javier, Osorio, Ana, Garcia, Maria Jose, Komenaka, Ian, Weitzel, Jeffrey N, Ganschow, Pamela, Peterlongo, Paolo, Bernard, Loris, Viel, Alessandra, Bonanni, Bernardo, Peissel, Bernard, Manoukian, Siranoush, Radice, Paolo, Papi, Laura, Ottini, Laura, Fostira, Florentia, Konstantopoulou, Irene, Garber, Judy, Frost, Debra, Perkins, Jo, Platte, Radka, Ellis, Steve, EMBRACE, Godwin, Andrew K, Schmutzler, Rita Katharina, Meindl, Alfons, Engel, Christoph, Sutter, Christian, Sinilnikova, Olga M, GEMO Study Collaborators, Damiola, Francesca, Mazoyer, Sylvie, Stoppa-Lyonnet, Dominique, Claes, Kathleen, De Leeneer, Kim, Kirk, Judy, Rodriguez, Gustavo C, Piedmonte, Marion, O'Malley, David M, de la Hoya, Miguel, Caldes, Trinidad, Aittomäki, Kristiina, Nevanlinna, Heli, Collée, J Margriet, Rookus, Matti A, Oosterwijk, Jan C, Breast Cancer Family Registry, Tihomirova, Laima, Tung, Nadine, Hamann, Ute, Isaccs, Claudine, Tischkowitz, Marc, Imyanitov, Evgeny N, Caligo, Maria A, Campbell, Ian G, Hogervorst, Frans BL, HEBON, Olah, Edith, Diez, Orland, Blanco, Ignacio, Brunet, Joan, Lazaro, Conxi, Pujana, Miquel Angel, Jakubowska, Anna, Gronwald, Jacek, Lubinski, Jan, and Sukiennicki, Grzegorz
Subjects: Australian Ovarian Cancer Study Group, Risk, Adult, Heterozygote, endocrine system diseases, Genotype, Adolescent, Quantitative Trait Loci, Medical and Health Sciences, EMBRACE, GEMO Study Collaborators, Young Adult, Rare Diseases, Breast Cancer Family Registry, Australian Cancer Study, Neoplasms, Ovarian Epithelial, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Genetic Testing, Polymorphism, Aetiology, Reporter, HEBON, Alleles, Cancer, Ovarian Neoplasms, BRCA2 Protein, BRCA1 Protein, Prevention, Carcinoma, Human Genome, Glandular and Epithelial, Single Nucleotide, Biological Sciences, female genital diseases and pregnancy complications, Ovarian Cancer, Genes, Consortium of Investigators of Modifiers of BRCA1 and BRCA2, Mutation, Female, KConFab Investigators, Genome-Wide Association Study, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
Published: 2015

21. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

Author: Peterlongo, Paolo, Chang-Claude, J., Moysich, Kirsten, Rudolph, Anja, Schmutzler, Rita, Simard, Jacques, Soucy, Penny, Tea, Rosalind, Easton, Douglas, Hamann, Ute, Wilkening, Stefan, Chen, Bowang, Rookus, Matti, Schmidt, Marjanka, van der Baan, Frederieke, Spurdle, Amanda, Walker, Logan, Lose, Felicity, Mai, Ana, Montagna, Marc, Matricardi, Laura, Lubinski, Jan, Jakubowska, Anna, Gómez Garcia, Encarna, Olopade, Olufunmilayo, Nussbaum, Robert, Nathanson, Katherine, Domchek, Susan, Rebbeck, Timothy, Arun, Anders, Karlan, Beth, Orsulic, Sandra, Lester, Jenny, Chung, Wendy, Miron, Alex, Southey, Melissa, Goldgar, David, Buys, Saundra, Janavicius, Ramunas, Dorfling, Cecilia, Van Rensburg, Elizabeth, Ding, Yuan Chun, Neuhausen, Susan, Hansen, Hans, Gerdes, Anne-Marie, Ejlertsen, Bent, Jønson, Lars, Osorio, Ana, Martínez-Bouzas, Cristina, Benitez, Javier, Conway, Edye, Blazer, Kathleen, Weitzel, Jeffrey, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniel, Scuvera, Giulietta, Barile, Monica, Ficarazzi, Filomena, Mariette, Frederique, Fortuzzi, Stefano, Viel, Alessandra, Giannini, Giuseppe, Papi, Laura, Martayan, Aline, Tibiletti, Maria Grazia, Radice, Paolo, Vratimos, Athanassios, Fostira, Florentia, Garber, Judy, Donaldson, Michael, Brewer, Carole, Foo, Claire, Evans, D Gareth R, Frost, Debra, Eccles, Diana, Kennedy, Angela, Cook, Jackie, Tischkowitz, Marc, Lee, Julian, Barwell, Julian, Walker, Lisa, Izatt, Louise, Side, Lucy, Kennedy, M John, Rogers, Mark, Porteous, Mary, Morrison, Patrick, Platte, Radka, Davidson, Rosemarie, Hodgson, Georg, Ellis, Steve, Cole, Trevor, Godwin, Andrew, Claes, Kathleen, Van Maerken, Tom, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Plendl, Hans, Kast, Karin, Rhiem, Kerstin, Ditsch, Nina, Arnold, Norbert, Varon-Mateeva, Raymonda, Wappenschmidt, Barbara, Wang, Shan, Bressac-de Paillerets, Brigitte, Buecher, Bruno, Delnatte, Capucine, Houdayer, Claude, Stoppa-Lyonnet, Dominique, Damiola, Francesca, Coupier, Isabelle, Barjhoux, Laure, Venat-Bouvet, Lauren, Golmard, Lisa, Boutry-Kryza, Nadia, Sinilnikova, Olga, Caron, Olivier, Pujol, Pascal, Mazoyer, Sylvie, Belotti, Muriel, Piedmonte, Marion, Friedlander, Michael, Rodriguez, Gustavo, Copeland, Larry, De La Hoya, Miguel, Segura, Pedro Perez, Nevanlinna, Heli, Aittomäki, Kristiina, Van Os, Theo, Meijers-Heijboer, Hanne, van der Hout, Annemarie, Vreeswijk, Maaike, Hoogerbrugge, Nicoline, Ausems, Margreet, van Doorn, Helena, Collée, J Margriet, Olah, Edith, Diez, Orland, Blanco, Ignacio, Lazaro, Conxi, Brunet, Joan, Feliubadaló, Lídia, Cybulski, Cezary, Gronwald, Jacek, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Sukiennicki, Grzegorz, Arason, Adalgeir, Chiquette, Jocelyne, Teixeira, Manuel, Olswold, Curtis, Couch, Fergus, Lindor, Noralane, Wang, Xianshu, Szabo, Csilla, Offit, Kenneth, Corines, Marina, Jacobs, Lauren, Robson, Mark, Zhang, Liying, Joseph, Vijai, Berger, Andreas, Singer, Christian, Rappaport, Christine, Kaulich, Daphne Geschwantler, Pfeiler, Georg, Tea, Muy-Kheng, Phelan, Catherine, Greene, Mark, Mai, Phuong, Rennert, Gad, Mulligan, Anna, Glendon, Gord, Tchatchou, Sandrine, Andrulis, Irene, Toland, Amanda Ewart, Bojesen, Anders, Pedersen, Inge Søkilde, Thomassen, Mads, Jensen, Uffe Birk, Laitman, Yael, Rantala, Johanna, von Wachenfeldt, Anna, Ehrencrona, Hans, Askmalm, Marie Stenmark, Borg, Åke, Kuchenbaecker, Karoline, Mcguffog, Lesley, Barrowdale, Daniel, Healey, Sue, Lee, Andrew, Pharoah, Paul, Chenevix-Trench, Georgia, Antoniou, Antonis, Friedman, Eitan, Schmutzler, K., Eeles, A., Rookus, A., Schmidt, K., Maia, A., Gomez Garcia, B., Rebbeck, R., Arun, K., Chung, K., Dorfling, M., van Rensburg, J., Ding, C., Hansen, O., Jonson, L., Martinez-Bouzas, C., Donaldson, A., Evans, R., Brady, A., Adlard, J., Kennedy, J., Hodgson, S., Godwin, K., Wang-Gohrke, S., Sinilnikova, M., Rodriguez, C., Copeland, J., Aittomaki, K., van Os, A., Meijers-Heijboer, J., Vreeswijk, P., Van Doorn, C., Collee, J., Teixeira, R., Couch, J., Lindor, M., Singer, F., Tea, K., Phelan, M., Andrulis, L., Pedersen, S., Askmalm, S., Borg, A., Chen, G., Human genetics, CCA - Oncogenesis, RS: GROW - Oncology, Department of Organisation and Personnel Management, Obstetrics & Gynecology, Clinical Genetics, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Human Genetics, Cancer Center Amsterdam, and Amsterdam Reproduction & Development (AR&D)
Subjects: Oncology, Candidate gene, endocrine system diseases, Epidemiology, Genes, BRCA2, Genes, BRCA1, Cohort Studies, 0302 clinical medicine, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Young adult, skin and connective tissue diseases, Genetics, Ovarian Neoplasms, 0303 health sciences, Single Nucleotide, Penetrance, 3. Good health, 030220 oncology & carcinogenesis, Female, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, Association, 03 medical and health sciences, Ovarian Neoplasms/genetics, Young Adult, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Polymorphism, Genotyping, Gene, 030304 developmental biology, Genetic association, Retrospective Studies, Mutation, business.industry, Retrospective cohort study, Genes, BRCA1/physiology, BRCA1, medicine.disease, BRCA2, Genes, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Ovarian cancer, Genes, BRCA2/physiology
Abstract: Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. (C)2014 AACR. European Community (COGS) [223175, HEALTH-F2-2009-223175]; Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/ A15007, C5047/A10692, C1287/A16563, C1287/A17523, C5047/A8385]; NIH [CA128978, R01-CA102776, R01CA083855]; Post-Cancer GWAS initiative [1U19CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute [UM1 CA164920, RC4CA153828]; Research Council of Lithuania [LIG-07/2012]; Cancer Association of South Africa (CANSA); Spanish Association against Cancer [AECC08, RTICC 06/0020/1060, FISPI12/00070]; Mutua Madrilena Foundation (FMMA); City of Hope Clinical Cancer Genetics Community Research Network and the Hereditary Cancer Research Registry (COH-CCGCRN); Fondazione IRCCS Istituto Nazionale dei Tumori; DKFZ; NIHR grant to the Biomedical Research Centre, Manchester; NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research; Royal Marsden NHS Foundation Trust; German Cancer Aid [109078]; Center for Molecular Medicine Cologne (CMMC); Ligue National Contre le Cancer; Association "Le cancer du sein, parlons-en!" Award; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program; Helsinki University Central Hospital Research Fund, Academy of Finland [266528]; Finnish Cancer Society and the Sigrid Juselius Foundation; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756]; Netherlands Organization of Scientific Research [NWO 91109024]; Pink Ribbon [110005]; BBMRI [NWO 184.021.007/CP46]; Hungarian Research Grants [KTIA OTKA CK-80745, OTKA K-112228]; Asociacion Espanola Contra el Cancer; Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia [ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, 2009SGR290]; Icelandic Association "Walking for Breast Cancer Research"; Landspitali University Hospital Research Fund; Ministero della Salute; Istituto Oncologico Veneto; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; U.S. Department of Defence Ovarian Cancer Idea award [W81XWH-10-1-0341]; David and Margaret T. Grohne Family Foundation; Ting Tsung and Wei Fong Chao Foundation; Robert and Kate Niehaus Clinical Cancer Genetics Initiative; Ohio State University Comprehensive Cancer Center; Swedish Cancer Society; Women's Cancer Program (WCP) at the Samuel Oschin Comprehensive Cancer Institute - American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; NEYE Foundation; European Union (European Social Fund - ESF); Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research Technology:; University of Kansas Cancer Center [P30 CA168524]; Kansas Bioscience Authority Eminent Scholar Program; National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank [CA 27469]; GOG Statistical and Data Center [CA 37517]; NCI's Community Clinical Oncology Program (CCOP) grant [CA 101165]; Canadian Breast Cancer Research Alliance-grant [019511]; Ministry of Economic Development, Innovation and Export Trade - grant [PSR-SIIRI-701]; Israel Cancer Association; Israeli Inherited Breast Cancer Consortium; Susan G. Komen Foundation; Basser Research Center; ISCIII [RD12/00369/0006]; European Regional Development funds, Spain; Morris and Horowitz Families Endowed Professorship; Chancellors Distinguished Chair in Biomedical Sciences Professorship; Intramural Research Program of the US National Cancer Institute; NIH; Westat, Inc; [PBZ_KBN_122/P05/2004]; [1R01 CA149429-01]; [5U01CA113916]; [R01CA140323]; [NO2-CP-11019- 50]; [N02-CP-65504]; Associazione Italiana per la Ricerca sul Cancro; Cancer Research UK [11174, 10119, 17528, 17523, 15007, 10124, 10118, 16561, 16563]; National Institute for Health Research [NF-SI-0510-10096] info:eu-repo/semantics/publishedVersion
Published: 2015

22. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers

Author: Osorio, Ana, Milne, Roger L, Kuchenbaecker, Karoline, Vaclová, Tereza, Pita, Guillermo, Alonso, Rosario, Peterlongo, Paolo, Blanco, Ignacio, de la Hoya, Miguel, Duran, Mercedes, Díez, Orland, Ramón Y Cajal, Teresa, Konstantopoulou, Irene, Martínez-Bouzas, Cristina, Andrés Conejero, Raquel, Soucy, Penny, McGuffog, Lesley, Barrowdale, Daniel, Lee, Andrew, SWE-BRCA, Arver, Brita, Rantala, Johanna, Loman, Niklas, Ehrencrona, Hans, Olopade, Olufunmilayo I, Beattie, Mary S, Domchek, Susan M, Nathanson, Katherine, Rebbeck, Timothy R, Arun, Banu K, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, John, Esther M, Whittemore, Alice S, Daly, Mary B, Southey, Melissa, Hopper, John, Terry, Mary B, Buys, Saundra S, Janavicius, Ramunas, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Steele, Linda, Neuhausen, Susan L, Ding, Yuan Chun, Hansen, Thomas VO, Jønson, Lars, Ejlertsen, Bent, Gerdes, Anne-Marie, Infante, Mar, Herráez, Belén, Moreno, Leticia Thais, Weitzel, Jeffrey N, Herzog, Josef, Weeman, Kisa, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Bonanni, Bernardo, Mariette, Frederique, Volorio, Sara, Viel, Alessandra, Varesco, Liliana, Papi, Laura, Ottini, Laura, Tibiletti, Maria Grazia, Radice, Paolo, Yannoukakos, Drakoulis, Garber, Judy, Ellis, Steve, Frost, Debra, Platte, Radka, Fineberg, Elena, Evans, Gareth, Lalloo, Fiona, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Eccles, Diana, Cook, Jackie, Hodgson, Shirley, Brewer, Carole, Tischkowitz, Marc, Douglas, Fiona, Porteous, Mary, Side, Lucy, Walker, Lisa, Morrison, Patrick, Donaldson, Alan, Kennedy, John, Foo, Claire, Godwin, Andrew K, Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Engel, Christoph, and Horwitz, Marshall S
Subjects: Risk, Adult, endocrine system diseases, DNA Repair, Genotype, Adolescent, Breast Neoplasms, and over, DNA Glycosylases, Rare Diseases, Breast Cancer, 80 and over, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Genetic Testing, Polymorphism, Aetiology, skin and connective tissue diseases, HEBON, Aged, Cancer, Ovarian Neoplasms, BRCA2 Protein, BRCA1 Protein, Prevention, Single Nucleotide, SWE-BRCA, Middle Aged, Ovarian Cancer, Female, KConFab Investigators, Developmental Biology
Abstract: Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p
Published: 2014

23. Evaluation of Rare Variants in the New Fanconi Anemia Gene ERCC4 (FANCQ) as Familial Breast/Ovarian Cancer Susceptibility Alleles

Author: Osorio, Ana, Bogliolo, Massimo, Fernández, Victoria, Barroso, Alicia, De la Hoya, Miguel, Caldés, Trinidad, Lasa, Adriana, Ramon y Cajal, Teresa, Santamariña, Marta, Vega, Ana, Quiles, Francisco, Lázaro, Conxi, Diez, Orland, Fernández García, Daniel, González-Sarmiento, Rogelio, Durán, Mercedes, Fernández Piqueras, José, Marín, Maria, Pujol i Calvet, M. Roser, Surrallés i Calonge, Jordi, Benítez, Javier, Universitat Autònoma de Barcelona, Ministerio de Economía y Competitividad (España), Fundación Mutua Madrileña, Generalitat de Catalunya, Institución Catalana de Investigación y Estudios Avanzados, European Commission, Instituto de Salud Carlos III, Asociación Española Contra el Cáncer, and Comunidad de Madrid
Subjects: XPF, Heterozygote, Breast Neoplasms, Biology, medicine.disease_cause, Breast cancer, Fanconi anemia, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Gene, Genetics (clinical), Alleles, FANCQ, Ovarian Neoplasms, Mutation, Genetic Variation, Exons, medicine.disease, FANCA, DNA-Binding Proteins, Phenotype, Amino Acid Substitution, Spain, Case-Control Studies, Cancer research, Hereditary Breast and Ovarian Cancer Syndrome, Female, Ovarian cancer, ERCC4
Abstract: Recently, it has been reported that biallelic mutations in the ERCC4 (FANCQ) gene cause Fanconi anemia (FA) subtype FA-Q. To investigate the possible role of ERCC4 in breast and ovarian cancer susceptibility, as occurs with other FA genes, we screened the 11 coding exons and exon-intron boundaries of ERCC4 in 1573 index cases from high-risk Spanish familial breast and ovarian cancer pedigrees that had been tested negative for BRCA1 and BRCA2 mutations and 854 controls. The frequency of ERCC4 mutation carriers does not differ between cases and controls, suggesting that ERCC4 is not a cancer susceptibility gene. Interestingly, the prevalence of ERCC4 mutation carriers (one in 288) is similar to that reported for FANCA, whereas there are approximately 100-fold more FA-A than FA-Q patients, indicating that most biallelic combinations of ERCC4 mutations are embryo lethal. Finally, we identified additional bone-fide FA ERCC4 mutations specifically disrupting interstrand cross-link repair. © 2013 WILEY PERIODICALS, INC., Contract grant sponsors: Mutua Madrileña Foundation (FMMA); Intrasalud PI12/00070; Accion Cooperativa y Colaborativa Intramural-CIBER2012; SAF2010-20493; Generalitat de Catalunya (SGR0489-2009), the ICREA-Academia award, the Spanish Ministry of Economy and Competitiveness (CIBERER CB06/07/0023, SAF2009-11936 and SAF2012-31881); the European Regional Development FEDER Funds; Fondo de Investigacion Sanitaria (FIS) (PI 12/00539); European Regional Development FEDER Funds; Asociacion Española Contra el Cáncer; Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia (ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, and 2009SGR290). Accion Cooperativa y Colaborativa Intramural-CIBERER 2012, the OncoCycle Pro-gramme (S2011/BMD-2470) and SAF2012-36556); and Fondo de Investigacion Sanitaria (PI10/00219).
Published: 2013

24. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

Author: Antoniou, Antonis C, Sinilnikova, Olga M, McGuffog, Lesley, Healey, Sue, Nevanlinna, Heli, Heikkinen, Tuomas, Simard, Jacques, Spurdle, Amanda B, Beesley, Jonathan, Chen, Xiaoqing, Kathleen Cuningham Foundation Consortium, for Research into Familial Breast Cancer, Neuhausen, Susan L, Ding, Yuan C, Couch, Fergus J, Wang, Xianshu, Fredericksen, Zachary, Peterlongo, Paolo, Peissel, Bernard, Bonanni, Bernardo, Viel, Alessandra, Bernard, Loris, Radice, Paolo, Szabo, Csilla I, Foretova, Lenka, Zikan, Michal, Claes, Kathleen, Greene, Mark H, Mai, Phuong L, Rennert, Gad, Lejbkowicz, Flavio, Andrulis, Irene L, Ozcelik, Hilmi, Glendon, Gord, Group, OCGN, Gerdes, Anne-Marie, Thomassen, Mads, Sunde, Lone, Caligo, Maria A, Laitman, Yael, Kontorovich, Tair, Cohen, Shimrit, Kaufman, Bella, Dagan, Efrat, Baruch, Ruth Gershoni, Friedman, Eitan, Harbst, Katja, Barbany-Bustinza, Gisela, Rantala, Johanna, Ehrencrona, Hans, Karlsson, Per, Domchek, Susan M, Nathanson, Katherine L, Osorio, Ana, Blanco, Ignacio, Lasa, Adriana, Benítez, Javier, Hamann, Ute, Hogervorst, Frans B L, Rookus, Matti A, Collee, J Margriet, Devilee, Peter, Ligtenberg, Marjolijn J, van der Luijt, Rob B, Aalfs, Cora M, Waisfisz, Quinten, Wijnen, Juul, van Roozendaal, Cornelis E P, Group, HEBON, Peock, Susan, Cook, Margaret, Frost, Debra, Oliver, Clare, Platte, Radka, Evans, D Gareth, Lalloo, Fiona, Eeles, Rosalind, Izatt, Louise, Davidson, Rosemarie, Chu, Carol, Eccles, Diana, Cole, Trevor, Hodgson, Shirley, Group, EMBRACE, Godwin, Andrew K, Stoppa-Lyonnet, Dominique, Buecher, Bruno, Léoné, Mélanie, Bressac-de Paillerets, Brigitte, Remenieras, Audrey, Caron, Olivier, Lenoir, Gilbert M, Sevenet, Nicolas, Longy, Michel, Ferrer, Sandra Fert, Prieur, Fabienne, Group, GEMO, Goldgar, David, Miron, Alexander, John, Esther M, Buys, Saundra S, Daly, Mary B, Hopper, John L, Terry, Mary Beth, Yassin, Yosuf, Family Registry, Breast Cancer, Singer, Christian, Gschwantler-Kaulich, Daphne, Staudigl, Christine, Hansen, Thomas v O, Barkardottir, Rosa Bjork, Kirchhoff, Tomas, Pal, Prodipto, Kosarin, Kristi, Offit, Kenneth, Piedmonte, Marion, Rodriguez, Gustavo C, Wakeley, Katie, Boggess, John F, Basil, Jack, Schwartz, Peter E, Blank, Stephanie V, Toland, Amanda E, Montagna, Marco, Casella, Cinzia, Imyanitov, Evgeny N, Allavena, Anna, Schmutzler, Rita K, Versmold, Beatrix, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Niederacher, Dieter, Deissler, Helmut, Fiebig, Britta, Suttner, Christian, Schönbuchner, Ines, Gadzicki, Dorothea, Caldes, Trinidad, de la Hoya, Miguel, Pooley, Karen A, Easton, Douglas F, Chenevix-Trench, Georgia, Group, CIMBA, University of Groningen, Human genetics, CCA - Oncogenesis, and Human Genetics
Subjects: endocrine system diseases, SUSCEPTIBILITY, 0302 clinical medicine, skin and connective tissue diseases, POPULATION, Genetics (clinical), Aged, 80 and over, 0303 health sciences, education.field_of_study, BRCA1 Protein, Association Studies Articles, Microfilament Proteins, General Medicine, Middle Aged, 3. Good health, Chromosomes, Human, Pair 2, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Female, Breast disease, Chromosomes, Human, Pair 8, Adult, EXPRESSION, Heterozygote, Population, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, OVARIAN-CANCER, Young Adult, 03 medical and health sciences, Breast cancer, Translational research [ONCOL 3], Genetics, medicine, Humans, Genetic Predisposition to Disease, ddc:610, GENOME-WIDE ASSOCIATION, education, Molecular Biology, Aged, 030304 developmental biology, BRCA2 Protein, Hereditary cancer and cancer-related syndromes [ONCOL 1], Genetic Variation, Cancer, Odds ratio, ALLELES, medicine.disease, GENE, Minor allele frequency, Genetics, Population, ESTROGEN-RECEPTOR, Mutation, Cancer research, Follow-Up Studies, Genome-Wide Association Study
Abstract: Contains fulltext : 81601.pdf (Publisher’s version ) (Closed access) Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.
Published: 2009

25. RAD51D Aberrant Splicing in Breast Cancer: Identification of Splicing Regulatory Elements and Minigene-Based Evaluation of 53 DNA Variants

Author: Bueno-Martínez, Elena, Sanoguera-Miralles, Lara, Valenzuela-Palomo, Alberto, Lorca, Víctor, Gómez-Sanz, Alicia, Carvalho, Sara, Allen, Jamie, Infante, Mar, Pérez-Segura, Pedro, Lázaro, Conxi, Easton, Douglas F, Devilee, Peter, Vreeswijk, Maaike P G, De La Hoya, Miguel, and Velasco, Eladio A
Subjects: Breast cancer, Minigene, Susceptibility genes, Ovarian cancer, Rad51d, Aberrant Splicing, Ess, Ese, Clinical Interpretation, 3. Good health, Vus
Abstract: RAD51D loss-of-function variants increase lifetime risk of breast and ovarian cancer. Splicing disruption is a frequent pathogenic mechanism associated with variants in susceptibility genes. Herein, we have assessed the splicing and clinical impact of splice-site and exonic splicing enhancer (ESE) variants identified through the study of ~113,000 women of the BRIDGES cohort. A RAD51D minigene with exons 2-9 was constructed in splicing vector pSAD. Eleven BRIDGES splice-site variants (selected by MaxEntScan) were introduced into the minigene by site-directed mutagenesis and tested in MCF-7 cells. The 11 variants disrupted splicing, collectively generating 25 different aberrant transcripts. All variants but one produced negligible levels (A demonstrated a complete aberrant splicing pattern without the FL transcript. On the other hand, c.214T>C increased efficiency of exon 3 recognition, so only the FL transcript was detected (100%). In conclusion, 41 RAD51D spliceogenic variants (28 of which were from the BRIDGES cohort) were identified by minigene assays. We show that minigene-based mapping of ESEs is a powerful approach for identifying ESE hotspots and ESE-disrupting variants. Finally, we have classified nine variants as likely pathogenic according to ACMG/AMP-based guidelines, highlighting the complex relationship between splicing alterations and variant interpretation.

26. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Author: Feng, Helian, Gusev, Alexander, Pasaniuc, Bogdan, Wu, Lang, Long, Jirong, Abu-Full, Zomoroda, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Asseryanis, Ella, Auer, Paul L, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barnes, Daniel R, Barrowdale, Daniel, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blanco, Ana, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Canisius, Sander, Campa, Daniele, Carter, Brian D, Carter, Jonathan, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, GC-HBOC Study Collaborators, Couch, Fergus J, Cox, Angela, Cross, Simon S, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, De La Hoya, Miguel, De Leeneer, Kim, Dennis, Joe, Devilee, Peter, Diez, Orland, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Ejlertsen, Bent, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gabrielson, Marike, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hake, Christopher, He, Wei, Heyworth, Jane, Hogervorst, Frans BL, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Huang, Guanmengqian, Hulick, Peter J, Humphreys, Keith, Imyanitov, Evgeny N, ABCTB Investigators, HEBON Investigators, BCFR Investigators, OCGN Investigators, Isaacs, Claudine, Jakimovska, Milena, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Jankowitz, Rachel C, John, Esther M, Johnson, Nichola, Joseph, Vijai, Jung, Audrey, Karlan, Beth Y, Khusnutdinova, Elza, Kiiski, Johanna I, Konstantopoulou, Irene, Kristensen, Vessela N, Laitman, Yael, Lambrechts, Diether, Lazaro, Conxi, Leroux, Dominique, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Lindor, Noralane, Lindström, Sara, Lo, Wing-Yee, Loud, Jennifer T, Lubiński, Jan, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martens, John WM, Martinez, Maria E, Matricardi, Laura, Maurer, Tabea, Mavroudis, Dimitrios, McGuffog, Lesley, Meindl, Alfons, Menon, Usha, Michailidou, Kyriaki, Kapoor, Pooja M, Miller, Austin, Montagna, Marco, Moreno, Fernando, Moserle, Lidia, Mulligan, Anna M, Muranen, Taru A, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Nevelsteen, Ines, Nielsen, Finn C, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olsson, Håkan, Osorio, Ana, Papp, Janos, Park-Simon, Tjoung-Won, Parsons, Michael T, Pedersen, Inge S, Peixoto, Ana, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul DP, Phillips, Kelly-Anne, Plaseska-Karanfilska, Dijana, Poppe, Bruce, Pradhan, Nisha, Prajzendanc, Karolina, Presneau, Nadege, Punie, Kevin, Pylkäs, Katri, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad Usman, Rennert, Gad, Risch, Harvey A, Robson, Mark, Romero, Atocha, Saloustros, Emmanouil, Sandler, Dale P, Santos, Catarina, Sawyer, Elinor J, Schmidt, Marjanka K, Schmidt, Daniel F, Schmutzler, Rita K, Schoemaker, Minouk J, Scott, Rodney J, Sharma, Priyanka, Shu, Xiao-Ou, Simard, Jacques, Singer, Christian F, Skytte, Anne-Bine, Soucy, Penny, Southey, Melissa C, Spinelli, John J, Spurdle, Amanda B, Stone, Jennifer, Swerdlow, Anthony J, Tapper, William J, Taylor, Jack A, Teixeira, Manuel R, Terry, Mary Beth, Teulé, Alex, Thomassen, Mads, Thöne, Kathrin, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tollenaar, Rob AEM, Torres, Diana, Truong, Thérèse, Tung, Nadine, Vachon, Celine M, Van Asperen, Christi J, Van Den Ouweland, Ans MW, Van Rensburg, Elizabeth J, Vega, Ana, Viel, Alessandra, Vieiro-Balo, Paula, Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R, Weitzel, Jeffrey N, Wendt, Camilla, Winqvist, Robert, Yang, Xiaohong R, Yannoukakos, Drakoulis, Ziogas, Argyrios, Milne, Roger L, Easton, Douglas F, Chenevix-Trench, Georgia, Zheng, Wei, Kraft, Peter, and Jiang, Xia
Subjects: causal gene, TWAS, Vesicular Transport Proteins, Breast Neoplasms, Estrogens, Genomics, Risk Assessment, 3. Good health, Receptors, Estrogen, breast cancer subtype, GWAS, Humans, Female, Genetic Predisposition to Disease, Transcriptome, Genome-Wide Association Study
Abstract: Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.

27. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Author: Blein, Sophie, Bardel, Claire, Danjean, Vincent, McGuffog, Lesley, Healey, Sue, Barrowdale, Daniel, Lee, Andrew, Dennis, Joe, Kuchenbaecker, Karoline B, Soucy, Penny, Terry, Mary Beth, Chung, Wendy K, Goldgar, David E, Buys, Saundra S, Breast Cancer Family Registry, Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M, Van Rensburg, Elizabeth J, Neuhausen, Susan L, Ding, Yuan Chun, Gerdes, Anne-Marie, Ejlertsen, Bent, Nielsen, Finn C, Hansen, Thomas Vo, Osorio, Ana, Benitez, Javier, Conejero, Raquel Andrés, Segota, Ena, Weitzel, Jeffrey N, Thelander, Margo, Peterlongo, Paolo, Radice, Paolo, Pensotti, Valeria, Dolcetti, Riccardo, Bonanni, Bernardo, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Manoukian, Siranoush, Varesco, Liliana, Capone, Gabriele L, Papi, Laura, Ottini, Laura, Yannoukakos, Drakoulis, Konstantopoulou, Irene, Garber, Judy, Hamann, Ute, Donaldson, Alan, Brady, Angela, Brewer, Carole, Foo, Claire, Evans, D Gareth, Frost, Debra, Eccles, Diana, EMBRACE, Douglas, Fiona, Cook, Jackie, Adlard, Julian, Barwell, Julian, Walker, Lisa, Izatt, Louise, Side, Lucy E, Kennedy, M John, Tischkowitz, Marc, Rogers, Mark T, Porteous, Mary E, Morrison, Patrick J, Platte, Radka, Eeles, Ros, Davidson, Rosemarie, Hodgson, Shirley, Cole, Trevor, Godwin, Andrew K, Isaacs, Claudine, Claes, Kathleen, De Leeneer, Kim, Meindl, Alfons, Gehrig, Andrea, Wappenschmidt, Barbara, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Plendl, Hansjoerg, Kast, Karin, Rhiem, Kerstin, Ditsch, Nina, Arnold, Norbert, Varon-Mateeva, Raymonda, Schmutzler, Rita K, Preisler-Adams, Sabine, Markov, Nadja Bogdanova, Wang-Gohrke, Shan, De Pauw, Antoine, Lefol, Cédrick, Lasset, Christine, Leroux, Dominique, Rouleau, Etienne, Damiola, Francesca, GEMO Study Collaborators, Dreyfus, Hélène, Barjhoux, Laure, Golmard, Lisa, Uhrhammer, Nancy, Bonadona, Valérie, Sornin, Valérie, Bignon, Yves-Jean, Carter, Jonathan, Van Le, Linda, Piedmonte, Marion, DiSilvestro, Paul A, De La Hoya, Miguel, Caldes, Trinidad, Nevanlinna, Heli, Aittomäki, Kristiina, Jager, Agnes, Van Den Ouweland, Ans Mw, Kets, Carolien M, Aalfs, Cora M, Van Leeuwen, Flora E, Hogervorst, Frans Bl, Meijers-Heijboer, Hanne Ej, HEBON, Oosterwijk, Jan C, Van Roozendaal, Kees Ep, Rookus, Matti A, Devilee, Peter, Van Der Luijt, Rob B, Olah, Edith, Diez, Orland, Teulé, Alex, Lazaro, Conxi, Blanco, Ignacio, Del Valle, Jesús, Jakubowska, Anna, Sukiennicki, Grzegorz, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Agnarsson, Bjarni A, Maugard, Christine, Amadori, Alberto, Montagna, Marco, Teixeira, Manuel R, Spurdle, Amanda B, Foulkes, William, Olswold, Curtis, Lindor, Noralane M, Pankratz, Vernon S, Szabo, Csilla I, Lincoln, Anne, Jacobs, Lauren, Corines, Marina, Robson, Mark, Vijai, Joseph, Berger, Andreas, Fink-Retter, Anneliese, Singer, Christian F, Rappaport, Christine, Kaulich, Daphne Geschwantler, Pfeiler, Georg, Tea, Muy-Kheng, Greene, Mark H, Mai, Phuong L, Rennert, Gad, Imyanitov, Evgeny N, Mulligan, Anna Marie, Glendon, Gord, Andrulis, Irene L, Tchatchou, Sandrine, Toland, Amanda Ewart, Pedersen, Inge Sokilde, Thomassen, Mads, Kruse, Torben A, Jensen, Uffe Birk, Caligo, Maria A, Friedman, Eitan, Zidan, Jamal, Laitman, Yael, Lindblom, Annika, Melin, Beatrice, Arver, Brita, Loman, Niklas, Rosenquist, Richard, Olopade, Olufunmilayo I, Nussbaum, Robert L, Ramus, Susan J, Nathanson, Katherine L, Domchek, Susan M, Rebbeck, Timothy R, Arun, Banu K, Mitchell, Gillian, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Stoppa-Lyonnet, Dominique, Thomas, Gilles, Simard, Jacques, Couch, Fergus J, Offit, Kenneth, Easton, Douglas F, Chenevix-Trench, Georgia, Antoniou, Antonis C, Mazoyer, Sylvie, Phelan, Catherine M, Sinilnikova, Olga M, and Cox, David G
Subjects: Risk, Heterozygote, Genes, Mitochondrial, Haplotypes, BRCA1 Protein, Genes, BRCA2, Mutation, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Phylogeny, 3. Good health
Abstract: INTRODUCTION: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. METHODS: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. RESULTS: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. CONCLUSIONS: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

28. Splicing predictions, minigene analyses, and ACMG-AMP clinical classification of 42 germline PALB2 splice-site variants

Author: Valenzuela-Palomo, Alberto, Bueno-Martínez, Elena, Sanoguera-Miralles, Lara, Lorca, Víctor, Fraile-Bethencourt, Eugenia, Esteban-Sánchez, Ada, Gómez-Barrero, Susana, Carvalho, Sara, Allen, Jamie, García-Álvarez, Alicia, Pérez-Segura, Pedro, Dorling, Leila, Easton, Douglas F, Devilee, Peter, Vreeswijk, Maaike Pg, De La Hoya, Miguel, and Velasco, Eladio A
Subjects: Breast Neoplasms, Exons, 3. Good health, VUS, clinical interpretation, aberrant splicing, splicing, Alternative Splicing, breast cancer, Case-Control Studies, PALB2, Databases, Genetic, Biomarkers, Tumor, MCF-7 Cells, Humans, Protein Isoforms, minigene, susceptibility genes, Female, RNA Splice Sites, Fanconi Anemia Complementation Group N Protein, functional assay
Abstract: PALB2 loss-of-function variants confer high risk of developing breast cancer. Here we present a systematic functional analysis of PALB2 splice-site variants detected in approximately 113,000 women in the large-scale sequencing project Breast Cancer After Diagnostic Gene Sequencing (BRIDGES; https://bridges-research.eu/). Eighty-two PALB2 variants at the intron-exon boundaries were analyzed with MaxEntScan. Forty-two variants were selected for the subsequent splicing functional assays. For this purpose, three splicing reporter minigenes comprising exons 1-12 were constructed. The 42 potential spliceogenic variants were introduced into the minigenes by site-directed mutagenesis and assayed in MCF-7/MDA-MB-231 cells. Splicing anomalies were observed in 35 variants, 23 of which showed no traces or minimal amounts of the expected full-length transcripts of each minigene. More than 30 different variant-induced transcripts were characterized, 23 of which were predicted to truncate the PALB2 protein. The pathogenicity of all variants was interpreted according to an in-house adaptation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) variant classification scheme. Up to 23 variants were classified as pathogenic/likely pathogenic. Remarkably, three ±1,2 variants (c.49-2A>T, c.108+2T>C, and c.211+1G>A) were classified as variants of unknown significance, as they produced significant amounts of either in-frame transcripts of unknown impact on the PALB2 protein function or the minigene full-length transcripts. In conclusion, we have significantly contributed to the ongoing effort of identifying spliceogenic variants in the clinically relevant PALB2 cancer susceptibility gene. Moreover, we suggest some approaches to classify the findings in accordance with the ACMG-AMP rationale. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.

29. DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Osario, Ana, Milne, Roger L., Kuchenbaecker, Karoline, Vaclova, Tereza, Pita, Guillermo, Alonso, Rosario, Peterlongo, Paolo, Blanco, Ignacio, De La Hoya, Miguel, Duran, Mercedes, Diez, Orland, Ramon Y Cajal, Teresa, Konstantopoulou, Irene, Martinez-Bouzas, Cristina, Soucy, Penny, Conejero, Raquel Andres, McGuffog, Lesley, Barrowdale, Daniel, Lee, Andrew, Arver, Brita, Rantala, Johanna, Loman, Niklas, Ehrencrona, Hans, Beattie, Mary S., Olopade, Olufunmilayo I., Domchek, Susan M., Nathanson, Katherine, Rebbeck, Timothy R., Arun, Banu K., Karlan, Beth Y., Walsh, Christine, Lester, Jenny, John, Esther M., Whittemore, Alice S., Daly, Mary B., Southey, Melissa, Hopper, John, Terry, Mary Beth, Buys, Saundra S., Janavicius, Ramunas, Dorfling, Cecilia M., Van Rensburg, Elizabeth J., Steele, Linda, Neuhausen, Susan L., Ding, Yuan Chun, Hansen, Thomas V. O., Jønson, Lars, Ejlertsen, Bent, Gerdes, Anne-Marie, Infante, Mar, Herraez, Belen, Moreno, Leticia Thais, Weitzel, Jeffrey N., Herzog, Josef, Weeman, Kisa, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Bonanni, Bernardo, Mariette, Frederique, Volorio, Sara, Viel, Alessandra, Varesco, Liliana, Papi, Laura, Ottini, Laura, Tibiletti, Maria Grazia, Radice, Paolo, Yannoukakos, Drakoulis, Garber, Judy, Ellis, Steve, Frost, Debra, Platte, Radka, Fineberg, Elena, Evans, Gareth, Lalloo, Fiona, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Eccles, Diana, Cook, Jackie, Hodgson, Shirley, Brewer, Carole, Tischkowitz, Marc, Douglas, Fiona, Porteous, Mary, Side, Lucy, Walker, Lisa, Morrison, Patrick, Donaldson, Alan, Kennedy, John, Foo, Claire, Godwin, Andrew K., Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hans Jorg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Gehrig, Andrea, Stoppa-Lyonnet, Dominique, Sinilnikova, Olga M., Mazoyer, Sylvie, Damiola, Francesca, Poppe, Bruce, Tucker, Kathy, Piedmonte, Marion, Claes, Kathleen, Backes, Floor, Rodriguez, Gustavo, Brewster, Wendy, Wakeley, Katie, Rutherford, Thomas, Caldes, Trinidad, Nevanlinna, Heli, Aittomaki, Kristiina, Rookus, Matti A., Van Os, Theo A. M., Kolk, Lizet Van Der, De Lange, J. L., Meijers-Heijboer, Hanne E. J., Van Der Hout, A. H., Van Asperen, Christi J., Gomez Garcia, Encarna B., Hoogerbrugge, Nicoline, Collee, J. Margriet, Van Deurzen, Carolien H. M, Van Der Luijt, Rob B., Devilee, Peter, Olah, Edith, Lazaro, Conxi, Teule, Alex, Menendez, Mireia, Jakubowska, Anna, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Th. Johannson, Oskar, Maugard, Christine, Montagna, Marco, Tognazzo, Silvia, Teixeira, Manuel R., Healey, Sue, Olswald, Curtis, Guidugli, Lucia, Slager, Susan, Lindor, Noralane, Szabo, Csilla I., Vijai, Joseph, Kauff, Noah, Fink-Retter, Anneliese, Zhang, Liying, Rau-Murthy, Rohini, Robson, Mark, Rappaport, Christine, Singer, Christian F., Tea, Muy-Kheng, Kaulich, Daphne Geschwantler, Berger, Andreas, Pfeiler, Georg, Mai, Phuong L., Phelan, Catherine M., Lejbkowicz, Flavio, Greene, Mark H., Andrulis, Irene, Mulligan, Anna Marie, Glendon, Gord, Toland, Amanda Ewart, Bojeson, Anders, Pederson, Inge Sokilde, Sunde, Lone, Thomassen, Mads, Kruse, Torben A., Jensen, Uffe Birk, Friedman, Eitan, Laitman, Yael, Shimon, Shani Paluch, Simard, Jacques, Offit, Kenneth, Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., Benitez, Javier, and Couch, Fergus J.
Subjects: Cancer--Genetic aspects, endocrine system diseases, Cancer--Risk factors, FOS: Biological sciences, Genetics, Single nucleotide polymorphisms, skin and connective tissue diseases, Biology, 3. Good health
Abstract: Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p

30. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Author: Rebbeck, Timothy R, Friebel, Tara M, Friedman, Eitan, Hamann, Ute, Huo, Dezheng, Kwong, Ava, Olah, Edith, Olopade, Olufunmilayo I, Solano, Angela R, Teo, Soo-Hwang, Thomassen, Mads, Weitzel, Jeffrey N, Chan, TL, Couch, Fergus J, Goldgar, David E, Kruse, Torben A, Palmero, Edenir Inêz, Park, Sue Kyung, Torres, Diana, Van Rensburg, Elizabeth J, McGuffog, Lesley, Parsons, Michael T, Leslie, Goska, Aalfs, Cora M, Abugattas, Julio, Adlard, Julian, Agata, Simona, Aittomäki, Kristiina, Andrews, Lesley, Andrulis, Irene L, Arason, Adalgeir, Arnold, Norbert, Arun, Banu K, Asseryanis, Ella, Auerbach, Leo, Azzollini, Jacopo, Balmaña, Judith, Barile, Monica, Barkardottir, Rosa B, Barrowdale, Daniel, Benitez, Javier, Berger, Andreas, Berger, Raanan, Blanco, Amie M, Blazer, Kathleen R, Blok, Marinus J, Bonadona, Valérie, Bonanni, Bernardo, Bradbury, Angela R, Brewer, Carole, Buecher, Bruno, Buys, Saundra S, Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A, Campbell, Ian, Caputo, Sandrine M, Chiquette, Jocelyne, Chung, Wendy K, Claes, Kathleen BM, Collée, J Margriet, Cook, Jackie, Davidson, Rosemarie, De La Hoya, Miguel, De Leeneer, Kim, De Pauw, Antoine, Delnatte, Capucine, Diez, Orland, Ding, Yuan Chun, Ditsch, Nina, Domchek, Susan M, Dorfling, Cecilia M, Velazquez, Carolina, Dworniczak, Bernd, Eason, Jacqueline, Easton, Douglas F, Eeles, Ros, Ehrencrona, Hans, Ejlertsen, Bent, EMBRACE, Engel, Christoph, Engert, Stefanie, Evans, D Gareth, Faivre, Laurence, Feliubadaló, Lidia, Ferrer, Sandra Fert, Foretova, Lenka, Fowler, Jeffrey, Frost, Debra, Galvão, Henrique CR, Ganz, Patricia A, Garber, Judy, Gauthier-Villars, Marion, Gehrig, Andrea, GEMO Study Collaborators, Gerdes, Anne-Marie, Gesta, Paul, Giannini, Giuseppe, Giraud, Sophie, Glendon, Gord, Godwin, Andrew K, Greene, Mark H, Gronwald, Jacek, Gutierrez-Barrera, Angelica, Hahnen, Eric, Hauke, Jan, HEBON, Henderson, Alex, Hentschel, Julia, Hogervorst, Frans BL, Honisch, Ellen, Imyanitov, Evgeny N, Isaacs, Claudine, Izatt, Louise, Izquierdo, Angel, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Jensen, Uffe Birk, John, Esther M, Vijai, Joseph, Kaczmarek, Katarzyna, Karlan, Beth Y, Kast, Karin, Investigators, KConFab, Kim, Sung-Won, Konstantopoulou, Irene, Korach, Jacob, Laitman, Yael, Lasa, Adriana, Lasset, Christine, Lázaro, Conxi, Lee, Annette, Lee, Min Hyuk, Lester, Jenny, Lesueur, Fabienne, Liljegren, Annelie, Lindor, Noralane M, Longy, Michel, Loud, Jennifer T, Lu, Karen H, Lubinski, Jan, Machackova, Eva, Manoukian, Siranoush, Mari, Véronique, Martínez-Bouzas, Cristina, Matrai, Zoltan, Mebirouk, Noura, Meijers-Heijboer, Hanne EJ, Meindl, Alfons, Mensenkamp, Arjen R, Mickys, Ugnius, Miller, Austin, Montagna, Marco, Moysich, Kirsten B, Mulligan, Anna Marie, Musinsky, Jacob, Neuhausen, Susan L, Nevanlinna, Heli, Ngeow, Joanne, Nguyen, Huu Phuc, Niederacher, Dieter, Nielsen, Henriette Roed, Nielsen, Finn Cilius, Nussbaum, Robert L, Offit, Kenneth, Öfverholm, Anna, Ong, Kai-Ren, Osorio, Ana, Papi, Laura, Papp, Janos, Pasini, Barbara, Pedersen, Inge Sokilde, Peixoto, Ana, Peruga, Nina, Peterlongo, Paolo, Pohl, Esther, Pradhan, Nisha, Prajzendanc, Karolina, Prieur, Fabienne, Pujol, Pascal, Radice, Paolo, Ramus, Susan J, Rantala, Johanna, Rashid, Muhammad Usman, Rhiem, Kerstin, Robson, Mark, Rodriguez, Gustavo C, Rogers, Mark T, Rudaitis, Vilius, Schmidt, Ane Y, Schmutzler, Rita Katharina, Senter, Leigha, Shah, Payal D, Sharma, Priyanka, Side, Lucy E, Simard, Jacques, Singer, Christian F, Skytte, Anne-Bine, Slavin, Thomas P, Snape, Katie, Sobol, Hagay, Southey, Melissa, Steele, Linda, Steinemann, Doris, Sukiennicki, Grzegorz, Sutter, Christian, Szabo, Csilla I, Tan, Yen Y, Teixeira, Manuel R, Terry, Mary Beth, Teulé, Alex, Thomas, Abigail, Thull, Darcy L, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda Ewart, Topka, Sabine, Trainer, Alison H, Tung, Nadine, Van Asperen, Christi J, Van Der Hout, Annemieke H, Van Der Kolk, Lizet E, Van Der Luijt, Rob B, Van Heetvelde, Mattias, Varesco, Liliana, Varon-Mateeva, Raymonda, Vega, Ana, Villarreal-Garza, Cynthia, Von Wachenfeldt, Anna, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weber, Bernhard HF, Yannoukakos, Drakoulis, Yoon, Sook-Yee, Zanzottera, Cristina, Zidan, Jamal, Zorn, Kristin K, Hutten Selkirk, Christina G, Hulick, Peter J, Chenevix-Trench, Georgia, Spurdle, Amanda B, Antoniou, Antonis C, and Nathanson, Katherine L
Subjects: BRCA2 Protein, Internationality, endocrine system diseases, Geography, BRCA1 Protein, BRCA1, BRCA2, 3. Good health, breast cancer, ovarian cancer, Databases, Genetic, Mutation, ethnicity, Humans, Family, skin and connective tissue diseases
Abstract: The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

31. Splicing predictions, minigene analyses, and ACMG-AMP clinical classification of 42 germline PALB2 splice-site variants

Author: Valenzuela-Palomo, Alberto, Bueno-Mart��nez, Elena, Sanoguera-Miralles, Lara, Lorca, V��ctor, Fraile-Bethencourt, Eugenia, Esteban-S��nchez, Ada, G��mez-Barrero, Susana, Carvalho, Sara, Allen, Jamie, Garc��a-��lvarez, Alicia, P��rez-Segura, Pedro, Dorling, Leila, Easton, Douglas, Devilee, Peter, Vreeswijk, Maaike Pg, De La Hoya, Miguel, and Velasco, Eladio A
Subjects: aberrant splicing, splicing, breast cancer, PALB2, minigene, susceptibility genes, functional assay, 3. Good health, VUS, clinical interpretation
Abstract: PALB2 loss-of-function variants confer high risk of developing breast cancer. Here we present a systematic functional analysis of PALB2 splice-site variants detected in approximately 113,000 women in the large-scale sequencing project Breast Cancer After Diagnostic Gene Sequencing (BRIDGES; https://bridges-research.eu/). Eighty-two PALB2 variants at the intron-exon boundaries were analyzed with MaxEntScan. Forty-two variants were selected for the subsequent splicing functional assays. For this purpose, three splicing reporter minigenes comprising exons 1-12 were constructed. The 42 potential spliceogenic variants were introduced into the minigenes by site-directed mutagenesis and assayed in MCF-7/MDA-MB-231 cells. Splicing anomalies were observed in 35 variants, 23 of which showed no traces or minimal amounts of the expected full-length transcripts of each minigene. More than 30 different variant-induced transcripts were characterized, 23 of which were predicted to truncate the PALB2 protein. The pathogenicity of all variants was interpreted according to an in-house adaptation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) variant classification scheme. Up to 23 variants were classified as pathogenic/likely pathogenic. Remarkably, three ��1,2 variants (c.49-2A>T, c.108+2T>C, and c.211+1G>A) were classified as variants of unknown significance, as they produced significant amounts of either in-frame transcripts of unknown impact on the PALB2 protein function or the minigene full-length transcripts. In conclusion, we have significantly contributed to the ongoing effort of identifying spliceogenic variants in the clinically relevant PALB2 cancer susceptibility gene. Moreover, we suggest some approaches to classify the findings in accordance with the ACMG-AMP rationale. �� 2021 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

32. Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women

Author: Breast Cancer Association Consortium, Dorling, Leila, Carvalho, Sara, Allen, Jamie, González-Neira, Anna, Luccarini, Craig, Wahlström, Cecilia, Pooley, Karen A, Parsons, Michael T, Fortuno, Cristina, Wang, Qin, Bolla, Manjeet K, Dennis, Joe, Keeman, Renske, Alonso, M Rosario, Álvarez, Nuria, Herraez, Belen, Fernandez, Victoria, Núñez-Torres, Rocio, Osorio, Ana, Valcich, Jeanette, Li, Minerva, Törngren, Therese, Harrington, Patricia A, Baynes, Caroline, Conroy, Don M, Decker, Brennan, Fachal, Laura, Mavaddat, Nasim, Ahearn, Thomas, Aittomäki, Kristiina, Antonenkova, Natalia N, Arnold, Norbert, Arveux, Patrick, Ausems, Margreet GEM, Auvinen, Päivi, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Białkowska, Katarzyna, Blomqvist, Carl, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Bremer, Michael, Briceno, Ignacio, Brüning, Thomas, Burwinkel, Barbara, Cameron, David A, Camp, Nicola J, Campbell, Archie, Carracedo, Angel, Castelao, Jose E, Cessna, Melissa H, Chanock, Stephen J, Christiansen, Hans, Collée, J Margriet, Cordina-Duverger, Emilie, Cornelissen, Sten, Czene, Kamila, Dörk, Thilo, Ekici, Arif B, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Försti, Asta, Gabrielson, Marike, Gago-Dominguez, Manuela, Georgoulias, Vassilios, Gil, Fabian, Giles, Graham G, Glendon, Gord, Garcia, Encarna B Gómez, Alnæs, Grethe I Grenaker, Guénel, Pascal, Hadjisavvas, Andreas, Haeberle, Lothar, Hahnen, Eric, Hall, Per, Hamann, Ute, Harkness, Elaine F, Hartikainen, Jaana M, Hartman, Mikael, He, Wei, Heemskerk-Gerritsen, Bernadette AM, Hillemanns, Peter, Hogervorst, Frans BL, Hollestelle, Antoinette, Ho, Weang Kee, Hooning, Maartje J, Howell, Anthony, Humphreys, Keith, Idris, Faiza, Jakubowska, Anna, Jung, Audrey, Kapoor, Pooja Middha, Kerin, Michael J, Khusnutdinova, Elza, Kim, Sung-Won, Ko, Yon-Dschun, Kosma, Veli-Matti, Kristensen, Vessela N, Kyriacou, Kyriacos, Lakeman, Inge MM, Lee, Jong Won, Lee, Min Hyuk, Li, Jingmei, Lindblom, Annika, Lo, Wing-Yee, Loizidou, Maria A, Lophatananon, Artitaya, Lubiński, Jan, MacInnis, Robert J, Madsen, Michael J, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Maurer, Tabea, Mavroudis, Dimitrios, McLean, Catriona, Meindl, Alfons, Mensenkamp, Arjen R, Michailidou, Kyriaki, Miller, Nicola, Mohd Taib, Nur Aishah, Muir, Kenneth, Mulligan, Anna Marie, Nevanlinna, Heli, Newman, William G, Nordestgaard, Børge G, Ng, Pei-Sze, Oosterwijk, Jan C, Park, Sue K, Park-Simon, Tjoung-Won, Perez, Jose IA, Peterlongo, Paolo, Porteous, David J, Prajzendanc, Karolina, Prokofyeva, Darya, Radice, Paolo, Rashid, Muhammad U, Rhenius, Valerie, Rookus, Matti A, Rüdiger, Thomas, Saloustros, Emmanouil, Sawyer, Elinor J, Schmutzler, Rita K, Schneeweiss, Andreas, Schürmann, Peter, Shah, Mitul, Sohn, Christof, Southey, Melissa C, Surowy, Harald, Suvanto, Maija, Thanasitthichai, Somchai, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Tzardi, Maria, Valova, Yana, Van Asperen, Christi J, Van Dam, Rob M, Van Den Ouweland, Ans MW, Van Der Kolk, Lizet E, Van Veen, Elke M, Wendt, Camilla, Williams, Justin A, Yang, Xiaohong R, Yoon, Sook-Yee, Zamora, M Pilar, Evans, D Gareth, De La Hoya, Miguel, Simard, Jacques, Antoniou, Antonis C, Borg, Åke, Andrulis, Irene L, Chang-Claude, Jenny, García-Closas, Montserrat, Chenevix-Trench, Georgia, Milne, Roger L, Pharoah, Paul DP, Schmidt, Marjanka K, Spurdle, Amanda B, Vreeswijk, Maaike PG, Benitez, Javier, Dunning, Alison M, Kvist, Anders, Teo, Soo H, Devilee, Peter, and Easton, Douglas F
Subjects: Adult, Aged, 80 and over, Risk, Adolescent, Age Factors, Mutation, Missense, Genetic Variation, Breast Neoplasms, Sequence Analysis, DNA, Middle Aged, 3. Good health, Young Adult, Logistic Models, Odds Ratio, Humans, Female, Genetic Predisposition to Disease, skin and connective tissue diseases, Aged
Abstract: BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).

33. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Author: Ferreira, Manuel A, Gamazon, Eric R, Al-Ejeh, Fares, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Asseryanis, Ella, Azzollini, Jacopo, Balmaña, Judith, Barnes, Daniel R, Barrowdale, Daniel, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Broeks, Annegien, Burwinkel, Barbara, Caldés, Trinidad, Caligo, Maria A, Campa, Daniele, Campbell, Ian, Canzian, Federico, Carter, Jonathan, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, De La Hoya, Miguel, Dennis, Joe, Devilee, Peter, Diez, Orland, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Ejlertsen, Bent, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Friedman, Eitan, Frost, Debra, Gabrielson, Marike, Gago-Dominguez, Manuela, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, He, Wei, Heyworth, Jane, Hogervorst, Frans BL, Hollestelle, Antoinette, Hoover, Robert N, Hopper, John L, Hulick, Peter J, Humphreys, Keith, Imyanitov, Evgeny N, ABCTB Investigators, HEBON Investigators, BCFR Investigators, Isaacs, Claudine, Jakimovska, Milena, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, Jankowitz, Rachel C, John, Esther M, Johnson, Nichola, Joseph, Vijai, Karlan, Beth Y, Khusnutdinova, Elza, Kiiski, Johanna I, Ko, Yon-Dschun, Jones, Michael E, Konstantopoulou, Irene, Kristensen, Vessela N, Laitman, Yael, Lambrechts, Diether, Lazaro, Conxi, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Lindström, Sara, Long, Jirong, Loud, Jennifer T, Lubiński, Jan, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Maurer, Tabea, Mavroudis, Dimitrios, McGuffog, Lesley, Meindl, Alfons, Menon, Usha, Michailidou, Kyriaki, Miller, Austin, Montagna, Marco, Moreno, Fernando, Moserle, Lidia, Mulligan, Anna Marie, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Nevelsteen, Ines, Nielsen, Finn C, Nikitina-Zake, Liene, Nussbaum, Robert L, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olsson, Håkan, Osorio, Ana, Papp, Janos, Park-Simon, Tjoung-Won, Parsons, Michael T, Pedersen, Inge Sokilde, Peixoto, Ana, Peterlongo, Paolo, Pharoah, Paul DP, Plaseska-Karanfilska, Dijana, Poppe, Bruce, Presneau, Nadege, Radice, Paolo, Rantala, Johanna, Rennert, Gad, Risch, Harvey A, Saloustros, Emmanouil, Sanden, Kristin, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Sharma, Priyanka, Shu, Xiao-Ou, Simard, Jacques, Singer, Christian F, Soucy, Penny, Southey, Melissa C, Spinelli, John J, Spurdle, Amanda B, Stone, Jennifer, Swerdlow, Anthony J, Tapper, William J, Taylor, Jack A, Teixeira, Manuel R, Terry, Mary Beth, Teulé, Alex, Thomassen, Mads, Thöne, Kathrin, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Truong, Thérèse, Tung, Nadine, Vachon, Celine M, Van Asperen, Christi J, Van Den Ouweland, Ans MW, Van Rensburg, Elizabeth J, Vega, Ana, Viel, Alessandra, Wang, Qin, Wappenschmidt, Barbara, Weitzel, Jeffrey N, Wendt, Camilla, Winqvist, Robert, Yang, Xiaohong R, Yannoukakos, Drakoulis, Ziogas, Argyrios, Kraft, Peter, Antoniou, Antonis C, Zheng, Wei, Easton, Douglas F, Milne, Roger L, Beesley, Jonathan, and Chenevix-Trench, Georgia
Subjects: Gene Expression Profiling, Quantitative Trait Loci, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, skin and connective tissue diseases, 3. Good health, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

34. Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

Author: Patel, Vivek L, Busch, Evan L, Friebel, Tara M, Cronin, Angel, Leslie, Goska, McGuffog, Lesley, Adlard, Julian, Agata, Simona, Agnarsson, Bjarni A, Ahmed, Munaza, Aittomäki, Kristiina, Alducci, Elisa, Andrulis, Irene L, Arason, Adalgeir, Arnold, Norbert, Artioli, Grazia, Arver, Brita, Auber, Bernd, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barnes, Daniel R, Barroso, Alicia, Barrowdale, Daniel, Belotti, Muriel, Benitez, Javier, Bertelsen, Birgitte, Blok, Marinus J, Bodrogi, Istvan, Bonadona, Valérie, Bonanni, Bernardo, Bondavalli, Davide, Boonen, Susanne E, Borde, Julika, Borg, Ake, Bradbury, Angela R, Brady, Angela, Brewer, Carole, Brunet, Joan, Buecher, Bruno, Buys, Saundra S, Cabezas-Camarero, Santiago, Caldés, Trinidad, Caliebe, Almuth, Caligo, Maria A, Calvello, Mariarosaria, Campbell, Ian G, Carnevali, Ileana, Carrasco, Estela, Chan, Tsun L, Chu, Annie TW, Chung, Wendy K, Claes, Kathleen BM, Collaborators, Gemo Study, Collaborators, Embrace, Cook, Jackie, Cortesi, Laura, Couch, Fergus J, Daly, Mary B, Damante, Giuseppe, Darder, Esther, Davidson, Rosemarie, De La Hoya, Miguel, Puppa, Lara Della, Dennis, Joe, Díez, Orland, Ding, Yuan Chun, Ditsch, Nina, Domchek, Susan M, Donaldson, Alan, Dworniczak, Bernd, Easton, Douglas F, Eccles, Diana M, Eeles, Rosalind A, Ehrencrona, Hans, Ejlertsen, Bent, Engel, Christoph, Evans, D Gareth, Faivre, Laurence, Faust, Ulrike, Feliubadaló, Lídia, Foretova, Lenka, Fostira, Florentia, Fountzilas, George, Frost, Debra, García-Barberán, Vanesa, Garre, Pilar, Gauthier-Villars, Marion, Géczi, Lajos, Gehrig, Andrea, Gerdes, Anne-Marie, Gesta, Paul, Giannini, Giuseppe, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, Greene, Mark H, Gutierrez-Barrera, Angelica M, Hahnen, Eric, Hamann, Ute, Hauke, Jan, Herold, Natalie, Hogervorst, Frans BL, Honisch, Ellen, Hopper, John L, Hulick, Peter J, Investigators, KConFab, Investigators, Hebon, Izatt, Louise, Jager, Agnes, James, Paul, Janavicius, Ramunas, Jensen, Uffe Birk, Jensen, Thomas Dyrso, Johannsson, Oskar Th, John, Esther M, Joseph, Vijai, Kang, Eunyoung, Kast, Karin, Kiiski, Johanna I, Kim, Sung-Won, Kim, Zisun, Ko, Kwang-Pil, Konstantopoulou, Irene, Kramer, Gero, Krogh, Lotte, Kruse, Torben A, Kwong, Ava, Larsen, Mirjam, Lasset, Christine, Lautrup, Charlotte, Lazaro, Conxi, Lee, Jihyoun, Lee, Jong Won, Lee, Min Hyuk, Lemke, Johannes, Lesueur, Fabienne, Liljegren, Annelie, Lindblom, Annika, Llovet, Patricia, Lopez-Fernández, Adria, Lopez-Perolio, Irene, Lorca, Victor, Loud, Jennifer T, Ma, Edmond SK, Mai, Phuong L, Manoukian, Siranoush, Mari, Veronique, Martin, Lynn, Matricardi, Laura, Mebirouk, Noura, Medici, Veronica, Meijers-Heijboer, Hanne EJ, Meindl, Alfons, Mensenkamp, Arjen R, Miller, Clare, Gomes, Denise Molina, Montagna, Marco, Mooij, Thea M, Moserle, Lidia, Mouret-Fourme, Emmanuelle, Mulligan, Anna Marie, Nathanson, Katherine L, Navratilova, Marie, Nevanlinna, Heli, Niederacher, Dieter, Nielsen, Finn C Cilius, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Ong, Kai-Ren, Osorio, Ana, Ott, Claus-Eric, Palli, Domenico, Park, Sue K, Parsons, Michael T, Pedersen, Inge Sokilde, Peissel, Bernard, Peixoto, Ana, Pérez-Segura, Pedro, Peterlongo, Paolo, Petersen, Annabeth Høgh, Porteous, Mary E, Pujana, Miguel Angel, Radice, Paolo, Ramser, Juliane, Rantala, Johanna, Rashid, Muhammad U, Rhiem, Kerstin, Rizzolo, Piera, Robson, Mark E, Rookus, Matti A, Rossing, Caroline M, Ruddy, Kathryn J, Santos, Catarina, Saule, Claire, Scarpitta, Rosa, Schmutzler, Rita K, Schuster, Hélène, Senter, Leigha, Seynaeve, Caroline M, Shah, Payal D, Sharma, Priyanka, Shin, Vivian Y, Silvestri, Valentina, Simard, Jacques, Singer, Christian F, Skytte, Anne-Bine, Snape, Katie, Solano, Angela R, Soucy, Penny, Southey, Melissa C, Spurdle, Amanda B, Steele, Linda, Steinemann, Doris, Stoppa-Lyonnet, Dominique, Stradella, Agostina, Sunde, Lone, Sutter, Christian, Tan, Yen Y, Teixeira, Manuel R, Teo, Soo Hwang, Thomassen, Mads, Tibiletti, Maria Grazia, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E, Tommasi, Stefania, Torres, Diana, Toss, Angela, Trainer, Alison H, Tung, Nadine, Van Asperen, Christi J, Van Der Baan, Frederieke H, Van Der Kolk, Lizet E, Van Der Luijt, Rob B, Van Hest, Liselotte P, Varesco, Liliana, Varon-Mateeva, Raymonda, Viel, Alessandra, Vierstraete, Jeroen, Villa, Roberta, Von Wachenfeldt, Anna, Wagner, Philipp, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weitzel, Jeffrey N, Wieme, Greet, Yadav, Siddhartha, Yannoukakos, Drakoulis, Yoon, Sook-Yee, Zanzottera, Cristina, Zorn, Kristin K, D'Amico, Anthony V, Freedman, Matthew L, Pomerantz, Mark M, Chenevix-Trench, Georgia, Antoniou, Antonis C, Neuhausen, Susan L, Ottini, Laura, Nielsen, Henriette Roed, and Rebbeck, Timothy R
Subjects: Adult, Aged, 80 and over, BRCA2 Protein, Male, Heterozygote, endocrine system diseases, Adolescent, BRCA1 Protein, Prostatic Neoplasms, Genomics, Middle Aged, Prognosis, 3. Good health, Young Adult, Risk Factors, Mutation, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases, Genetic Association Studies, Aged
Abstract: Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

35. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

Author: Fachal, Laura, Aschard, Hugues, Beesley, Jonathan, Barnes, Daniel R, Allen, Jamie, Kar, Siddhartha, Pooley, Karen A, Dennis, Joe, Michailidou, Kyriaki, Turman, Constance, Soucy, Penny, Lemaçon, Audrey, Lush, Michael, Tyrer, Jonathan P, Ghoussaini, Maya, Moradi Marjaneh, Mahdi, Jiang, Xia, Agata, Simona, Aittomäki, Kristiina, Alonso, M Rosario, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Auber, Bernd, Auer, Paul L, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blanco, Amie M, Blomqvist, Carl, Blot, William, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Borg, Ake, Bosse, Kristin, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Brock, Ian W, Brooks-Wilson, Angela, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Camp, Nicola J, Campbell, Ian, Canzian, Federico, Carroll, Jason S, Carter, Brian D, Castelao, Jose E, Chiquette, Jocelyne, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, Collée, J Margriet, Cornelissen, Sten, Couch, Fergus J, Cox, Angela, Cross, Simon S, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, De La Hoya, Miguel, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Dite, Gillian S, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Droit, Arnaud, Dubois, Stéphane, Dumont, Martine, Duran, Mercedes, Durcan, Lorraine, Dwek, Miriam, Eccles, Diana M, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Fletcher, Olivia, Floris, Giuseppe, Flyger, Henrik, Foretova, Lenka, Foulkes, William D, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gabrielson, Marike, Gago-Dominguez, Manuela, Gambino, Gaetana, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, García-Sáenz, José A, Gaudet, Mia M, Georgoulias, Vassilios, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Tibiletti, Maria Grazia, Greene, Mark H, Grip, Mervi, Gronwald, Jacek, Grundy, Anne, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hartikainen, Jaana M, Hartman, Mikael, He, Wei, Healey, Catherine S, Heemskerk-Gerritsen, Bernadette AM, Heyworth, Jane, Hillemanns, Peter, Hogervorst, Frans BL, Hollestelle, Antoinette, Hooning, Maartje J, Hopper, John L, Howell, Anthony, Huang, Guanmengqian, Hulick, Peter J, Imyanitov, Evgeny N, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Isaacs, Claudine, Iwasaki, Motoki, Jager, Agnes, Jakimovska, Milena, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, Jankowitz, Rachel C, John, Esther M, Johnson, Nichola, Jones, Michael E, Jukkola-Vuorinen, Arja, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Kapoor, Pooja Middha, Karlan, Beth Y, Keeman, Renske, Kerin, Michael J, Khusnutdinova, Elza, Kiiski, Johanna I, Kirk, Judy, Kitahara, Cari M, Ko, Yon-Dschun, Konstantopoulou, Irene, Kosma, Veli-Matti, Koutros, Stella, Kubelka-Sabit, Katerina, Kwong, Ava, Kyriacou, Kyriacos, Laitman, Yael, Lambrechts, Diether, Lee, Eunjung, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Lindblom, Annika, Lo, Wing-Yee, Long, Jirong, Lophatananon, Artitaya, Loud, Jennifer T, Lubiński, Jan, MacInnis, Robert J, Maishman, Tom, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Matsuo, Keitaro, Maurer, Tabea, Mavroudis, Dimitrios, Mayes, Rebecca, McGuffog, Lesley, McLean, Catriona, Mebirouk, Noura, Meindl, Alfons, Miller, Austin, Miller, Nicola, Montagna, Marco, Moreno, Fernando, Muir, Kenneth, Mulligan, Anna Marie, Muñoz-Garzon, Victor M, Muranen, Taru A, Narod, Steven A, Nassir, Rami, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Nielsen, Finn C, Nikitina-Zake, Liene, Norman, Aaron, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olsson, Håkan, Orr, Nick, Osorio, Ana, Pankratz, V Shane, Papp, Janos, Park, Sue K, Park-Simon, Tjoung-Won, Parsons, Michael T, Paul, James, Pedersen, Inge Sokilde, Peissel, Bernard, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Prajzendanc, Karolina, Prentice, Ross, Presneau, Nadege, Prokofyeva, Darya, Pujana, Miquel Angel, Pylkäs, Katri, Radice, Paolo, Ramus, Susan J, Rantala, Johanna, Rau-Murthy, Rohini, Rennert, Gad, Risch, Harvey A, Robson, Mark, Romero, Atocha, Rossing, Maria, Saloustros, Emmanouil, Sánchez-Herrero, Estela, Sandler, Dale P, Santamariña, Marta, Saunders, Christobel, Sawyer, Elinor J, Scheuner, Maren T, Schmidt, Daniel F, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, Schöttker, Ben, Schürmann, Peter, Scott, Christopher, Scott, Rodney J, Senter, Leigha, Seynaeve, Caroline M, Shah, Mitul, Sharma, Priyanka, Shen, Chen-Yang, Shu, Xiao-Ou, Singer, Christian F, Slavin, Thomas P, Smichkoska, Snezhana, Southey, Melissa C, Spinelli, John J, Spurdle, Amanda B, Stone, Jennifer, Stoppa-Lyonnet, Dominique, Sutter, Christian, Swerdlow, Anthony J, Tamimi, Rulla M, Tan, Yen Yen, Tapper, William J, Taylor, Jack A, Teixeira, Manuel R, Tengström, Maria, Teo, Soo Hwang, Terry, Mary Beth, Teulé, Alex, Thomassen, Mads, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tollenaar, Rob AEM, Tomlinson, Ian, Torres, Diana, Torres-Mejía, Gabriela, Troester, Melissa A, Truong, Thérèse, Tung, Nadine, Tzardi, Maria, Ulmer, Hans-Ulrich, Vachon, Celine M, Van Asperen, Christi J, Van Der Kolk, Lizet E, Van Rensburg, Elizabeth J, Vega, Ana, Viel, Alessandra, Vijai, Joseph, Vogel, Maartje J, Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R, Weitzel, Jeffrey N, Wendt, Camilla, Wildiers, Hans, Winqvist, Robert, Wolk, Alicja, Wu, Anna H, Yannoukakos, Drakoulis, Zhang, Yan, Zheng, Wei, Hunter, David, Pharoah, Paul DP, Chang-Claude, Jenny, García-Closas, Montserrat, Schmidt, Marjanka K, Milne, Roger L, Kristensen, Vessela N, French, Juliet D, Edwards, Stacey L, Antoniou, Antonis C, Chenevix-Trench, Georgia, Simard, Jacques, Easton, Douglas F, Kraft, Peter, and Dunning, Alison M
Subjects: Quantitative Trait Loci, Chromosome Mapping, Bayes Theorem, Breast Neoplasms, Regulatory Sequences, Nucleic Acid, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 3. Good health, Risk Factors, Biomarkers, Tumor, Humans, Female, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract: Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

36. Polygenic Risk Modelling for Prediction of Epithelial Ovarian Cancer Risk

Author: Dareng, Eileen O, Tyrer, Jonathan, Barnes, Daniel, Jones, Michelle R, Yang, Xin, Aben, Katja KH, Adank, Muriel A, Agata, Simona, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Aravantinos, Gerasimos, Arun, Banu K, Augustinsson, Annelie, Balma��a, Judith, Bandera, Elisa V, Barkardottir, Rosa B, Barrowdale, Daniel, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q, Bjorge, Line, Black, Amanda, Bogdanova, Natalia V, Bonanni, Bernardo, Borg, Ake, Brenton, James, Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S, Cai, Hui, Caligo, Maria A, Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K, Claes, Kathleen BM, Colanna, Sarah, Cook, Linda S, Couch, Fergus J, Daly, Mary B, Dao, Fanny, Davies, Eleanor, De La Hoya, Miguel, Putter, Robin De, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A, Domchek, Susan M, D��rk, Thilo, Bois, Andreas Du, D��rst, Matthias, Eccles, Diana M, Eliassen, Heather A, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Flanagan, James M, Foretova, Lenka, Fortner, Ren��e T, Friedman, Eitan, Ganz, Patricia A, Garber, Judy, Gensini, Francesca, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goodman, Marc T, Greene, Mark H, Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A, H��kansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, H��gdall, Estrid, H��gdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, Huntsman, David G, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th, John, Esther M, Jones, Michael E, Kang, Daehee, Karlan, Beth Y, Karnezis, Anthony, Kelemen, Linda E, Khusnutdinova, Elza, Kiemeney, Lambertus A, Kim, Byoung-Gie, Kjaer, Susanne K, Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W, Kwong, Ava, Lambrechts, Diether, Larson, Melissa C, Lazaro, Conxi, Le, Nhu D, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A, Li, Lian, Li, Jingmei, Loud, Jennifer T, Lu, Karen H, Lubi��ski, Jan, Machackova, Eva, Mai, Phuong L, Manoukian, Siranoush, Marks, Jeffrey R, Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R, McNeish, Iain A, Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L, Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B, Munro, Elizabeth, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C, Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I, Olson, Sara H, Olsson, H��kan, Osorio, Ana, Papi, Laura, Park, Sue K, Parsons, Michael T, Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B, Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J, Risch, Harvey A, Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P, Santamari��a, Marta, Soucy, Penny, Schmutzler, Rita K, Setiawan, V Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F, Sokolenko, Anna P, Song, Honglin, Southey, Melissa C, Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J, Tan, Yen Yen, Teixeira, Manuel R, Teo, Soo Hwang, Terry, Kathryn L, Terry, Mary Beth, Thomassen, Mads, Thompson, Pamela J, Vestrheim Thomsen, Liv Cecilie, Thull, Darcy L, Tischkowitz, Marc, Titus, Linda, Toland, Amanda E, Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S, Valen, Ellen, Van Altena, Anne M, Van Der Hout, Annemieke H, Van Nieuwenhuysen, Els, Van Rensburg, Elizabeth J, Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A, Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M, Weinberg, Clarice R, Weitzel, Jeffrey N, Wentzensen, Nicolas, White, Emily, Whittemore, Alice S, Winham, Stacey J, Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H, Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M, Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A, Ramus, Susan J, Pearce, Celeste L, Monteiro, Alvaro N, Cunningham, Julie, Goode, Ellen L, Schildkraut, Joellen M, Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A, Antoniou, Antonis C, and Pharoah, Paul DP
Subjects: 3. Good health
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, ��select and shrink for summary statistics�� (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28��1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08��1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30��1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

37. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Author: Couch, Fergus J., Wang, Xianshu, McGuffog, Lesley, Lee, Andrew, Olswold, Curtis, Kuchenbaecker, Karoline B., Soucy, Penny, Fredericksen, Zachary, Barrowdale, Daniel, Dennis, Joe, Gaudet, Mia M., Dicks, Ed, Kosel, Matthew, Healey, Sue, Sinilnikova, Olga M., Lee, Adam, Bacot, François, Vincent, Daniel, Hogervorst, Frans B. L., Peock, Susan, Stoppa-Lyonnet, Dominique, Jakubowska, Anna, Radice, Paolo, Schmutzler, Rita Katharina, Domchek, Susan M., Piedmonte, Marion, Singer, Christian F., Friedman, Eitan, Thomassen, Mads, Hansen, Thomas V. O., Neuhausen, Susan L., Szabo, Csilla I., Blanco, Ignacio, Greene, Mark H., Karlan, Beth Y., Garber, Judy, Phelan, Catherine M., Weitzel, Jeffrey N., Montagna, Marco, Olah, Edith, Andrulis, Irene L., Godwin, Andrew K., Yannoukakos, Drakoulis, Goldgar, David E., Caldes, Trinidad, Nevanlinna, Heli, Osorio, Ana, Terry, Mary Beth, Daly, Mary B., Van Rensburg, Elizabeth J., Hamann, Ute, Ramus, Susan J., Toland, Amanda Ewart, Caligo, Maria A., Olopade, Olufunmilayo I., Tung, Nadine, Claes, Kathleen, Beattie, Mary S., Southey, Melissa C., Imyanitov, Evgeny N., Tischkowitz, Marc, Janavicius, Ramunas, John, Esther M., Kwong, Ava, Diez, Orland, Balmaña, Judith, Barkardottir, Rosa B., Arun, Banu K., Rennert, Gad, Teo, Soo-Hwang, Ganz, Patricia A., Campbell, Ian, Van Der Hout, Annemarie H., Van Deurzen, Carolien H. M., Seynaeve, Caroline, Gómez Garcia, Encarna B., Van Leeuwen, Flora E., Meijers-Heijboer, Hanne E. J., Gille, Johannes J. P., Ausems, Margaret G. E. M., Blok, Marinus J., Ligtenberg, Marjolijn J. L., Rookus, Matti A., Devilee, Peter, Verhoef, Senno, Van Os, Theo A. M., Wijnen, Juul T., Frost, Debra, Ellis, Steve, Fineberg, Elena, Izatt, Louise, Platte, Radka, Evans, D. Gareth, Eeles, Rosalind A., Adlard, Julian, Eccles, Diana M., Cook, Jackie, Brewer, Carole, Douglas, Fiona, Hodgson, Shirley, Murray, Alex, Morrison, Patrick J., Side, Lucy E., Gregory, Helen, Donaldson, Alan, Dorkins, Huw, Houghton, Catherine, Rogers, Mark T., McCann, Emma, Eason, Jacqueline, Calender, Alain, Hardouin, Agnès, Berthet, Pascaline, Delnatte, Capucine, Nogues, Catherine, Lasset, Christine, Houdayer, Claude, Leroux, Dominique, Rouleau, Etienne, Prieur, Fabienne, Damiola, Francesca, Sobol, Hagay, Coupier, Isabelle, Venat-Bouvet, Laurence, Castera, Laurent, Gauthier-Villars, Marion, Léoné, Mélanie, Pujol, Pascal, Mazoyer, Sylvie, Bignon, Yves-Jean, GEMO Study Collaborators, Złowocka-Perłowska, Elżbieta, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska, Katarzyna, Huzarski, Tomasz, Spurdle, Amanda B., Viel, Alessandra, Peissel, Bernard, Bonanni, Bernardo, Melloni, Giulia, Ottini, Laura, Papi, Laura, Varesco, Liliana, Tibiletti, Maria Grazia, Peterlongo, Paolo, Volorio, Sara, Manoukian, Siranoush, Pensotti, Valeria, Arnold, Norbert, Engel, Chrisoph, Deissler, Helmut, Gadzicki, Dorothea, Gehrig, Andrea, Kast, Karin, Rhiem, Kerstin, Meindl, Alfons, Niederacher, Dieter, Ditsch, Nina, Plendl, Hansjoerg, Preisler-Adams, Sabine, Engert, Stefanie, Sutter, Christian, Varon-Mateeva, Raymonda, Wappenschmidt, Barbara, Weber, Bernhard H. F., Arver, Brita, Stenmark-Askmalm, Marie, Loman, Niklas, Rosenquist, Richard, Einbeigi, Zakaria, Nathanson, Katherine L., Rebbeck, Timothy R., Blank, Stephanie V., Cohn, David E., Friedlander, Michael, Small, Laurie, Rodriguez, Gustavo C., Bae-Jump, Victoria L., Fink-Retter, Anneliese, Rappaport, Christine, Gschwantler-Kaulich, Daphne, Pfeiler, Georg, Tea, Muy-Kheng, Lindor, Noralane M., Kaufman, Bella, Paluch, Shani Shimon, Skytte, Anne-Bine, Laitman, Yael, Kruse, Torben A., Pedersen, Inge Sokilde, Gerdes, Anne-Marie, Moeller, Sanne Traasdahl, Jensen, Uffe Birk, Vijai, Joseph, Sarrel, Kara, Robson, Mark, Kauff, Noah, Mulligan, Anna Marie, Glendon, Gord, Ejlertsen, Bent, Ozcelik, Hilmi, Nielsen, Finn C., Jønson, Lars, Andersen, Mette K., Ding, Yuan Chun, Steele, Linda, Foretova, Lenka, Lazaro, Conxi, Teule, Alex, Brunet, Joan, Pujana, Miquel Angel, Mai, Phuong L., Loud, Jennifer T., Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Narod, Steven A., Herzog, Josef, Tognazzo, Silvia, Sand, Sharon R., Weaver, Joellen, Agata, Simona, Vaszko, Tibor, Stavropoulou, Alexandra V., Buys, Saundra S., Romero, Atocha, De La Hoya, Miguel, Aittomäki, Kristiina, Muranen, Taru A., Duran, Mercedes, Chung, Wendy K., Lasa, Adriana, Dorfling, Cecilia M., Miron, Alexander, BCFR, Benitez, Javier, Senter, Leigha, Chan, Salina B., Huo, Dezheng, Sokolenko, Anna P., Chiquette, Jocelyne, Tihomirova, Laima, Friebel, Tara M., Agnarsson, Bjarni A., Lu, Karen H., James, Paul A., Lejbkowicz, Flavio, Hall, Per, Dunning, Alison M., Tessier, Daniel, Cunningham, Julie, Slager, Susan L., Wang, Chen, Hart, Steven, Stevens, Kristen, Simard, Jacques, Pastinen, Tomi, Pankratz, Vernon S., Offit, Kenneth, Easton, Douglas F., Chenevix-Trench, Georgia, and Antoniou, Antonis C.
Subjects: Breast--Cancer--Genetic aspects, Ovaries--Cancer--Risk factors, Breast--Cancer--Epidemiology, endocrine system diseases, Epidemiology, Ovaries--Cancer--Genetic aspects, skin and connective tissue diseases, 3. Good health, Breast--Cancer--Risk factors
Abstract: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10⁻⁸, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10⁻⁸, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10⁻⁸, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10⁻⁴). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

38. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Author: Barnes, Daniel R, Silvestri, Valentina, Leslie, Goska, McGuffog, Lesley, Dennis, Joe, Yang, Xin, Adlard, Julian, Agnarsson, Bjarni A, Ahmed, Munaza, Aittomäki, Kristiina, Andrulis, Irene L, Arason, Adalgeir, Arnold, Norbert, Auber, Bernd, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Barwell, Julian, Belotti, Muriel, Benitez, Javier, Berthet, Pascaline, Boonen, Susanne E, Borg, Åke, Bozsik, Aniko, Brady, Angela F, Brennan, Paul, Brewer, Carole, Brunet, Joan, Bucalo, Agostino, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Cassingham, Hayley, Christensen, Lise Lotte, Cini, Giulia, Claes, Kathleen BM, GEMO Study Collaborators, EMBRACE Collaborators, Cook, Jackie, Coppa, Anna, Cortesi, Laura, Damante, Giuseppe, Darder, Esther, Davidson, Rosemarie, De La Hoya, Miguel, De Leeneer, Kim, De Putter, Robin, Del Valle, Jesús, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Donaldson, Alan, Eason, Jacqueline, Eeles, Ros, Engel, Christoph, Evans, D Gareth, Feliubadaló, Lidia, Fostira, Florentia, Frone, Megan, Frost, Debra, Gallagher, David, Gehrig, Andrea, Giraud, Sophie, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, Greene, Mark H, Gregory, Helen, Gross, Eva, Hahnen, Eric, Hamann, Ute, Hansen, Thomas VO, Hanson, Helen, Hentschel, Julia, Horvath, Judit, KConFab Investigators, HEBON Investigators, Izatt, Louise, Izquierdo, Angel, James, Paul A, Janavicius, Ramunas, Jensen, Uffe Birk, Johannsson, Oskar Th, John, Esther M, Kramer, Gero, Kroeldrup, Lone, Kruse, Torben A, Lautrup, Charlotte, Lazaro, Conxi, Lesueur, Fabienne, Lopez-Fernández, Adria, Mai, Phuong L, Manoukian, Siranoush, Matrai, Zoltan, Matricardi, Laura, Maxwell, Kara N, Mebirouk, Noura, Meindl, Alfons, Montagna, Marco, Monteiro, Alvaro N, Morrison, Patrick J, Muranen, Taru A, Murray, Alex, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Nguyen-Dumont, Tu, Niederacher, Dieter, Olah, Edith, Olopade, Olufunmilayo I, Palli, Domenico, Parsons, Michael T, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Peterlongo, Paolo, Petersen, Annabeth H, Pinto, Pedro, Porteous, Mary E, Pottinger, Caroline, Pujana, Miquel Angel, Radice, Paolo, Ramser, Juliane, Rantala, Johanna, Robson, Mark, Rogers, Mark T, Rønlund, Karina, Rump, Andreas, Sánchez De Abajo, Ana María, Shah, Payal D, Sharif, Saba, Side, Lucy E, Singer, Christian F, Stadler, Zsofia, Steele, Linda, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R, Teulé, Alex, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tommasi, Stefania, Toss, Angela, Trainer, Alison H, Tripathi, Vishakha, Valentini, Virginia, Van Asperen, Christi J, Venturelli, Marta, Viel, Alessandra, Vijai, Joseph, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Whaite, Anna, Zanna, Ines, Offit, Kenneth, Thomassen, Mads, Couch, Fergus J, Schmutzler, Rita K, Simard, Jacques, Easton, Douglas F, Chenevix-Trench, Georgia, Antoniou, Antonis C, Ottini, Laura, and Consortium Of Investigators Of Modifiers Of BRCA1 And BRCA2
Subjects: Aged, 80 and over, BRCA2 Protein, Male, Heterozygote, BRCA1 Protein, Prostatic Neoplasms, Breast Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, 3. Good health, Risk Factors, Mutation, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases
Abstract: BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.

39. Comprehensive Functional Characterization and Clinical Interpretation of 20 Splice-Site Variants of the RAD51C Gene

Author: Sanoguera-Miralles, Lara, Valenzuela-Palomo, Alberto, Bueno-Martínez, Elena, Llovet, Patricia, Díez-Gómez, Beatriz, Caloca, María José, Pérez-Segura, Pedro, Fraile-Bethencourt, Eugenia, Colmena, Marta, Carvalho, Sara, Allen, Jamie, Easton, Douglas F, Devilee, Peter, Vreeswijk, Maaike PG, De La Hoya, Miguel, and Velasco, Eladio A
Subjects: aberrant splicing, splicing, breast cancer, ovarian cancer, RAD51C, genetic variants, minigene, susceptibility genes, functional assay, 3. Good health, VUS, clinical interpretation
Abstract: Hereditary breast and/or ovarian cancer is a highly heterogeneous disease with more than 10 known disease-associated genes. In the framework of the BRIDGES project (Breast Cancer Risk after Diagnostic Gene Sequencing), the RAD51C gene has been sequenced in 60,466 breast cancer patients and 53,461 controls. We aimed at functionally characterizing all the identified genetic variants that are predicted to disrupt the splicing process. Forty RAD51C variants of the intron-exon boundaries were bioinformatically analyzed, 20 of which were selected for splicing functional assays. To test them, a splicing reporter minigene with exons 2 to 8 was designed and constructed. This minigene generated a full-length transcript of the expected size (1062 nucleotides), sequence, and structure (Vector exon V1- RAD51C exons_2-8- Vector exon V2). The 20 candidate variants were genetically engineered into the wild type minigene and functionally assayed in MCF-7 cells. Nineteen variants (95%) impaired splicing, while 18 of them produced severe splicing anomalies. At least 35 transcripts were generated by the mutant minigenes: 16 protein-truncating, 6 in-frame, and 13 minor uncharacterized isoforms. According to ACMG/AMP-based standards, 15 variants could be classified as pathogenic or likely pathogenic variants: c.404G > A, c.405-6T > A, c.571 + 4A > G, c.571 + 5G > A, c.572-1G > T, c.705G > T, c.706-2A > C, c.706-2A > G, c.837 + 2T > C, c.905-3C > G, c.905-2A > C, c.905-2_905-1del, c.965 + 5G > A, c.1026 + 5_1026 + 7del, and c.1026 + 5G > T.

40. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author: Barnes, Daniel R, Rookus, Matti A, McGuffog, Lesley, Leslie, Goska, Mooij, Thea M, Dennis, Joe, Mavaddat, Nasim, Adlard, Julian, Ahmed, Munaza, Aittomäki, Kristiina, Andrieu, Nadine, Andrulis, Irene L, Arnold, Norbert, Arun, Banu K, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Benitez, Javier, Berthet, Pascaline, Białkowska, Katarzyna, Blanco, Amie M, Blok, Marinus J, Bonanni, Bernardo, Boonen, Susanne E, Borg, Åke, Bozsik, Aniko, Bradbury, Angela R, Brennan, Paul, Brewer, Carole, Brunet, Joan, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Christensen, Lise Lotte, Chung, Wendy K, Claes, Kathleen BM, Colas, Chrystelle, GEMO Study Collaborators, EMBRACE Collaborators, Collonge-Rame, Marie-Agnès, Cook, Jackie, Daly, Mary B, Davidson, Rosemarie, De La Hoya, Miguel, De Putter, Robin, Delnatte, Capucine, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Dorfling, Cecilia M, Dumont, Martine, Eeles, Ros, Ejlertsen, Bent, Engel, Christoph, Evans, D Gareth, Faivre, Laurence, Foretova, Lenka, Fostira, Florentia, Friedlander, Michael, Friedman, Eitan, Frost, Debra, Ganz, Patricia A, Garber, Judy, Gehrig, Andrea, Gerdes, Anne-Marie, Gesta, Paul, Giraud, Sophie, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gschwantler-Kaulich, Daphne, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hentschel, Julia, Hogervorst, Frans BL, Hooning, Maartje J, Horvath, Judit, Hu, Chunling, Hulick, Peter J, Imyanitov, Evgeny N, KConFab Investigators, HEBON Investigators, GENEPSO Investigators, Isaacs, Claudine, Izatt, Louise, Izquierdo, Angel, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, John, Esther M, Joseph, Vijai, Karlan, Beth Y, Kast, Karin, Koudijs, Marco, Kruse, Torben A, Kwong, Ava, Laitman, Yael, Lasset, Christine, Lazaro, Conxi, Lester, Jenny, Lesueur, Fabienne, Liljegren, Annelie, Loud, Jennifer T, Lubiński, Jan, Mai, Phuong L, Manoukian, Siranoush, Mari, Véronique, Mebirouk, Noura, Meijers-Heijboer, Hanne EJ, Meindl, Alfons, Mensenkamp, Arjen R, Miller, Austin, Montagna, Marco, Mouret-Fourme, Emmanuelle, Mukherjee, Semanti, Mulligan, Anna Marie, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Niederacher, Dieter, Nielsen, Finn Cilius, Nikitina-Zake, Liene, Noguès, Catherine, Olah, Edith, Olopade, Olufunmilayo I, Ong, Kai-Ren, O'Shaughnessy-Kirwan, Aoife, Osorio, Ana, Ott, Claus-Eric, Papi, Laura, Park, Sue K, Parsons, Michael T, Pedersen, Inge Sokilde, Peissel, Bernard, Peixoto, Ana, Peterlongo, Paolo, Pfeiler, Georg, Phillips, Kelly-Anne, Prajzendanc, Karolina, Pujana, Miquel Angel, Radice, Paolo, Ramser, Juliane, Ramus, Susan J, Rantala, Johanna, Rennert, Gad, Risch, Harvey A, Robson, Mark, Rønlund, Karina, Salani, Ritu, Schuster, Hélène, Senter, Leigha, Shah, Payal D, Sharma, Priyanka, Side, Lucy E, Singer, Christian F, Slavin, Thomas P, Soucy, Penny, Southey, Melissa C, Spurdle, Amanda B, Steinemann, Doris, Steinsnyder, Zoe, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R, Teo, Soo Hwang, Thull, Darcy L, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E, Trainer, Alison H, Tung, Nadine, Van Engelen, Klaartje, Van Rensburg, Elizabeth J, Vega, Ana, Vierstraete, Jeroen, Wagner, Gabriel, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weitzel, Jeffrey N, Yadav, Siddhartha, Yang, Xin, Yannoukakos, Drakoulis, Zimbalatti, Dario, Offit, Kenneth, Thomassen, Mads, Couch, Fergus J, Schmutzler, Rita K, Simard, Jacques, Easton, Douglas F, Chenevix-Trench, Georgia, Antoniou, Antonis C, and Consortium Of Investigators Of Modifiers Of BRCA And BRCA2
Subjects: BRCA2 Protein, Ovarian Neoplasms, Heterozygote, endocrine system diseases, BRCA1 Protein, Breast Neoplasms, Carcinoma, Ovarian Epithelial, PRS, 3. Good health, breast cancer, ovarian cancer, BRCA1/2, Risk Factors, Mutation, Humans, genetics, Female, Genetic Predisposition to Disease, Prospective Studies, Retrospective Studies
Abstract: PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

41. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Author: Blein, Sophie, Bardel, Claire, Danjean, Vincent, McGuffog, Lesley, Healey, Sue, Barrowdale, Daniel, Lee, Andrew, Dennis, Joe, Kuchenbaecker, Karoline B., Soucy, Penny, Terry, Mary Beth, Chung, Wendy K., Goldgar, David E., Janavicius, Ramunas, Buys, Saundra S., Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M., Neuhausen, Susan L., Van Rensburg, Elizabeth J., Ding, Yuan Chun, Gerdes, Anne-Marie, Ejlertsen, Bent, Nielsen, Finn C., Hansen, Thomas V. O., Osorio, Ana, Benitez, Javier, Conejero, Raquel Andrés, Segota, Ena, Weitzel, Jeffrey N., Thelander, Margo, Peterlongo, Paolo, Radice, Paolo, Pensotti, Valeria, Dolcetti, Riccardo, Peissel, Bernard, Bonanni, Bernardo, Zaffaroni, Daniela, Scuvera, Giulietta, Manoukian, Siranoush, Capone, Gabriele L., Varesco, Liliana, Papi, Laura, Ottini, Laura, Yannoukakos, Drakoulis, Konstantopoulou, Irene, Garber, Judy, Donaldson, Alan, Hamann, Ute, Brady, Angela, Brewer, Carole, Foo, Claire, Evans, D Gareth, Frost, Debra, Eccles, Diana, Douglas, Fiona, Cook, Jackie, Adlard, Julian, Barwell, Julian, Walker, Lisa, Izatt, Louise, Kennedy, M. John, Rogers, Mark T., Side, Lucy E., Tischkowitz, Marc, Porteous, Mary E., Morrison, Patrick J., Platte, Radka, Davidson, Rosemarie, Eeles, Ros, Hodgson, Shirley, Cole, Trevor, Godwin, Andrew K., Isaacs, Claudine, Claes, Kathleen, Leeneer, Kim De, Meindl, Alfons, Gehrig, Andrea, Wappenschmidt, Barbara, Engel, Christoph, Sutter, Christian, Niederacher, Dieter, Steinemann, Doris, Plendl, Hansjoerg, Kast, Karin, Rhiem, Kerstin, Ditsch, Nina, Arnold, Norbert, Varon-Mateeva, Raymonda, Schmutzler, Rita K., Preisler-Adams, Sabine, Markov, Nadja Bogdanova, Wang-Gohrke, Shan, De Pauw, Antoine, Lefol, Cédrick, Leroux, Dominique, Lasset, Christine, Rouleau, Etienne, Damiola, Francesca, Dreyfus, Hélène, Barjhoux, Laure, Golmard, Lisa, Uhrhammer, Nancy, Bonadona, Valérie, Bignon, Yves-Jean, Sornin, Valérie, Carter, Jonathan, Le, Linda Van, Piedmonte, Marion, DiSilvestro, Paul A., De La Hoya, Miguel, Caldes, Trinidad, Nevanlinna, Heli, Aittomäki, Kristiina, Van Den Ouweland, Ans M. W., Kets, Carolien M., Aalfs, Cora M., Jager, Agnes, Van Leeuwen, Flora E., Hogervorst, Frans B. L., Meijers-Heijboer, Hanne E. J., Oosterwijk, Jan C., Van Roozendaal, Kees E. P., Rookus, Matti A., Devilee, Peter, Van Der Luijt, Rob B., Olah, Edith, Diez, Orland, Lazaro, Conxi, Teulé, Alex, Blanco, Ignacio, Del Valle, Jesús, Jakubowska, Anna, Sukiennicki, Grzegorz, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Agnarsson, Bjarni A., Amadori, Alberto, Maugard, Christine, Montagna, Marco, Teixeira, Manuel R., Spurdle, Amanda B., Foulkes, William, Olswold, Curtis, Lindor, Noralane M., Pankratz, Vernon S., Szabo, Csilla I., Lincoln, Anne, Jacobs, Lauren, Corines, Marina, Robson, Mark, Vijai, Joseph, Fink-Retter, Anneliese, Berger, Andreas, Singer, Christian F., Rappaport, Christine, Kaulich, Daphne Geschwantler, Pfeiler, Georg, Tea, Muy-Kheng, Mai, Phuong L., Greene, Mark H., Rennert, Gad, Imyanitov, Evgeny N., Mulligan, Anna Marie, Glendon, Gord, Andrulis, Irene L., Tchatchou, Sandrine, Toland, Amanda Ewart, Pedersen, Inge Sokilde, Thomassen, Mads, Kruse, Torben A., Caligo, Maria A., Jensen, Uffe Birk, Friedman, Eitan, Zidan, Jamal, Laitman, Yael, Melin, Beatrice, Lindblom, Annika, Arver, Brita, Loman, Niklas, Rosenquist, Richard, Olopade, Olufunmilayo I., Nussbaum, Robert L., Ramus, Susan J., Nathanson, Katherine L., Domchek, Susan M., Rebbeck, Timothy R., Arun, Banu K., Mitchell, Gillian, Karlan, Beth Y., Lester, Jenny, Orsulic, Sandra, Stoppa-Lyonnet, Dominique, Thomas, Gilles, Simard, Jacques, Offit, Kenneth, Couch, Fergus J., Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., Mazoyer, Sylvie, Phelan, Catherine M., Sinilnikova, Olga M., Cox, David G., EMBRACE, HEBON, and GEMO Study Collaborators
Subjects: Breast--Cancer--Genetic aspects, Oncology, Mutation (Biology), Mitochondrial DNA, 3. Good health
Abstract: Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

42. The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Author: Figlioli, Gisella, Bogliolo, Massimo, Catucci, Irene, Caleca, Laura, Lasheras, Sandra Viz, Pujol, Roser, Kiiski, Johanna I., Muranen, Taru A., Barnes, Daniel R., Dennis, Joe, Michailidou, Kyriaki, Bolla, Manjeet K., Leslie, Goska, Aalfs, Cora M., Adank, Muriel A., Adlard, Julian, Agata, Simona, Cadoo, Karen, Agnarsson, Bjarni A., Ahearn, Thomas, Aittomäki, Kristiina, Ambrosone, Christine B., Andrews, Lesley, Anton-Culver, Hoda, Antonenkova, Natalia N., Arndt, Volker, Arnold, Norbert, Aronson, Kristan J., Arun, Banu K., Asseryanis, Ella, Auber, Bernd, Auvinen, Päivi, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B., Barrowdale, Daniel, Barwell, Julian, Beane Freeman, Laura E., Beauparlant, Charles Joly, Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Berger, Raanan, Bermisheva, Marina, Blanco, Amie M., Blomqvist, Carl, Bogdanova, Natalia V., Bojesen, Anders, Bojesen, Stig E., Bonanni, Bernardo, Borg, Ake, Brady, Angela F., Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S., Caldés, Trinidad, Caliebe, Almuth, Caligo, Maria A., Campa, Daniele, Campbell, Ian G., Canzian, Federico, Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Claes, Kathleen B. M., Clarke, Christine L., Collavoli, Anita, Conner, Thomas A., Cox, David G., Cybulski, Cezary, Czene, Kamila, Daly, Mary B., De La Hoya, Miguel, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Dite, Gillian S., Ditsch, Nina, Domchek, Susan M., Dorfling, Cecilia M., Dos-Santos-Silva, Isabel, Durda, Katarzyna, Dwek, Miriam, Eccles, Diana M., Ekici, Arif B., Eliassen, A. Heather, Ellberg, Carolina, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Foulkes, William D., Friebel, Tara M., Friedman, Eitan, Gabrielson, Marike, Gaddam, Pragna, Gago-Dominguez, Manuela, Gao, Chi, Gapstur, Susan M., Garber, Judy, García-Closas, Montserrat, García-Sáenz, José A., Gaudet, Mia M., Gayther, Simon A., Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., Guénel, Pascal, Gutierrez-Barrera, Angelica M., Haeberle, Lothar, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A., Hein, Alexander, Heyworth, Jane, Hillemanns, Peter, Hollestelle, Antoinette, Hopper, John L., Hosgood, H. Dean, Howell, Anthony, Hu, Chunling, Hulick, Peter J., Hunter, David J., Imyanitov, Evgeny N., Isaacs, Claudine, Jakimovska, Milena, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Janni, Wolfgang, John, Esther M., Jones, Michael E., Jung, Audrey, Kaaks, Rudolf, Karlan, Beth Y., Khusnutdinova, Elza, Kitahara, Cari M., Konstantopoulou, Irene, Koutros, Stella, Kraft, Peter, Lambrechts, Diether, Lazaro, Conxi, Le Marchand, Loic, Lester, Jenny, Lesueur, Fabienne, Lilyquist, Jenna, Loud, Jennifer T., Lu, Karen H., Luben, Robert N., Lubinski, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Maurer, Tabea, Mavroudis, Dimitrios, Mebirouk, Noura, Meindl, Alfons, Menon, Usha, Miller, Austin, Montagna, Marco, Nathanson, Katherine L., Neuhausen, Susan L., Newman, William G., Nguyen-Dumont, Tu, Nielsen, Finn Cilius, Nielsen, Sarah, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olshan, Andrew F., Olson, Janet E., Olsson, Håkan, Osorio, Ana, Ottini, Laura, Peissel, Bernard, Peixoto, Ana, Peto, Julian, Plaseska-Karanfilska, Dijana, Pocza, Timea, Presneau, Nadege, Pujana, Miquel Angel, Punie, Kevin, Rack, Brigitte, Rantala, Johanna, Rashid, Muhammad U., Rau-Murthy, Rohini, Rennert, Gad, Lejbkowicz, Flavio, Rhenius, Valerie, Romero, Atocha, Rookus, Matti A., Ross, Eric A., Rossing, Maria, Rudaitis, Vilius, Ruebner, Matthias, Saloustros, Emmanouil, Sanden, Kristin, Santamariña, Marta, Scheuner, Maren T., Schmutzler, Rita K., Schneider, Michael, Scott, Christopher, Senter, Leigha, Shah, Mitul, Sharma, Priyanka, Shu, Xiao-Ou, Simard, Jacques, Singer, Christian F., Sohn, Christof, Soucy, Penny, Southey, Melissa C., Spinelli, John J., Steele, Linda, Stoppa-Lyonnet, Dominique, Tapper, William J., Teixeira, Manuel R., Terry, Mary Beth, Thomassen, Mads, Thompson, Jennifer, Thull, Darcy L., Tischkowitz, Marc, Tollenaar, Rob A.E.M., Torres, Diana, Troester, Melissa A., Truong, Thérèse, Tung, Nadine, Untch, Michael, Vachon, Celine M., Van Rensburg, Elizabeth J., Van Veen, Elke M., Vega, Ana, Viel, Alessandra, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Wendt, Camilla, Wieme, Greet, Wolk, Alicja, Yang, Xiaohong R., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Dunning, Alison M., Lush, Michael, Wang, Qin, McGuffog, Lesley, Parsons, Michael T., Pharoah, Paul D. P., Fostira, Florentia, Toland, Amanda E., Andrulis, Irene L., Ramus, Susan J., Swerdlow, Anthony J., Greene, Mark H., Chung, Wendy K., Milne, Roger L., Chenevix-Trench, Georgia, Dörk, Thilo, Schmidt, Marjanka K., Easton, Douglas F., Radice, Paolo, Hahnen, Eric, Antoniou, Antonis C., Couch, Fergus J., Nevanlinna, Heli, Surrallés, Jordi, Peterlongo, Paolo, Balleine, Rosemary, Baxter, Robert, Braye, Stephen, Carpenter, Jane, Dahlstrom, Jane, Forbes, John, Lee, C. Soon, Marsh, Deborah, Morey, Adrienne, Pathmanathan, Nirmala, Scott, Rodney, Simpson, Peter, Spigelman, Allan, Wilcken, Nicholas, Yip, Desmond, Zeps, Nikolajs, Belotti, Muriel, Bertrand, Ophélie, Birot, Anne-Marie, Buecher, Bruno, Caputo, Sandrine, Dupré, Anaïs, Fourme, Emmanuelle, Gauthier-Villars, Marion, Golmard, Lisa, Le Mentec, Marine, Moncoutier, Virginie, De Pauw, Antoine, Saule, Claire, Boutry-Kryza, Nadia, Calender, Alain, Giraud, Sophie, Léone, Mélanie, Bressac-De-Paillerets, Brigitte, Caron, Olivier, Guillaud-Bataille, Marine, Bignon, Yves-Jean, Uhrhammer, Nancy, Bonadona, Valérie, Lasset, Christine, Berthet, Pascaline, Castera, Laurent, Vaur, Dominique, Bourdon, Violaine, Noguès, Catherine, Noguchi, Tetsuro, Popovici, Cornel, Remenieras, Audrey, Sobol, Hagay, Coupier, Isabelle, Pujol, Pascal, Adenis, Claude, Dumont, Aurélie, Révillion, Françoise, Muller, Danièle, Barouk-Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Longy, Michel, Sevenet, Nicolas, Gladieff, Laurence, Guimbaud, Rosine, Feillel, Viviane, Toulas, Christine, Dreyfus, Hélène, Leroux, Christine Dominique, Peysselon, Magalie, Rebischung, Christine, Legrand, Clémentine, Baurand, Amandine, Bertolone, Geoffrey, Coron, Fanny, Faivre, Laurence, Jacquot, Caroline, Lizard, Sarab, Kientz, Caroline, Lebrun, Marine, Prieur, Fabienne, Fert-Ferrer, Sandra, Mari, Véronique, Vénat-Bouvet, Laurence, Bézieau, Stéphane, Delnatte, Capucine, Mortemousque, Isabelle, Colas, Chrystelle, Coulet, Florence, Soubrier, Florent, Warcoin, Mathilde, Bronner, Myriam, Sokolowska, Johanna, Collonge-Rame, Marie-Agnès, Damette, Alexandre, Gesta, Paul, Lallaoui, Hakima, Chiesa, Jean, Molina-Gomes, Denise, Ingster, Olivier, Manouvrier-Hanu, Sylvie, Lejeune, Sophie, Aghmesheh, Morteza, Greening, Sian, Amor, David, Gattas, Mike, Botes, Leon, Buckley, Michael, Friedlander, Michael, Koehler, Jessica, Meiser, Bettina, Saleh, Mona, Salisbury, Elizabeth, Trainer, Alison, Tucker, Kathy, Antill, Yoland, Dobrovic, Alexander, Fellows, Andrew, Fox, Stephen, Harris, Marion, Nightingale, Sophie, Phillips, Kelly, Sambrook, Joe, Thorne, Heather, Armitage, Shane, Arnold, Leanne, Kefford, Rick, Kirk, Judy, Rickard, Edwina, Bastick, Patti, Beesley, Jonathan, Hayward, Nick, Spurdle, Amanda, Walker, Logan, Beilby, John, Saunders, Christobel, Bennett, Ian, Blackburn, Anneke, Bogwitz, Michael, Gaff, Clara, Lindeman, Geoff, Pachter, Nick, Scott, Clare, Sexton, Adrienne, Visvader, Jane, Taylor, Jessica, Winship, Ingrid, Brennan, Meagan, Brown, Melissa, French, Juliet, Edwards, Stacey, Burgess, Matthew, Burke, Jo, Patterson, Briony, Butow, Phyllis, Culling, Bronwyn, Caldon, Liz, Callen, David, Chauhan, Deepa, Eisenbruch, Maurice, Heiniger, Louise, Chauhan, Manisha, Christian, Alice, Dixon, Joanne, Kidd, Alexa, Cohen, Paul, Colley, Alison, Fenton, Georgina, Crook, Ashley, Dickson, Rebecca, Field, Michael, Cui, James, Cummings, Margaret, Dawson, Sarah-Jane, DeFazio, Anna, Delatycki, Martin, Dudding, Tracy, Edkins, Ted, Farshid, Gelareh, Flanagan, James, Fong, Peter, Forrest, Laura, Gallego-Ortega, David, George, Peter, Gill, Grantley, Kollias, James, Haan, Eric, Hart, Stewart, Jenkins, Mark, Hunt, Clare, Lakhani, Sunil, Lipton, Lara, Lobb, Liz, Mann, Graham, McLachlan, Sue Anne, O’Connell, Shona, O’Sullivan, Sarah, Pieper, Ellen, Robinson, Bridget, Saunus, Jodi, Scott, Elizabeth, Shelling, Andrew, Williams, Rachael, and Young, Mary Ann
Subjects: 692/4028/67/68, 631/67/68, article, nutritional and metabolic diseases, 631/208/68, skin and connective tissue diseases, 3. Good health
Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

43. RAD51D Aberrant Splicing in Breast Cancer: Identification of Splicing Regulatory Elements and Minigene-Based Evaluation of 53 DNA Variants

Author: Bueno-Martínez, Elena, Sanoguera-Miralles, Lara, Valenzuela-Palomo, Alberto, Lorca, Víctor, Gómez-Sanz, Alicia, Carvalho, Sara, Allen, Jamie, Infante, Mar, Pérez-Segura, Pedro, Lázaro, Conxi, Easton, Douglas F, Devilee, Peter, Vreeswijk, Maaike PG, De La Hoya, Miguel, and Velasco, Eladio A
Subjects: aberrant splicing, breast cancer, ovarian cancer, RAD51D, ESS, minigene, susceptibility genes, ESE, 3. Good health, VUS, clinical interpretation
Abstract: RAD51D loss-of-function variants increase lifetime risk of breast and ovarian cancer. Splicing disruption is a frequent pathogenic mechanism associated with variants in susceptibility genes. Herein, we have assessed the splicing and clinical impact of splice-site and exonic splicing enhancer (ESE) variants identified through the study of ~113,000 women of the BRIDGES cohort. A RAD51D minigene with exons 2-9 was constructed in splicing vector pSAD. Eleven BRIDGES splice-site variants (selected by MaxEntScan) were introduced into the minigene by site-directed mutagenesis and tested in MCF-7 cells. The 11 variants disrupted splicing, collectively generating 25 different aberrant transcripts. All variants but one produced negligible levels (A demonstrated a complete aberrant splicing pattern without the FL transcript. On the other hand, c.214T>C increased efficiency of exon 3 recognition, so only the FL transcript was detected (100%). In conclusion, 41 RAD51D spliceogenic variants (28 of which were from the BRIDGES cohort) were identified by minigene assays. We show that minigene-based mapping of ESEs is a powerful approach for identifying ESE hotspots and ESE-disrupting variants. Finally, we have classified nine variants as likely pathogenic according to ACMG/AMP-based guidelines, highlighting the complex relationship between splicing alterations and variant interpretation.

44. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

Author: Mulligan, Anna, Couch, Fergus, Barrowdale, Daniel, Domchek, Susan, Eccles, Diana, Nevanlinna, Heli, Ramus, Susan, Robson, Mark, Sherman, Mark, Spurdle, Amanda, Wappenschmidt, Barbara, Lee, Andrew, McGuffog, Lesley, Healey, Sue, Sinilnikova, Olga, Janavicius, Ramunas, Hansen, Thomas, Nielsen, Finn, Ejlertsen, Bent, Osorio, Ana, Muñoz-Repeto, Ivan, Duran, Mercedes, Godino, Javier, Pertesi, Maroulio, Benítez, Javier, Peterlongo, Paolo, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Cattaneo, Elisa, Bonanni, Bernardo, Viel, Alessandra, Pasini, Barbara, Papi, Laura, Ottini, Laura, Savarese, Antonella, Bernard, Loris, Radice, Paolo, Hamann, Ute, Verheus, Martijn, Meijers-Heijboer, Hanne, Wijnen, Juul, Gómez García, Encarna, Nelen, Marcel, Kets, C Marleen, Seynaeve, Caroline, Tilanus-Linthorst, Madeleine, Van Der Luijt, Rob, Os, Theo, Rookus, Matti, Frost, Debra, Jones, J. Louise, Evans, D. Gareth, Lalloo, Fiona, Eeles, Ros, Izatt, Louise, Adlard, Julian, Davidson, Rosemarie, Cook, Jackie, Donaldson, Alan, Dorkins, Huw, Gregory, Helen, Eason, Jacqueline, Houghton, Catherine, Barwell, Julian, Side, Lucy, McCann, Emma, Murray, Alex, Peock, Susan, Godwin, Andrew, Schmutzler, Rita, Rhiem, Kerstin, Engel, Christoph, Meindl, Alfons, Ruehl, Ina, Arnold, Norbert, Niederacher, Dieter, Sutter, Christian, Deissler, Helmut, Gadzicki, Dorothea, Kast, Karin, Preisler-Adams, Sabine, Varon-Mateeva, Raymonda, Schoenbuchner, Ines, Fiebig, Britta, Heinritz, Wolfram, Schäfer, Dieter, Gevensleben, Heidrun, Caux-Moncoutier, Virginie, Fassy-Colcombet, Marion, Cornelis, François, Mazoyer, Sylvie, Léoné, Mélanie, Boutry-Kryza, Nadia, Hardouin, Agnès, Berthet, Pascaline, Muller, Danièle, Fricker, Jean-Pierre, Mortemousque, Isabelle, Pujol, Pascal, Coupier, Isabelle, Lebrun, Marine, Kientz, Caroline, Longy, Michel, Sevenet, Nicolas, Stoppa-Lyonnet, Dominique, Isaacs, Claudine, Caldes, Trinidad, De La Hoya, Miguel, Heikkinen, Tuomas, Aittomäki, Kristiina, Blanco, Ignacio, Lazaro, Conxi, Barkardottir, Rosa, Soucy, Penny, Dumont, Martine, Simard, Jacques, Montagna, Marco, Tognazzo, Silvia, D'Andrea, Emma, Fox, Stephen, Yan, Max, Rebbeck, Tim, Olopade, Olufunmilayo, Weitzel, Jeffrey, Lynch, Henry, Ganz, Patricia, Tomlinson, Gail, Wang, Xianshu, Fredericksen, Zachary, Pankratz, Vernon, Lindor, Noralane, Szabo, Csilla, Offit, Kenneth, Sakr, Rita, Gaudet, Mia, Bhatia, Jasmine, Kauff, Noah, Singer, Christian, Tea, Muy-Kheng, Gschwantler-Kaulich, Daphne, Fink-Retter, Anneliese, Mai, Phuong, Greene, Mark, Imyanitov, Evgeny, O'Malley, Frances, Ozcelik, Hilmi, Glendon, Gordon, Toland, Amanda, Gerdes, Anne-Marie, Thomassen, Mads, Kruse, Torben, Jensen, Uffe, Skytte, Anne-Bine, Caligo, Maria, Soller, Maria, Henriksson, Karin, Wachenfeldt, Von Anna, Arver, Brita, Stenmark-Askmalm, Marie, Karlsson, Per, Ding, Yuan, Neuhausen, Susan, Beattie, Mary, Pharoah, Paul, Moysich, Kirsten, Nathanson, Katherine, Karlan, Beth, Gross, Jenny, John, Esther, Daly, Mary, Buys, Saundra, Southey, Melissa, Hopper, John, Terry, Mary Beth, Chung, Wendy K., Miron, Alexander, Goldgar, David, Chenevix-Trench, Georgia, Easton, Douglas, Andrulis, Irene, and Antoniou, Antonis
Subjects: endocrine system diseases, Molecular biology, Breast--Cancer, FOS: Biological sciences, Genetics, Mutation (Biology), skin and connective tissue diseases, 3. Good health
Abstract: Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

45. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author: Barnes, Daniel R., Rookus, Matti A., McGuffog, Lesley, Leslie, Goska, Mooij, Thea M., Dennis, Joe, Mavaddat, Nasim, Adlard, Julian, Ahmed, Munaza, Aittomäki, Kristiina, Andrieu, Nadine, Andrulis, Irene L., Arnold, Norbert, Arun, Banu K., Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B., Barrowdale, Daniel, Benitez, Javier, Berthet, Pascaline, Białkowska, Katarzyna, Blanco, Amie M., Blok, Marinus J., Bonanni, Bernardo, Boonen, Susanne E., Borg, Åke, Bozsik, Aniko, Bradbury, Angela R., Brennan, Paul, Brewer, Carole, Brunet, Joan, Buys, Saundra S., Caldés, Trinidad, Caligo, Maria A., Campbell, Ian, Christensen, Lise Lotte, Chung, Wendy K., Claes, Kathleen B. M., Colas, Chrystelle, Collonge-Rame, Marie-Agnès, Cook, Jackie, Daly, Mary B., Davidson, Rosemarie, De La Hoya, Miguel, De Putter, Robin, Delnatte, Capucine, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M., Dorfling, Cecilia M., Dumont, Martine, Eeles, Ros, Ejlertsen, Bent, Engel, Christoph, Evans, D. Gareth, Faivre, Laurence, Foretova, Lenka, Fostira, Florentia, Friedlander, Michael, Friedman, Eitan, Frost, Debra, Ganz, Patricia A., Garber, Judy, Gehrig, Andrea, Gerdes, Anne-Marie, Gesta, Paul, Giraud, Sophie, Glendon, Gord, Godwin, Andrew K., Goldgar, David E., González-Neira, Anna, Greene, Mark H., Gschwantler-Kaulich, Daphne, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hentschel, Julia, Hogervorst, Frans B. L., Hooning, Maartje J., Horvath, Judit, Hu, Chunling, Hulick, Peter J., Imyanitov, Evgeny N., Isaacs, Claudine, Izatt, Louise, Izquierdo, Angel, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, John, Esther M., Joseph, Vijai, Karlan, Beth Y., Kast, Karin, Koudijs, Marco, Kruse, Torben A., Kwong, Ava, Laitman, Yael, Lasset, Christine, Lazaro, Conxi, Lester, Jenny, Lesueur, Fabienne, Liljegren, Annelie, Loud, Jennifer T., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Mari, Véronique, Mebirouk, Noura, Meijers-Heijboer, Hanne E. J., Meindl, Alfons, Mensenkamp, Arjen R., Miller, Austin, Montagna, Marco, Mouret-Fourme, Emmanuelle, Mukherjee, Semanti, Mulligan, Anna Marie, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Niederacher, Dieter, Nielsen, Finn Cilius, Nikitina-Zake, Liene, Noguès, Catherine, Olah, Edith, Olopade, Olufunmilayo I., Ong, Kai-Ren, O’Shaughnessy-Kirwan, Aoife, Osorio, Ana, Ott, Claus-Eric, Papi, Laura, Park, Sue K., Parsons, Michael T., Pedersen, Inge Sokilde, Peissel, Bernard, Peixoto, Ana, Peterlongo, Paolo, Pfeiler, Georg, Phillips, Kelly-Anne, Prajzendanc, Karolina, Pujana, Miquel Angel, Radice, Paolo, Ramser, Juliane, Ramus, Susan J., Rantala, Johanna, Rennert, Gad, Risch, Harvey A., Robson, Mark, Rønlund, Karina, Salani, Ritu, Schuster, Hélène, Senter, Leigha, Shah, Payal D., Sharma, Priyanka, Side, Lucy E., Singer, Christian F., Slavin, Thomas P., Soucy, Penny, Southey, Melissa C., Spurdle, Amanda B., Steinemann, Doris, Steinsnyder, Zoe, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Thull, Darcy L., Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E., Trainer, Alison H., Tung, Nadine, Van Engelen, Klaartje, Van Rensburg, Elizabeth J., Vega, Ana, Vierstraete, Jeroen, Wagner, Gabriel, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Yadav, Siddhartha, Yang, Xin, Yannoukakos, Drakoulis, Zimbalatti, Dario, Offit, Kenneth, Thomassen, Mads, Couch, Fergus J., Schmutzler, Rita K., Simard, Jacques, Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., Antoniou, Antonis, Easton, Douglas, Side, Lucy, Spurdle, Amanda, Blok, Marinus, Hogervorst, Frans, Hooning, Maartje, Mensenkamp, Arjen, Meijers-Heijboer, Hanne, Rookus, Matti, and Engelen, Klaartje Van
Subjects: breast cancer, ovarian cancer, endocrine system diseases, BRCA1/2, article, genetics, PRS, 3. Good health
Abstract: Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)–negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25–1.33], P = 3×10−72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27–1.36], P = 7×10−50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25–1.40], P = 3×10−22) and BRCA2 (HR = 1.44 [95% CI 1.30–1.60], P = 4×10−12) carriers. The associations in the prospective cohort were similar. Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

46. RAD51D Aberrant Splicing in Breast Cancer: Identification of Splicing Regulatory Elements and Minigene-Based Evaluation of 53 DNA Variants

Author: Bueno-Martínez, Elena, Sanoguera-Miralles, Lara, Valenzuela-Palomo, Alberto, Lorca, Víctor, Gómez-Sanz, Alicia, Carvalho, Sara, Allen, Jamie, Infante, Mar, Pérez-Segura, Pedro, Lázaro, Conxi, Easton, Douglas F., Devilee, Peter, Vreeswijk, Maaike P. G., De La Hoya, Miguel, and Velasco, Eladio A.
Subjects: aberrant splicing, breast cancer, ovarian cancer, RAD51D, ESS, susceptibility genes, minigene, ESE, 3. Good health, VUS, clinical interpretation
Abstract: RAD51D loss-of-function variants increase lifetime risk of breast and ovarian cancer. Splicing disruption is a frequent pathogenic mechanism associated with variants in susceptibility genes. Herein, we have assessed the splicing and clinical impact of splice-site and exonic splicing enhancer (ESE) variants identified through the study of ~113,000 women of the BRIDGES cohort. A RAD51D minigene with exons 2–9 was constructed in splicing vector pSAD. Eleven BRIDGES splice-site variants (selected by MaxEntScan) were introduced into the minigene by site-directed mutagenesis and tested in MCF-7 cells. The 11 variants disrupted splicing, collectively generating 25 different aberrant transcripts. All variants but one produced negligible levels (3.4%) of the full-length (FL) transcript. In addition, ESE elements of the alternative exon 3 were mapped by testing four overlapping exonic microdeletions (≥30-bp), revealing an ESE-rich interval (c.202_235del) with critical sequences for exon 3 recognition that might have been affected by germline variants. Next, 26 BRIDGES variants and 16 artificial exon 3 single-nucleotide substitutions were also assayed. Thirty variants impaired splicing with variable amounts (0–65.1%) of the FL transcript, although only c.202G>A demonstrated a complete aberrant splicing pattern without the FL transcript. On the other hand, c.214T>C increased efficiency of exon 3 recognition, so only the FL transcript was detected (100%). In conclusion, 41 RAD51D spliceogenic variants (28 of which were from the BRIDGES cohort) were identified by minigene assays. We show that minigene-based mapping of ESEs is a powerful approach for identifying ESE hotspots and ESE-disrupting variants. Finally, we have classified nine variants as likely pathogenic according to ACMG/AMP-based guidelines, highlighting the complex relationship between splicing alterations and variant interpretation.

47. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

Author: Antoniou, Antonis, Kuchenbaecker, Karoline, Soucy, Penny, Beesley, Jonathan, Chen, Xiaoqing, McGuffog, Lesley, Lee, Andrew, Barrowdale, Daniel, Healey, Sue, Sinilnikova, Olga, Caligo, Maria, Loman, Niklas, Harbst, Katja, Lindblom, Annika, Arver, Brita, Rosenquist, Richard, Karlsson, Per, Nathanson, Kate, Domchek, Susan, Rebbeck, Tim, Jakubowska, Anna, Lubinski, Jan, Jaworska, Katarzyna, Durda, Katarzyna, Złowowcka-Perłowska, Elżbieta, Osorio, Ana, Durán, Mercedes, Andrés, Raquel, Benítez, Javier, Hamann, Ute, Hogervorst, Frans, Van Os, Theo, Verhoef, Senno, Meijers-Heijboer, Hanne, Wijnen, Juul, Gómez Garcia, Encarna, Ligtenberg, Marjolijn, Kriege, Mieke, Collée, J. Margriet, Ausems, Margreet, Oosterwijk, Jan, Peock, Susan, Frost, Debra, Ellis, Steve, Platte, Radka, Fineberg, Elena, Evans, D. Gareth, Lalloo, Fiona, Jacobs, Chris, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Cook, Jackie, Paterson, Joan, Douglas, Fiona, Brewer, Carole, Hodgson, Shirley, Morrison, Patrick, Walker, Lisa, Rogers, Mark, Donaldson, Alan, Dorkins, Huw, Godwin, Andrew, Bove, Betsy, Stoppa-Lyonnet, Dominique, Houdayer, Claude, Buecher, Bruno, De Pauw, Antoine, Mazoyer, Sylvie, Calender, Alain, Léoné, Mélanie, Bressac-De Paillerets, Brigitte, Caron, Olivier, Sobol, Hagay, Frenay, Marc, Prieur, Fabienne, Ferrer, Sandra, Mortemousque, Isabelle, Buys, Saundra, Daly, Mary, Miron, Alexander, Terry, Mary Beth, Hopper, John, John, Esther, Southey, Melissa, Goldgar, David, Singer, Christian, Fink-Retter, Anneliese, Tea, Muy-Kheng, Kaulich, Daphne, Hansen, Thomas, Nielsen, Finn, Barkardottir, Rosa, Gaudet, Mia, Kirchhoff, Tomas, Joseph, Vijai, Dutra-Clarke, Ana, Offit, Kenneth, Piedmonte, Marion, Kirk, Judy, Cohn, David, Hurteau, Jean, Byron, John, Fiorica, James, Toland, Amanda, Montagna, Marco, Oliani, Cristina, Imyanitov, Evgeny, Isaacs, Claudine, Tihomirova, Laima, Blanco, Ignacio, Lazaro, Conxi, Teulé, Alex, Valle, J. Del, Gayther, Simon, Odunsi, Kunle, Gross, Jenny, Karlan, Beth, Olah, Edith, Teo, Soo-Hwang, Ganz, Patricia, Beattie, Mary, Dorfling, Cecelia, Van Rensburg, Elizabeth, Diez, Orland, Kwong, Ava, Schmutzler, Rita, Wappenschmidt, Barbara, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Heidemann, Simone, Niederacher, Dieter, Preisler-Adams, Sabine, Gadzicki, Dorothea, Varon-Mateeva, Raymonda, Deissler, Helmut, Gehrig, Andrea, Sutter, Christian, Kast, Karin, Fiebig, Britta, Schäfer, Dieter, Caldes, Trinidad, De La Hoya, Miguel, Nevanlinna, Heli, Muranen, Taru, Lespérance, Bernard, Spurdle, Amanda, Neuhausen, Susan, Ding, Yuan, Wang, Xianshu, Fredericksen, Zachary, Pankratz, Vernon, Lindor, Noralane, Peterlongo, Paolo, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Bonanni, Bernardo, Bernard, Loris, Dolcetti, Riccardo, Papi, Laura, Ottini, Laura, Radice, Paolo, Greene, Mark, Loud, Jennifer, Andrulis, Irene, Ozcelik, Hilmi, Mulligan, Anna, Glendon, Gord, Thomassen, Mads, Gerdes, Anne-Marie, Jensen, Uffe, Skytte, Anne-Bine, Kruse, Torben, Chenevix-Trench, Georgia, Couch, Fergus, Simard, Jacques, and Easton, Douglas
Subjects: FOS: Biological sciences, Genetics, skin and connective tissue diseases, 3. Good health
Abstract: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

48. Towards controlled terminology for reporting germline cancer susceptibility variants: an ENIGMA report

Author: Spurdle, Amanda B, Greville-Heygate, Stephanie, Antoniou, Antonis C, Brown, Melissa, Burke, Leslie, De La Hoya, Miguel, Domchek, Susan, Dörk, Thilo, Firth, Helen V, Monteiro, Alvaro N, Mensenkamp, Arjen, Parsons, Michael T, Radice, Paolo, Robson, Mark, Tischkowitz, Marc, Tudini, Emma, Turnbull, Clare, Vreeswijk, Maaike Pg, Walker, Logan C, Tavtigian, Sean, and Eccles, Diana M
Subjects: genetic variant, reporting, Gene Expression Profiling, Genes, BRCA2, Genes, BRCA1, Computational Biology, Genetic Variation, High-Throughput Nucleotide Sequencing, Neoplasms, Germ Cell and Embryonal, cancer susceptibility, 3. Good health, Vocabulary, Controlled, International Classification of Diseases, Terminology as Topic, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, interpretation, Germ-Line Mutation, vocabulary
Abstract: The vocabulary currently used to describe genetic variants and their consequences reflects many years of studying and discovering monogenic disease with high penetrance. With the recent rapid expansion of genetic testing brought about by wide availability of high-throughput massively parallel sequencing platforms, accurate variant interpretation has become a major issue. The vocabulary used to describe single genetic variants in silico, in vitro, in vivo and as a contributor to human disease uses terms in common, but the meaning is not necessarily shared across all these contexts. In the setting of cancer genetic tests, the added dimension of using data from genetic sequencing of tumour DNA to direct treatment is an additional source of confusion to those who are not experienced in cancer genetics. The language used to describe variants identified in cancer susceptibility genetic testing typically still reflects an outdated paradigm of Mendelian inheritance with dichotomous outcomes. Cancer is a common disease with complex genetic architecture; an improved lexicon is required to better communicate among scientists, clinicians and patients, the risks and implications of genetic variants detected. This review arises from a recognition of, and discussion about, inconsistencies in vocabulary usage by members of the ENIGMA international multidisciplinary consortium focused on variant classification in breast-ovarian cancer susceptibility genes. It sets out the vocabulary commonly used in genetic variant interpretation and reporting, and suggests a framework for a common vocabulary that may facilitate understanding and clarity in clinical reporting of germline genetic tests for cancer susceptibility.

49. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author: Barnes, Daniel R., Rookus, Matti A., McGuffog, Lesley, Leslie, Goska, Mooij, Thea M., Dennis, Joe, Mavaddat, Nasim, Adlard, Julian, Ahmed, Munaza, Aittomäki, Kristiina, Andrieu, Nadine, Andrulis, Irene L., Arnold, Norbert, Arun, Banu K., Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B., Barrowdale, Daniel, Benitez, Javier, Berthet, Pascaline, Białkowska, Katarzyna, Blanco, Amie M., Blok, Marinus J., Bonanni, Bernardo, Boonen, Susanne E., Borg, Åke, Bozsik, Aniko, Bradbury, Angela R., Brennan, Paul, Brewer, Carole, Brunet, Joan, Buys, Saundra S., Caldés, Trinidad, Caligo, Maria A., Campbell, Ian, Christensen, Lise Lotte, Chung, Wendy K., Claes, Kathleen B. M., Colas, Chrystelle, Collonge-Rame, Marie-Agnès, Cook, Jackie, Daly, Mary B., Davidson, Rosemarie, De La Hoya, Miguel, De Putter, Robin, Delnatte, Capucine, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M., Dorfling, Cecilia M., Dumont, Martine, Eeles, Ros, Ejlertsen, Bent, Engel, Christoph, Evans, D. Gareth, Faivre, Laurence, Foretova, Lenka, Fostira, Florentia, Friedlander, Michael, Friedman, Eitan, Frost, Debra, Ganz, Patricia A., Garber, Judy, Gehrig, Andrea, Gerdes, Anne-Marie, Gesta, Paul, Giraud, Sophie, Glendon, Gord, Godwin, Andrew K., Goldgar, David E., González-Neira, Anna, Greene, Mark H., Gschwantler-Kaulich, Daphne, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hentschel, Julia, Hogervorst, Frans B. L., Hooning, Maartje J., Horvath, Judit, Hu, Chunling, Hulick, Peter J., Imyanitov, Evgeny N., Isaacs, Claudine, Izatt, Louise, Izquierdo, Angel, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, John, Esther M., Joseph, Vijai, Karlan, Beth Y., Kast, Karin, Koudijs, Marco, Kruse, Torben A., Kwong, Ava, Laitman, Yael, Lasset, Christine, Lazaro, Conxi, Lester, Jenny, Lesueur, Fabienne, Liljegren, Annelie, Loud, Jennifer T., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Mari, Véronique, Mebirouk, Noura, Meijers-Heijboer, Hanne E. J., Meindl, Alfons, Mensenkamp, Arjen R., Miller, Austin, Montagna, Marco, Mouret-Fourme, Emmanuelle, Mukherjee, Semanti, Mulligan, Anna Marie, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Niederacher, Dieter, Nielsen, Finn Cilius, Nikitina-Zake, Liene, Noguès, Catherine, Olah, Edith, Olopade, Olufunmilayo I., Ong, Kai-Ren, O’Shaughnessy-Kirwan, Aoife, Osorio, Ana, Ott, Claus-Eric, Papi, Laura, Park, Sue K., Parsons, Michael T., Pedersen, Inge Sokilde, Peissel, Bernard, Peixoto, Ana, Peterlongo, Paolo, Pfeiler, Georg, Phillips, Kelly-Anne, Prajzendanc, Karolina, Pujana, Miquel Angel, Radice, Paolo, Ramser, Juliane, Ramus, Susan J., Rantala, Johanna, Rennert, Gad, Risch, Harvey A., Robson, Mark, Rønlund, Karina, Salani, Ritu, Schuster, Hélène, Senter, Leigha, Shah, Payal D., Sharma, Priyanka, Side, Lucy E., Singer, Christian F., Slavin, Thomas P., Soucy, Penny, Southey, Melissa C., Spurdle, Amanda B., Steinemann, Doris, Steinsnyder, Zoe, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Thull, Darcy L., Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E., Trainer, Alison H., Tung, Nadine, Van Engelen, Klaartje, Van Rensburg, Elizabeth J., Vega, Ana, Vierstraete, Jeroen, Wagner, Gabriel, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Yadav, Siddhartha, Yang, Xin, Yannoukakos, Drakoulis, Zimbalatti, Dario, Offit, Kenneth, Thomassen, Mads, Couch, Fergus J., Schmutzler, Rita K., Simard, Jacques, Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., Antoniou, Antonis, Easton, Douglas, Side, Lucy, Spurdle, Amanda, Blok, Marinus, Hogervorst, Frans, Hooning, Maartje, Mensenkamp, Arjen, Meijers-Heijboer, Hanne, Rookus, Matti, and Engelen, Klaartje Van
Subjects: breast cancer, ovarian cancer, endocrine system diseases, BRCA1/2, article, genetics, PRS, 3. Good health
Abstract: Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)–negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25–1.33], P = 3×10−72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27–1.36], P = 7×10−50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25–1.40], P = 3×10−22) and BRCA2 (HR = 1.44 [95% CI 1.30–1.60], P = 4×10−12) carriers. The associations in the prospective cohort were similar. Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

50. The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Author: Figlioli, Gisella, Bogliolo, Massimo, Catucci, Irene, Caleca, Laura, Lasheras, Sandra Viz, Pujol, Roser, Kiiski, Johanna I, Muranen, Taru A, Barnes, Daniel R, Dennis, Joe, Michailidou, Kyriaki, Bolla, Manjeet K, Leslie, Goska, Aalfs, Cora M, ABCTB Investigators, Adank, Muriel A, Adlard, Julian, Agata, Simona, Cadoo, Karen, Agnarsson, Bjarni A, Ahearn, Thomas, Aittomäki, Kristiina, Ambrosone, Christine B, Andrews, Lesley, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J, Arun, Banu K, Asseryanis, Ella, Auber, Bernd, Auvinen, Päivi, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Barwell, Julian, Beane Freeman, Laura E, Beauparlant, Charles Joly, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Berger, Raanan, Bermisheva, Marina, Blanco, Amie M, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Anders, Bojesen, Stig E, Bonanni, Bernardo, Borg, Ake, Brady, Angela F, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Caldés, Trinidad, Caliebe, Almuth, Caligo, Maria A, Campa, Daniele, Campbell, Ian G, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Claes, Kathleen BM, Clarke, Christine L, Collavoli, Anita, Conner, Thomas A, Cox, David G, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, De La Hoya, Miguel, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Dite, Gillian S, Ditsch, Nina, Domchek, Susan M, Dorfling, Cecilia M, Dos-Santos-Silva, Isabel, Durda, Katarzyna, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Ellberg, Carolina, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Foulkes, William D, Friebel, Tara M, Friedman, Eitan, Gabrielson, Marike, Gaddam, Pragna, Gago-Dominguez, Manuela, Gao, Chi, Gapstur, Susan M, Garber, Judy, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Gayther, Simon A, GEMO Study Collaborators, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, Guénel, Pascal, Gutierrez-Barrera, Angelica M, Haeberle, Lothar, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hein, Alexander, Heyworth, Jane, Hillemanns, Peter, Hollestelle, Antoinette, Hopper, John L, Hosgood, H Dean, Howell, Anthony, Hu, Chunling, Hulick, Peter J, Hunter, David J, Imyanitov, Evgeny N, KConFab, Isaacs, Claudine, Jakimovska, Milena, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Janni, Wolfgang, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Karlan, Beth Y, Khusnutdinova, Elza, Kitahara, Cari M, Konstantopoulou, Irene, Koutros, Stella, Kraft, Peter, Lambrechts, Diether, Lazaro, Conxi, Le Marchand, Loic, Lester, Jenny, Lesueur, Fabienne, Lilyquist, Jenna, Loud, Jennifer T, Lu, Karen H, Luben, Robert N, Lubinski, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martens, John WM, Maurer, Tabea, Mavroudis, Dimitrios, Mebirouk, Noura, Meindl, Alfons, Menon, Usha, Miller, Austin, Montagna, Marco, Nathanson, Katherine L, Neuhausen, Susan L, Newman, William G, Nguyen-Dumont, Tu, Nielsen, Finn Cilius, Nielsen, Sarah, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olshan, Andrew F, Olson, Janet E, Olsson, Håkan, Osorio, Ana, Ottini, Laura, Peissel, Bernard, Peixoto, Ana, Peto, Julian, Plaseska-Karanfilska, Dijana, Pocza, Timea, Presneau, Nadege, Pujana, Miquel Angel, Punie, Kevin, Rack, Brigitte, Rantala, Johanna, Rashid, Muhammad U, Rau-Murthy, Rohini, Rennert, Gad, Lejbkowicz, Flavio, Rhenius, Valerie, Romero, Atocha, Rookus, Matti A, Ross, Eric A, Rossing, Maria, Rudaitis, Vilius, Ruebner, Matthias, Saloustros, Emmanouil, Sanden, Kristin, Santamariña, Marta, Scheuner, Maren T, Schmutzler, Rita K, Schneider, Michael, Scott, Christopher, Senter, Leigha, Shah, Mitul, Sharma, Priyanka, Shu, Xiao-Ou, Simard, Jacques, Singer, Christian F, Sohn, Christof, Soucy, Penny, Southey, Melissa C, Spinelli, John J, Steele, Linda, Stoppa-Lyonnet, Dominique, Tapper, William J, Teixeira, Manuel R, Terry, Mary Beth, Thomassen, Mads, Thompson, Jennifer, Thull, Darcy L, Tischkowitz, Marc, Tollenaar, Rob AEM, Torres, Diana, Troester, Melissa A, Truong, Thérèse, Tung, Nadine, Untch, Michael, Vachon, Celine M, Van Rensburg, Elizabeth J, Van Veen, Elke M, Vega, Ana, Viel, Alessandra, Wappenschmidt, Barbara, Weitzel, Jeffrey N, Wendt, Camilla, Wieme, Greet, Wolk, Alicja, Yang, Xiaohong R, Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K, Dunning, Alison M, Lush, Michael, Wang, Qin, McGuffog, Lesley, Parsons, Michael T, Pharoah, Paul DP, Fostira, Florentia, Toland, Amanda E, Andrulis, Irene L, Ramus, Susan J, Swerdlow, Anthony J, Greene, Mark H, Chung, Wendy K, Milne, Roger L, Chenevix-Trench, Georgia, Dörk, Thilo, Schmidt, Marjanka K, Easton, Douglas F, Radice, Paolo, Hahnen, Eric, Antoniou, Antonis C, Couch, Fergus J, Nevanlinna, Heli, Surrallés, Jordi, and Peterlongo, Paolo
Subjects: nutritional and metabolic diseases, skin and connective tissue diseases, Cancer genetics, 3. Good health
Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

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