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1. Additional file 1 of A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome

Author

Walker, Romy, Mahmood, Khalid, Joo, Jihoon E., Clendenning, Mark, Georgeson, Peter, Como, Julia, Joseland, Sharelle, Preston, Susan G., Antill, Yoland, Austin, Rachel, Boussioutas, Alex, Bowman, Michelle, Burke, Jo, Campbell, Ainsley, Daneshvar, Simin, Edwards, Emma, Gleeson, Margaret, Goodwin, Annabel, Harris, Marion T., Henderson, Alex, Higgins, Megan, Hopper, John L., Hutchinson, Ryan A., Ip, Emilia, Isbister, Joanne, Kasem, Kais, Marfan, Helen, Milnes, Di, Ng, Annabelle, Nichols, Cassandra, O’Connell, Shona, Pachter, Nicholas, Pope, Bernard J., Poplawski, Nicola, Ragunathan, Abiramy, Smyth, Courtney, Spigelman, Allan, Storey, Kirsty, Susman, Rachel, Taylor, Jessica A., Warwick, Linda, Wilding, Mathilda, Williams, Rachel, Win, Aung K., Walsh, Michael D., Macrae, Finlay A., Jenkins, Mark A., Rosty, Christophe, Winship, Ingrid M., and Buchanan, Daniel D.

Abstract

Additional file 1: Table S1. Table displaying optimal cut-offs for the six tumor features determined previously (Walker et al. 2023) in the additive feature combination approach. Table S2. SLS tumors (n=13) that showed discordant MMR IHC findings between clinical diagnostic testing before study entry and testing completed internally during this study and the change in their MMR status and/or pattern of MMR protein loss. Table S3. The concordance between the final MMR IHC result and the predicted dMMR status from the additive feature combination approach overall and by tumor type. Table S4. The tumor MLH1 methylation testing completed for SLS tumors prior to entering the study showing either negative, inconclusive, or not tested results and the subsequent MLH1 methylation testing results from internal testing using MethyLight and MS-HRM assays highlighting the positive MLH1 methylation results found by this study. Table S5. Presentation of germline pathogenic variants and variants of uncertain clinical significance (VUS) identified in the MMR, MUTYH and POLE genes. Table S6. Summary of the clinicopathological features for the double somatic MMR mutation (dMMR-DS) tumors overall and by tumor type. Figure S1. Bar plots presenting the results from the additive tumor feature combination approach to assess the MMR status in the double somatic mutation cohort for A) all tumors combined and separated by B) CRC, C) EC and D) SST tissue types. Figure S2. Bar plot presenting the prevalence of pathogenic/likely pathogenic somatic mutations (including loss of heterozygosity, LOH) by subtype for the study cohort. Figure S3. Pie graphs displaying the frequency of the mutation combination type (two single somatic mutations versus a single somatic mutation with loss of heterozygosity (LOH)) as well as the type of mutation A) overall and B) separated by tissue type. Figure S4. Bar graphs presenting the site distribution in the double somatic mutation cohort across all CRCs and SSTs. Figure S5. Boxplots presenting the site distribution in the double somatic mutation cohort across all A) CRCs and B) SSTs. Significant (< 0.05) p-values are indicated for pairwise (t-test) and multigroup comparisons (Anova). Figure S6. Scatter plots presenting the PREMM5 score distribution in the test cohort for A) all tumors combined and separated by B) CRC, C) EC and D) SST tissue types. Figure S7. The distribution of tumor values for each of the six features that are included in the additive feature combination approach for determining tumor dMMR status grouped by molecular subtype and by combining sporadic dMMR groups dMMR-DS and dMMR-MLH1me into a “sporadic combined” group.

Published
2023
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2. CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Author

Johnson, Nichola, Maguire, Sarah, Morra, Anna, Kapoor, Pooja Middha, Tomczyk, Katarzyna, Jones, Michael E., Schoemaker, Minouk J., Gilham, Clare, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Ahearn, Thomas U., Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Arndt, Volker, Aronson, Kristan J., Augustinsson, Annelie, Baynes, Caroline, Freeman, Laura E. Beane, Beckmann, Matthias W., Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V., Bojesen, Stig E., Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E., Chanock, Stephen J., Chenevix-Trench, Georgia, Clarke, Christine L., Conroy, Don M., Couch, Fergus J., Cox, Angela, Cross, Simon S., Czene, Kamila, Dörk, Thilo, Eliassen, A. Heather, Engel, Christoph, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Floris, Giuseppe, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M., García-Closas, Montserrat, Gaudet, Mia M., Giles, Graham G., Goldberg, Mark S., González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A., Hart, Steven N., Hooning, Maartje J., Hopper, John L., Howell, Anthony, Hunter, David J., Jager, Agnes, Jakubowska, Anna, John, Esther M., Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M., Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N., Kurian, Allison W., Lambrechts, Diether, Le Marchand, Loic, Linet, Martha, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Mavroudis, Dimitrios, Mayes, Rebecca, Meindl, Alfons, Milne, Roger L., Neuhausen, Susan L., Nevanlinna, Heli, Newman, William G., Nielsen, Sune F., Nordestgaard, Børge G., Obi, Nadia, Olshan, Andrew F., Olson, Janet E., Olsson, Håkan, Orban, Ester, Park-Simon, Tjoung-Won, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Rennert, Gad, Rennert, Hedy S., Ruddy, Kathryn J., Saloustros, Emmanouil, Sandler, Dale P., Sawyer, Elinor J., Schmutzler, Rita K., Scott, Christopher, Shu, Xiao-Ou, Simard, Jacques, Smichkoska, Snezhana, Sohn, Christof, Southey, Melissa C., Spinelli, John J., Stone, Jennifer, Tamimi, Rulla M., Taylor, Jack A., Tollenaar, Rob A. E. M., Tomlinson, Ian, Troester, Melissa A., Truong, Thérèse, Vachon, Celine M., van Veen, Elke M., Wang, Sophia S., Weinberg, Clarice R., Wendt, Camilla, Wildiers, Hans, Winqvist, Robert, Wolk, Alicja, Zheng, Wei, Ziogas, Argyrios, Dunning, Alison M., Pharoah, Paul D. P., Easton, Douglas F., Howie, A. Forbes, Peto, Julian, dos-Santos-Silva, Isabel, Swerdlow, Anthony J., Chang-Claude, Jenny, Schmidt, Marjanka K., Orr, Nick, Fletcher, Olivia, Børresen-Dale, Anne-Lise, Alnæs, Grethe I. Grenaker, Sahlberg, Kristine K., Ottestad, Lars, Kåresen, Rolf, Schlichting, Ellen, Holmen, Marit Muri, Sauer, Toril, Haakensen, Vilde, Engebråten, Olav, Naume, Bjørn, Fosså, Alexander, Kiserud, Cecile E., Reinertsen, Kristin V., Helland, Åslaug, Riis, Margit, Geisler, Jürgen, Bowtell, David D. L., deFazio, Anna, Webb, Penelope M., Clarke, Christine, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Carpenter, Jane, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Graham, Dinny, Sachchithananthan, Mythily, Amor, David, Andrews, Lesley, Antill, Yoland, Balleine, Rosemary, Beesley, Jonathan, Bennett, Ian, Bogwitz, Michael, Botes, Leon, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burke, Jo, Butow, Phyllis, Caldon, Liz, Campbell, Ian, Chauhan, Deepa, Chauhan, Manisha, Christian, Alice, Cohen, Paul, Colley, Alison, Crook, Ashley, Cui, James, Cummings, Margaret, Dawson, Sarah-Jane, DeFazio, Anna, Delatycki, Martin, Dickson, Rebecca, Dixon, Joanne, Edkins, Ted, Edwards, Stacey, Farshid, Gelareh, Fellows, Andrew, Fenton, Georgina, Field, Michael, Flanagan, James, Fong, Peter, Forrest, Laura, Fox, Stephen, French, Juliet, Friedlander, Michael, Gaff, Clara, Gattas, Mike, George, Peter, Greening, Sian, Harris, Marion, Hart, Stewart, Hayward, Nick, Hopper, John, Hoskins, Cass, Hunt, Clare, James, Paul, Jenkins, Mark, Kidd, Alexa, Kirk, Judy, Koehler, Jessica, Kollias, James, Lakhani, Sunil, Lawrence, Mitchell, Lindeman, Geoff, Lipton, Lara, Lobb, Liz, Mann, Graham, McLachlan, Sue Anne, Meiser, Bettina, Milne, Roger, Nightingale, Sophie, O’Connell, Shona, O’Sullivan, Sarah, Ortega, David Gallego, Pachter, Nick, Patterson, Briony, Pearn, Amy, Phillips, Kelly, Pieper, Ellen, Rickard, Edwina, Robinson, Bridget, Saleh, Mona, Salisbury, Elizabeth, Saunders, Christobel, Saunus, Jodi, Scott, Clare, Sexton, Adrienne, Shelling, Andrew, Southey, Melissa, Spurdle, Amanda, Taylor, Jessica, Taylor, Renea, Thorne, Heather, Trainer, Alison, Tucker, Kathy, Visvader, Jane, Walker, Logan, Williams, Rachael, Winship, Ingrid, Young, Mary Ann, Johnson, Nichola [0000-0002-8230-5662], Kapoor, Pooja Middha [0000-0001-5503-8215], Dennis, Joe [0000-0003-4591-1214], Brenner, Hermann [0000-0002-6129-1572], Canzian, Federico [0000-0002-4261-4583], Cox, Angela [0000-0002-5138-1099], Fasching, Peter A. [0000-0003-4885-8471], Hart, Steven N. [0000-0001-7714-2734], Jakubowska, Anna [0000-0002-5650-0501], Kurian, Allison W. [0000-0002-6175-9470], Peterlongo, Paolo [0000-0001-6951-6855], Sawyer, Elinor J. [0000-0001-8285-4111], Tomlinson, Ian [0000-0003-3037-1470], Truong, Thérèse [0000-0002-2943-6786], Pharoah, Paul D. P. [0000-0001-8494-732X], Peto, Julian [0000-0002-1685-8912], Apollo - University of Cambridge Repository, Medical Oncology, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Helsinki University Hospital Area, University of Helsinki, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Fasching, Peter A [0000-0003-4885-8471], Hart, Steven N [0000-0001-7714-2734], Kurian, Allison W [0000-0002-6175-9470], Sawyer, Elinor J [0000-0001-8285-4111], and Pharoah, Paul DP [0000-0001-8494-732X]

Subjects
Cancer Research, CYP3A5, Physiology, Genome-wide association study, Breast cancer, 0302 clinical medicine, Epidemiology, Receptors, IMPUTATION, Medicine, Cytochrome P-450 CYP3A, Cancer genetics, Progesterone, 0303 health sciences, article, 1112 Oncology and Carcinogenesis, 1117 Public Health and Health Services, AOCS Group, Single Nucleotide, humanities, 3. Good health, Receptors, Estrogen, Oncology, Hormone receptor, 030220 oncology & carcinogenesis, kConFab Investigators, Pregnanediol, Female, Receptors, Progesterone, Medical Genetics, medicine.medical_specialty, Estrone, Urinary system, 3122 Cancers, ABCTB Investigators, 631/67/2324, Breast Neoplasms, Polymorphism, Single Nucleotide, NBCS Collaborators, 03 medical and health sciences, Cancer epidemiology, SDG 3 - Good Health and Well-being, 631/67/68, Humans, Oncology & Carcinogenesis, Allele, GENOME-WIDE ASSOCIATION, Polymorphism, CYP3A7, Alleles, 030304 developmental biology, Medicinsk genetik, business.industry, 631/67/1347, medicine.disease, Case-Control Studies, Genome-Wide Association Study, Premenopause, Estrogen, business, Hormone
Abstract

Background Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10–18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10–8). Conclusions The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

Published
2021

3. Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations

Author

Bancroft, Elizabeth K, Saya, Sibel, Page, Elizabeth C, Myhill, Kathryn, Thomas, Sarah, Pope, Jennifer, Chamberlain, Anthony, Hart, Rachel, Glover, Wayne, Cook, Jackie, Rosario, Derek J, Helfand, Brian T, Selkirk, Christina Hutten, Davidson, Rosemarie, Longmuir, Mark, Eccles, Diana M, Gadea, Neus, Brewer, Carole, Barwell, Julian, Salinas, Monica, Greenhalgh, Lynn, Tischkowitz, Marc, Henderson, Alex, Evans, David Gareth, Buys, Saundra S, Eeles, Rosalind A, Aaronson, Neil K, Eeles, Rosalind, Bancroft, Elizabeth, Page, Elizabeth, Kote-Jarai, Zsofia, Ardern-Jones, Audrey, Bangma, Chris, Castro, Elena, Dearnaley, David, Falconer, Alison, Foster, Christopher, Gronberg, Henrik, Hamdy, Freddie C, Johannsson, Oskar Thor, Khoo, Vincent, Eccles, Diana, Lilja, Hans, Evans, Gareth, Eyfjord, Jorunn, Lubinski, Jan, Maehle, Lovise, Mikropoulos, Christos, Millner, Alan, Mitra, Anita, Offman, Judith, Moynihan, Clare, Rennert, Gad, Suri, Mohnish, Dias, Alex, Taylor, Natalie, D'Mello, Lucia, Pope, Jenny, James, Paul, Mitchell, Gillian, Shanley, Sue, Richardson, Kate, McKinley, Joanne, Petelin, Lara, Murphy, Morgan, Mascarenhas, Lyon, Murphy, Declan, Lam, Jimmy, Taylor, Louise, Miller, Cathy, Stapleton, Alan, Chong, Michael, Suthers, Graeme, Poplawski, Nicola, Tucker, Katherine, Andrews, Lesley, Duffy, Jessica, Millard, Richard, Ward, Robyn, Williams, Rachel, Stricker, Phillip, Kirk, Judy, Bowman, Michelle, Patel, Manish, Harris, Marion, O'Connell, Shona, Hunt, Clare, Smyth, Courtney, Frydenberg, Mark, Lindeman, Geoffrey, Shackleton, Kylie, Morton, Catherine, Susman, Rachel, McGaughran, Julie, Boon, Melanie, Pachter, Nicholas, Townshend, Sharron, Schofield, Lyn, Nicholls, Cassandra, Spigelman, Allan, Gleeson, Margaret, Amor, David, Burke, Jo, Patterson, Briony, Swindle, Peter, Scott, Rodney, Foulkes, William, Boshari, Talia, Aprikian, Armen, Jensen, Thomas, Bojeson, Anders, Osther, Palle, Skytte, Anne-Bine, Cruger, Dorthe, Tondering, Majbritt Kure, Gerdes, Anne-Marie, Schmutzler, Rita, Rhiem, Kerstin, Wihler, Petra, Kast, K, Griebsch, C, Johannsson, Oskar, Stefansdottir, Vigdis, Murthy, Vedang, Sarin, Rajiv, Awatagiri, Kasturi, Ghonge, Sujata, Kowtal, Pradnya, Mulgund, Gouri, Gallagher, David, Bambury, Richard, Farrell, Michael, Gallagher, Fergal, Kiernan, Ingrid, Friedman, Eitan, Chen-Shtoyerman, Rakefet, Basevitch, Alon, Leibovici, Dan, Melzer, Ehud, Ben-Yehoshua, Sagi Josefsberg, Nicolai, Nicola, Radice, Paolo, Valdagni, Riccardo, Magnani, Tiziana, Gay, Simona, Teo, Soo Hwang, Tan, Hui Meng, Yoon, Sook-Yee, Thong, Meow Keong, Vasen, Hans, Ringleberg, Janneke, van Asperen, Christi, Kiemeney, Bart, van Zelst-Stams, Wendy, Ausems, Margreet GEM, van der Luijt, Rob B, van Os, Theo, Ruijs, Marielle WG, Adank, Muriel A, Oldenburg, Rogier A, Helderman-van den Enden, A Paula TJM, Caanen, BAH, Oosterwijk, Jan C, Moller, Pal, Brennhovd, Bjorn, Medvik, Heidi, Hanslien, Eldbjorg, Grindedal, Eli Marie, Cybulski, Cezary, Wokolorczyk, Dominika, Teixeira, Manuel, Maia, Sofia, Peixoto, Ana, Henrique, Rui, Oliveira, Jorge, Goncalves, Nuno, Araujo, Luis, Seixas, Manuela, Souto, Joao Paulo, Nogueira, Pedro, Copakova, Lucia, Zgajnar, Janez, Krajc, Mateja, Vrecar, Alenka, Capella, Gabriel, Ramon y Cajal, Teresa, Fisas, David, Mora, Josefina, Esquena, Salvador, Balmana, Judith, Morote, Juan, Liljegren, Annelie, Hjalm-Eriksson, Marie, Ekdahl, Karl-Johan, Carlsson, Stefan, George, Angela, Kemp, Zoe, Wiggins, Jennifer, Moss, Cathryn, Van As, Nicholas, Thompson, Alan, Ogden, Chris, Woodhouse, Christopher, Kumar, Pardeep, Evans, D Gareth, Bulman, Barbara, Rothwell, Jeanette, Tricker, Karen, Wise, Gillian, Mercer, Catherine, McBride, Donna, Costello, Philandra, Pearce, Allison, Torokwa, Audrey, Paterson, Joan, Clowes, Virginia, Taylor, Amy, Newcombe, Barbara, Walker, Lisa, Halliday, Dorothy, Stayner, Barbara, Fleming-Brown, D, Snape, Katie, Hanson, Helen, Hodgson, Shirley, Brice, Glen, Homfray, Tessa, Hammond, Carrie, Kohut, Kelly, Anjum, Uruj, Dearing, Audrey, Mencias, Mark, Potter, Alison, Renton, Caroline, Searle, Anne, Hill, Kathryn, Goodman, Selina, Garcia, Lynda, Devlin, Gemma, Everest, Sarah, Nadolski, Maria, Douglas, Fiona, Jobson, Irene, Paez, Edgar, Donaldson, Alan, Tomkins, Sue, Langman, Caroline, Jacobs, Chris, Pichert, Gabriella, Shaw, Adam, Kulkarni, Anju, Tripathi, Vishakha, Rose, Sarah, Compton, Cecilia, Watson, Michelle, Reinholtz, Cherylin, Brady, Angela, Dorkins, Huw, Melville, Athalie, Kosicka-Slawinska, Monika, Cummings, Carole, Kiesel, Vicki, Bartlett, Marion, Randhawa, Kashmir, Ellery, Natalie, Side, Lucy, Male, Alison, Simon, Kate, Rees, Katie, Tidey, Lizzie, Gurasashvili, Jana, Nevitt, Louise, Ingram, Stuart, Howell, Alice, Rosario, Derek, Catto, James, Howson, Joanne, Ong, Kai-Ren, Chapman, Cyril, Cole, Trevor, Heaton, Tricia, Hoffman, Jonathan, Burgess, Lucy, Huber, Camilla, Islam, Farah, Watt, Cathy, Duncan, Alexis, Kockelbergh, Roger, Mzazi, Shumikazi, Dineen, Amy, Sattar, Ayisha, Kaemba, Beckie, Sidat, Zahirah, Patel, Nafisa, Siguake, Kas, Birt, Angela, Poultney, Una, Umez-Eronini, Nkem, Mom, Jaswant, Sutton, Vivienne, Cornford, Philip, Bermingham, Nicola, Yesildag, Pembe, Treherne, Katy, Griffiths, Julie, Cogley, Lyn, Gott, Hannah, Rubinstein, Wendy S, Hulick, Peter, McGuire, Michael, Shevrin, Daniel, Kaul, Karen, Weissman, Scott, Newlin, Anna, Vogel, Kristen, Weiss, Shelly, Hook, Nicole, Buys, Saundra, Goldgar, David, Conner, Tom, Venne, Vickie, Stephenson, Robert, Dechet, Christopher, Domchek, Susan, Powers, Jacquelyn, Rustgi, Neil, Strom, Sara, Arun, Banu, Davis, John W, Yamamura, Yuko, Obeid, Elias, Giri, Veda, Gross, Laura, Bealin, Lisa, Cooney, Kathy, Stoffel, Elena, Okoth, Linda, Comm, IMPACT Study Steering, Collaborators, IMPACT, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), General Practice, Urology, and Clinical Genetics

Subjects
psychosocial, Male, Health Knowledge, Attitudes, Practice, Urological Oncology, Genes, BRCA2, Genes, BRCA1, #pcsm, RISK PERCEPTION, Anxiety, Hospital Anxiety and Depression Scale, FAMILY-HISTORY, PSA, 0302 clinical medicine, Quality of life, QUALITY-OF-LIFE, Risk Factors, Surveys and Questionnaires, Medicine, 030212 general & internal medicine, Longitudinal Studies, Depressió psíquica, Early Detection of Cancer, POPULATION, Prostatic Neoplasms/diagnosis, education.field_of_study, Prostate cancer, Depression, Anxiety/etiology, Urology & Nephrology, Middle Aged, Distress, Prostate cancer screening, Mental depression, #ProstateCancer, Estudi de casos, 030220 oncology & carcinogenesis, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Cohort, HEALTH, medicine.symptom, Psychosocial, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, Urology, Depression/etiology, Population, HOSPITAL ANXIETY, Early Detection of Cancer/psychology, OVARIAN-CANCER, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, SDG 3 - Good Health and Well-being, BRCA1/2, Internal medicine, Humans, education, Psychiatric Status Rating Scales, Càncer de pròstata, business.industry, Prostatic Neoplasms, BRCA1, BRCA2, quality of life, Case-Control Studies, Mutation, Perception, Case studies, business, PSYCHOLOGICAL IMPACT
Abstract

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICIPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS:A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening.

Published
2019

4. Annexin A1 expression in a pooled breast cancer series: Association with tumor subtypes and prognosis

Author

Sobral-Leite, Marcelo, Wesseling, Jelle, Smit, Vincent T H B M, Nevanlinna, Heli, van Miltenburg, Martine H., Sanders, Joyce, Hofland, Ingrid, Blows, Fiona M., Coulson, Penny, Patrycja, Gazinska, Schellens, Jan H M, Fagerholm, Rainer, Heikkilä, Päivi, Aittomäki, Kristiina, Blomqvist, Carl, Provenzano, Elena, Ali, Hamid Raza, Figueroa, Jonine, Sherman, Mark, Lissowska, Jolanta, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli Matti, Hartikainen, Jaana M., Phillips, Kelly Anne, Couch, Fergus J., Olson, Janet E., Vachon, Celine, Visscher, Daniel, Brenner, Hermann, Butterbach, Katja, Arndt, Volker, Holleczek, Bernd, Hooning, Maartje J., Hollestelle, Antoinette, Martens, John W M, van Deurzen, Carolien H M, van de Water, Bob, Broeks, Annegien, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Easton, Douglas F., Pharoah, Paul D P, García-Closas, Montserrat, de Graauw, Marjo, Schmidt, Marjanka K., Aghmesheh, Morteza, Amor, David, Andrews, Lesley, Antill, Yoland, Armitage, Shane, Arnold, Leanne, Balleine, Rosemary, Bankier, Agnes, Bastick, Patti, Beesley, Jonathan, Beilby, John, Bennett, Barbara, Bennett, Ian, Berry, Geoffrey, Blackburn, Anneke, Bogwitz, Michael, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burgess, Matthew, Burke, Jo, Butow, Phyllis, Byron, Keith, Callen, David, Campbell, Ian, Chauhan, Deepa, Chauhan, Manisha, Christian, Alice, Clarke, Christine, Colley, Alison, Cotton, Dick, Crook, Ashley, Cui, James, Culling, Bronwyn, Cummings, Margaret, Dawson, Sarah Jane, deFazio, Anna, Delatycki, Martin, Dickson, Rebecca, Dixon, Joanne, Dobrovic, Alexander, Dudding, Tracy, Edkins, Ted, Edwards, Stacey, Eisenbruch, Maurice, Farshid, Gelareh, Fawcett, Susan, Fellows, Andrew, Fenton, Georgina, Field, Michael, Firgaira, Frank, Flanagan, James, Fleming, Jean, Fong, Peter, Forbes, John, Fox, Stephen, French, Juliet, Friedlander, Michael, Gaff, Clara, Gardner, Mac, Gattas, Mike, George, Peter, Giles, Graham, Gill, Grantley, Goldblatt, Jack, Greening, Sian, Grist, Scott, Haan, Eric, Hardie, Kate, Harris, Marion, Hart, Stewart, Hayward, Nick, Healey, Sue, Heiniger, Louise, Hopper, John, Humphrey, Evelyn, Hunt, Clare, James, Paul, Jenkins, Mark, Jones, Alison, Kefford, Rick, Kidd, Alexa, Kiely, Belinda, Kirk, Judy, Koehler, Jessica, Kollias, James, Kovalenko, Serguei, Lakhani, Sunil, Leaming, Amanda, Leary, Jennifer, Lim, Jacqueline, Lindeman, Geoff, Lipton, Lara, Lobb, Liz, Mann, Graham, Marsh, Deborah, McLachlan, Sue Anne, Meiser, Bettina, Meldrum, Cliff, Milne, Roger, Mitchell, Gillian, Newman, Beth, Niedermayr, Eveline, Nightingale, Sophie, O'Connell, Shona, O'Loughlin, Imelda, Osborne, Richard, Pachter, Nick, Patterson, Briony, Peters, Lester, Phillips, Kelly, Price, Melanie, Purser, Lynne, Reeve, Tony, Reeve, Jeanne, Richards, Robert, Rickard, Edwina, Robinson, Bridget, Rudzki, Barney, Saleh, Mona, Salisbury, Elizabeth, Sambrook, Joe, Saunders, Christobel, Saunus, Jodi, Sayer, Robyn, Scott, Elizabeth, Scott, Rodney, Scott, Clare, Seshadri, Ram, Sexton, Adrienne, Sharma, Raghwa, Shelling, Andrew, Simpson, Peter, Southey, Melissa, Spurdle, Amanda, Suthers, Graeme, Sykes, Pamela, Tassell, Margaret, Taylor, Donna, Taylor, Jessica, Thierry, Benjamin, Thomas, Susan, Thompson, Ella, Thorne, Heather, Townshend, Sharron, Trainer, Alison, Tran, Lan, Tucker, Kathy, Tyler, Janet, Visvader, Jane, Walker, Logan, Walpole, Ian, Ward, Robin, Waring, Paul, Warner, Bev, Warren, Graham, Williams, Rachael, Wilson, Judy, Winship, Ingrid, Wu, Kathy, Young, Mary Ann, Bowtell, D., Green, A., Webb, P., de Fazio, A., Gertig, D., Pharmacoepidemiology and Clinical Pharmacology, Sub Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, and Sub Clinical Pharmacology

Subjects
Medicine(all), endocrine system, Breast cancer, skin and connective tissue diseases, Annexin A1, BRCA1 and BRCA2 mutations
Abstract

Background: Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods: Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2

Published
2015

5. CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Author

Johnson, Nichola, Maguire, Sarah, Morra, Anna, Kapoor, Pooja Middha, Tomczyk, Katarzyna, Jones, Michael E., Schoemaker, Minouk J., Gilham, Clare, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Ahearn, Thomas U., Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Arndt, Volker, Aronson, Kristan J., Augustinsson, Annelie, Baynes, Caroline, Freeman, Laura E. Beane, Beckmann, Matthias W., Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V., Bojesen, Stig E., Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E., Chanock, Stephen J., Chenevix-Trench, Georgia, Clarke, Christine L., Conroy, Don M., Couch, Fergus J., Cox, Angela, Cross, Simon S., Czene, Kamila, Dörk, Thilo, Eliassen, A. Heather, Engel, Christoph, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Floris, Giuseppe, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M., García-Closas, Montserrat, Gaudet, Mia M., Giles, Graham G., Goldberg, Mark S., González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A., Hart, Steven N., Hooning, Maartje J., Hopper, John L., Howell, Anthony, Hunter, David J., Jager, Agnes, Jakubowska, Anna, John, Esther M., Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M., Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N., Kurian, Allison W., Lambrechts, Diether, Le Marchand, Loic, Linet, Martha, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Mavroudis, Dimitrios, Mayes, Rebecca, Meindl, Alfons, Milne, Roger L., Neuhausen, Susan L., Nevanlinna, Heli, Newman, William G., Nielsen, Sune F., Nordestgaard, Børge G., Obi, Nadia, Olshan, Andrew F., Olson, Janet E., Olsson, Håkan, Orban, Ester, Park-Simon, Tjoung-Won, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Rennert, Gad, Rennert, Hedy S., Ruddy, Kathryn J., Saloustros, Emmanouil, Sandler, Dale P., Sawyer, Elinor J., Schmutzler, Rita K., Scott, Christopher, Shu, Xiao-Ou, Simard, Jacques, Smichkoska, Snezhana, Sohn, Christof, Southey, Melissa C., Spinelli, John J., Stone, Jennifer, Tamimi, Rulla M., Taylor, Jack A., Tollenaar, Rob A. E. M., Tomlinson, Ian, Troester, Melissa A., Truong, Thérèse, Vachon, Celine M., Van Veen, Elke M., Wang, Sophia S., Weinberg, Clarice R., Wendt, Camilla, Wildiers, Hans, Winqvist, Robert, Wolk, Alicja, Zheng, Wei, Ziogas, Argyrios, Dunning, Alison M., Pharoah, Paul D. P., Easton, Douglas F., Howie, A. Forbes, Peto, Julian, Dos-Santos-Silva, Isabel, Swerdlow, Anthony J., Chang-Claude, Jenny, Schmidt, Marjanka K., Orr, Nick, Fletcher, Olivia, Børresen-Dale, Anne-Lise, Alnæs, Grethe I. Grenaker, Sahlberg, Kristine K., Ottestad, Lars, Kåresen, Rolf, Schlichting, Ellen, Holmen, Marit Muri, Sauer, Toril, Haakensen, Vilde, Engebråten, Olav, Naume, Bjørn, Fosså, Alexander, Kiserud, Cecile E., Reinertsen, Kristin V., Helland, Åslaug, Riis, Margit, Geisler, Jürgen, Bowtell, David D. L., DeFazio, Anna, Webb, Penelope M., Clarke, Christine, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Carpenter, Jane, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Graham, Dinny, Sachchithananthan, Mythily, Amor, David, Andrews, Lesley, Antill, Yoland, Balleine, Rosemary, Beesley, Jonathan, Bennett, Ian, Bogwitz, Michael, Botes, Leon, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burke, Jo, Butow, Phyllis, Caldon, Liz, Campbell, Ian, Chauhan, Deepa, Chauhan, Manisha, Christian, Alice, Cohen, Paul, Colley, Alison, Crook, Ashley, Cui, James, Cummings, Margaret, Dawson, Sarah-Jane, Delatycki, Martin, Dickson, Rebecca, Dixon, Joanne, Edkins, Ted, Edwards, Stacey, Farshid, Gelareh, Fellows, Andrew, Fenton, Georgina, Field, Michael, Flanagan, James, Fong, Peter, Forrest, Laura, Fox, Stephen, French, Juliet, Friedlander, Michael, Gaff, Clara, Gattas, Mike, George, Peter, Greening, Sian, Harris, Marion, Hart, Stewart, Hayward, Nick, Hopper, John, Hoskins, Cass, Hunt, Clare, James, Paul, Jenkins, Mark, Kidd, Alexa, Kirk, Judy, Koehler, Jessica, Kollias, James, Lakhani, Sunil, Lawrence, Mitchell, Lindeman, Geoff, Lipton, Lara, Lobb, Liz, Mann, Graham, McLachlan, Sue Anne, Meiser, Bettina, Milne, Roger, Nightingale, Sophie, O’Connell, Shona, O’Sullivan, Sarah, Ortega, David Gallego, Pachter, Nick, Patterson, Briony, Pearn, Amy, Phillips, Kelly, Pieper, Ellen, Rickard, Edwina, Robinson, Bridget, Saleh, Mona, Salisbury, Elizabeth, Saunders, Christobel, Saunus, Jodi, Scott, Clare, Sexton, Adrienne, Shelling, Andrew, Southey, Melissa, Spurdle, Amanda, Taylor, Jessica, Taylor, Renea, Thorne, Heather, Trainer, Alison, Tucker, Kathy, Visvader, Jane, Walker, Logan, Williams, Rachael, Winship, Ingrid, and Young, Mary Ann

Subjects
631/67/68, article, 631/67/2324, 631/67/1347, 3. Good health
Abstract

Funder: Breast Cancer Now (BCN); doi: https://doi.org/10.13039/100009794, Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289, Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265, Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH), Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440, Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): HEALTH-F2-2009-223175, HEALTH-F2-2009-223175, Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762, Funder: Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); doi: https://doi.org/10.13039/501100000024, Funder: Quebec Breast cancer Foundation Genome Quebec, Funder: U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (NLM); doi: https://doi.org/10.13039/100000092, Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)), Funder: European Union’s Horizon 2020, Funder: Deutsche Krebshilfe (German Cancer Aid); doi: https://doi.org/10.13039/501100005972, Funder: BCAST - European Union’s Horizon 2020, Funder: Breast Cancer Now; doi: https://doi.org/10.13039/501100007913, Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10–18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10–8). Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

6. Homologous recombination DNA repair defects in PALB2- associated breast cancers

Author

Li, Anqi, Geyer, Felipe C., Blecua, Pedro, Lee, Ju Youn, Selenica, Pier, Brown, David N., Pareja, Fresia, Lee, Simon S. K., Kumar, Rahul, Rivera, Barbara, Bi, Rui, Piscuoglio, Salvatore, Wen, Hannah Y., Lozada, John R., Gularte-Mérida, Rodrigo, Cavallone, Luca, Rezoug, Zoulikha, Nguyen-Dumont, Tu, Peterlongo, Paolo, Tondini, Carlo, Terkelsen, Thorkild, Rønlund, Karina, Boonen, Susanne E., Mannerma, Arto, Winqvist, Robert, Janatova, Marketa, Rajadurai, Pathmanathan, Xia, Bing, Norton, Larry, Robson, Mark E., Ng, Pei-Sze, Looi, Lai-Meng, Southey, Melissa C., Weigelt, Britta, Soo-Hwang, Teo, Tischkowitz, Marc, Foulkes, William D., Reis-Filho, Jorge S., Aghmesheh, Morteza, Amor, David, Andrews, Leslie, Antill, Yoland, Balleine, Rosemary, Beesley, Jonathan, Blackburn, Anneke, Bogwitz, Michael, Brown, Melissa, Burgess, Matthew, Burke, Jo, Butow, Phyllis, Caldon, Liz, Campbell, Ian, Christian, Alice, Clarke, Christine, Cohen, Paul, Crook, Ashley, Cui, James, Cummings, Margaret, Dawson, Sarah-Jane, De Fazio, Anna, Delatycki, Martin, Dobrovic, Alex, Dudding, Tracy, Duijf, Pascal, Edkins, Edward, Edwards, Stacey, Farshid, Gelareh, Fellows, Andrew, Field, Michael, Flanagan, James, Fong, Peter, Forbes, John, Forrest, Laura, Fox, Stephen, French, Juliet, Friedlander, Michael, Ortega, David Gallego, Gattas, Michael, Giles, Graham, Gill, Grantley, Gleeson, Margaret, Greening, Sian, Haan, Eric, Harris, Marion, Hayward, Nick, Hickie, Ian, Hopper, John, Hunt, Clare, James, Paul, Jenkins, Mark, Kefford, Rick, Kentwell, Maira, Kirk, Judy, Kollias, James, Lakhani, Sunil, Lindeman, Geoff, Lipton, Lara, Lobb, Lizz, Lok, Sheau, Macrea, Finlay, Mann, Graham, Marsh, Deb, McLachlan, Sue-Anne, Meiser, Bettina, Milne, Roger, Nightingale, Sophie, O’Connell, Shona, Pachter, Nick, Patterson, Briony, Phillips, Kelly, Saleh, Mona, Salisbury, Elizabeth, Saunders, Christobel, Saunus, Jodi, Scott, Clare, Scott, Rodney, Sexton, Adrienne, Shelling, Andrew, Simpson, Peter, Spigelman, Allan, Spurdle, Mandy, Stone, Jennifer, Taylor, Jessica, Thorne, Heather, Trainer, Alison, Trench, Georgia, Tucker, Kathy, Visvader, Jane, Walker, Logan, Wallis, Mathew, Williams, Rachael, Winship, Ingrid, Wu, Kathy, and Young, Mary Anne

Subjects
631/67/68, article, 631/67/1347, 692/699/67/69, 3. Good health
Abstract

Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.

7. 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.

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