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1. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author: Silvestri, Valentina, Barrowdale, Daniel, Mulligan, Anna Marie, Neuhausen, Susan L, Fox, Stephen, Karlan, Beth Y, Mitchell, Gillian, James, Paul, Thull, Darcy L, Zorn, Kristin K, Carter, Natalie J, Nathanson, Katherine L, Domchek, Susan M, Rebbeck, Timothy R, Ramus, Susan J, Nussbaum, Robert L, Olopade, Olufunmilayo I, Rantala, Johanna, Yoon, Sook-Yee, Caligo, Maria A, Spugnesi, Laura, Bojesen, Anders, Pedersen, Inge Sokilde, Thomassen, Mads, Jensen, Uffe Birk, Toland, Amanda Ewart, Senter, Leigha, Andrulis, Irene L, Glendon, Gord, Hulick, Peter J, Imyanitov, Evgeny N, Greene, Mark H, Mai, Phuong L, Singer, Christian F, Rappaport-Fuerhauser, Christine, Kramer, Gero, Vijai, Joseph, Offit, Kenneth, Robson, Mark, Lincoln, Anne, Jacobs, Lauren, Machackova, Eva, Foretova, Lenka, Navratilova, Marie, Vasickova, Petra, Couch, Fergus J, Hallberg, Emily, Ruddy, Kathryn J, Sharma, Priyanka, Kim, Sung-Won, kConFab Investigators, Teixeira, Manuel R, Pinto, Pedro, Montagna, Marco, Matricardi, Laura, Arason, Adalgeir, Johannsson, Oskar Th, Barkardottir, Rosa B, Jakubowska, Anna, Lubinski, Jan, Izquierdo, Angel, Pujana, Miguel Angel, Balmaña, Judith, Diez, Orland, Ivady, Gabriella, Papp, Janos, Olah, Edith, Kwong, Ava, Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Nevanlinna, Heli, Aittomäki, Kristiina, Perez Segura, Pedro, Caldes, Trinidad, Van Maerken, Tom, Poppe, Bruce, Claes, Kathleen BM, Isaacs, Claudine, Elan, Camille, Lasset, Christine, Stoppa-Lyonnet, Dominique, Barjhoux, Laure, Belotti, Muriel, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Hahnen, Eric, Kast, Karin, Arnold, Norbert, Varon-Mateeva, Raymonda, Wand, Dorothea, Godwin, Andrew K, Evans, D Gareth, Frost, Debra, Perkins, Jo, Adlard, Julian, Izatt, Louise, and Platte, Radka
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Cancer, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Breast Neoplasms, Male, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, Neoplasm Staging, Polymorphism, Single Nucleotide, Male breast cancer, BRCA1/2, Pathology, Histologic grade, Genotype-phenotype correlations, kConFab Investigators, Hereditary Breast and Ovarian Cancer Research Group Netherlands, EMBRACE, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: BackgroundBRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs).MethodsWe characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database.ResultsAmong BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)).ConclusionsOn the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.
Published: 2016

2. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2.

Author: Silvestri, Valentina, Barrowdale, Daniel, Mulligan, Anna Marie, Neuhausen, Susan L, Fox, Stephen, Karlan, Beth Y, Mitchell, Gillian, James, Paul, Thull, Darcy L, Zorn, Kristin K, Carter, Natalie J, Nathanson, Katherine L, Domchek, Susan M, Rebbeck, Timothy R, Ramus, Susan J, Nussbaum, Robert L, Olopade, Olufunmilayo I, Rantala, Johanna, Yoon, Sook-Yee, Caligo, Maria A, Spugnesi, Laura, Bojesen, Anders, Pedersen, Inge Sokilde, Thomassen, Mads, Jensen, Uffe Birk, Toland, Amanda Ewart, Senter, Leigha, Andrulis, Irene L, Glendon, Gord, Hulick, Peter J, Imyanitov, Evgeny N, Greene, Mark H, Mai, Phuong L, Singer, Christian F, Rappaport-Fuerhauser, Christine, Kramer, Gero, Vijai, Joseph, Offit, Kenneth, Robson, Mark, Lincoln, Anne, Jacobs, Lauren, Machackova, Eva, Foretova, Lenka, Navratilova, Marie, Vasickova, Petra, Couch, Fergus J, Hallberg, Emily, Ruddy, Kathryn J, Sharma, Priyanka, Kim, Sung-Won, kConFab Investigators, Teixeira, Manuel R, Pinto, Pedro, Montagna, Marco, Matricardi, Laura, Arason, Adalgeir, Johannsson, Oskar Th, Barkardottir, Rosa B, Jakubowska, Anna, Lubinski, Jan, Izquierdo, Angel, Pujana, Miguel Angel, Balmaña, Judith, Diez, Orland, Ivady, Gabriella, Papp, Janos, Olah, Edith, Kwong, Ava, Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Nevanlinna, Heli, Aittomäki, Kristiina, Perez Segura, Pedro, Caldes, Trinidad, Van Maerken, Tom, Poppe, Bruce, Claes, Kathleen BM, Isaacs, Claudine, Elan, Camille, Lasset, Christine, Stoppa-Lyonnet, Dominique, Barjhoux, Laure, Belotti, Muriel, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Hahnen, Eric, Kast, Karin, Arnold, Norbert, Varon-Mateeva, Raymonda, Wand, Dorothea, Godwin, Andrew K, Evans, D Gareth, Frost, Debra, Perkins, Jo, Adlard, Julian, Izatt, Louise, and Platte, Radka
Subjects: kConFab Investigators, Hereditary Breast and Ovarian Cancer Research Group Netherlands, EMBRACE, Humans, Breast Neoplasms, Breast Neoplasms, Male, Genetic Predisposition to Disease, BRCA1 Protein, BRCA2 Protein, Neoplasm Staging, Mutation, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, Male, Male breast cancer, BRCA1/2, Pathology, Histologic grade, Genotype-phenotype correlations, Polymorphism, Single Nucleotide, Breast Cancer, Cancer, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract: BackgroundBRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs).MethodsWe characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database.ResultsAmong BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)).ConclusionsOn the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.
Published: 2016

3. 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, and Rouleau, Etienne
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Breast Cancer, Cancer, 2.1 Biological and endogenous factors, Aetiology, BRCA1 Protein, Breast Neoplasms, Female, Genes, BRCA2, Genes, Mitochondrial, Genetic Predisposition to Disease, Haplotypes, Heterozygote, Humans, Mutation, Phylogeny, Risk, Breast Cancer Family Registry, EMBRACE, GEMO Study Collaborators, HEBON, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: IntroductionIndividuals 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.MethodsWe 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.ResultsWe 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.ConclusionsThis 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.
Published: 2015

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

Author: Blein, S, Bardel, C, Danjean, V, McGuffog, L, Healey, S, Barrowdale, D, Lee, A, Dennis, J, Kuchenbaecker, KB, Soucy, P, Terry, MB, Chung, WK, Goldgar, DE, Buys, SS, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Gerdes, AM, Ejlertsen, B, Nielsen, FC, Hansen, TVO, Osorio, A, Benitez, J, Conejero, RA, Segota, E, Weitzel, JN, Thelander, M, Peterlongo, P, Radice, P, Pensotti, V, Dolcetti, R, Bonanni, B, Peissel, B, Zaffaroni, D, Scuvera, G, Manoukian, S, Varesco, L, Capone, GL, Papi, L, Ottini, L, Yannoukakos, D, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brady, A, Brewer, C, Foo, C, Evans, DG, Frost, D, Eccles, D, Douglas, F, Cook, J, Adlard, J, Barwell, J, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Tischkowitz, M, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Cole, T, Godwin, AK, Isaacs, C, Claes, K, De Leeneer, K, Meindl, A, Gehrig, A, Wappenschmidt, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Plendl, H, Kast, K, Rhiem, K, Ditsch, N, Arnold, N, Varon-Mateeva, R, Schmutzler, RK, Preisler-Adams, S, Markov, NB, Wang-Gohrke, S, de Pauw, A, Lefol, C, Lasset, C, Leroux, D, Rouleau, E, Damiola, F, and Dreyfus, H
Subjects: Oncology & Carcinogenesis, Oncology and Carcinogenesis
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.
Published: 2015

5. 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, and Rouleau, Etienne
Subjects: Breast Cancer Family Registry, EMBRACE, GEMO Study Collaborators, HEBON, Humans, Breast Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, Risk, Phylogeny, Haplotypes, Heterozygote, Mutation, Genes, BRCA2, Female, Genes, Mitochondrial, Genes, BRCA2, Mitochondrial, Cancer, Breast Cancer, Genetics, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract: IntroductionIndividuals 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.MethodsWe 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.ResultsWe 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.ConclusionsThis 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.
Published: 2015

6. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

Author: Rebbeck, Timothy R, Mitra, Nandita, Wan, Fei, Sinilnikova, Olga M, Healey, Sue, McGuffog, Lesley, Mazoyer, Sylvie, Chenevix-Trench, Georgia, Easton, Douglas F, Antoniou, Antonis C, Nathanson, Katherine L, CIMBA Consortium, Laitman, Yael, Kushnir, Anya, Paluch-Shimon, Shani, Berger, Raanan, Zidan, Jamal, Friedman, Eitan, Ehrencrona, Hans, Stenmark-Askmalm, Marie, Einbeigi, Zakaria, Loman, Niklas, Harbst, Katja, Rantala, Johanna, Melin, Beatrice, Huo, Dezheng, Olopade, Olufunmilayo I, Seldon, Joyce, Ganz, Patricia A, Nussbaum, Robert L, Chan, Salina B, Odunsi, Kunle, Gayther, Simon A, Domchek, Susan M, Arun, Banu K, Lu, Karen H, Mitchell, Gillian, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Godwin, Andrew K, Pathak, Harsh, Ross, Eric, Daly, Mary B, Whittemore, Alice S, John, Esther M, Miron, Alexander, Terry, Mary Beth, Chung, Wendy K, Goldgar, David E, Buys, Saundra S, Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Steele, Linda, Neuhausen, Susan L, Ding, Yuan Chun, Ejlertsen, Bent, Gerdes, Anne-Marie, Hansen, Thomas VO, Ramón y Cajal, Teresa, Osorio, Ana, Benitez, Javier, Godino, Javier, Tejada, Maria-Isabel, Duran, Mercedes, Weitzel, Jeffrey N, Bobolis, Kristie A, Sand, Sharon R, Fontaine, Annette, Savarese, Antonella, Pasini, Barbara, Peissel, Bernard, Bonanni, Bernardo, Zaffaroni, Daniela, Vignolo-Lutati, Francesca, Scuvera, Giulietta, Giannini, Giuseppe, Bernard, Loris, Genuardi, Maurizio, Radice, Paolo, Dolcetti, Riccardo, Manoukian, Siranoush, Pensotti, Valeria, Gismondi, Viviana, Yannoukakos, Drakoulis, Fostira, Florentia, Garber, Judy, Torres, Diana, Rashid, Muhammad Usman, Hamann, Ute, Peock, Susan, Frost, Debra, Platte, Radka, Evans, D Gareth, Eeles, Rosalind, Davidson, Rosemarie, and Eccles, Diana
Subjects: CIMBA Consortium, Humans, Breast Neoplasms, Ovarian Neoplasms, Genetic Predisposition to Disease, Nucleotides, Risk Factors, Age of Onset, Heterozygote, Mutation, Genes, BRCA1, Genes, BRCA2, Adult, Middle Aged, Female, Cancer, Prevention, Rare Diseases, Breast Cancer, Clinical Research, Ovarian Cancer, General & Internal Medicine, Medical and Health Sciences
Abstract: ImportanceLimited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.ObjectiveTo identify mutation-specific cancer risks for carriers of BRCA1/2.Design, setting, and participantsObservational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.ExposuresMutations of BRCA1 or BRCA2.Main outcomes and measuresBreast and ovarian cancer risks.ResultsAmong BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.Conclusions and relevanceBreast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
Published: 2015

7. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

Author: Rebbeck, Timothy R, Mitra, Nandita, Wan, Fei, Sinilnikova, Olga M, Healey, Sue, McGuffog, Lesley, Mazoyer, Sylvie, Chenevix-Trench, Georgia, Easton, Douglas F, Antoniou, Antonis C, Nathanson, Katherine L, CIMBA Consortium, Laitman, Yael, Kushnir, Anya, Paluch-Shimon, Shani, Berger, Raanan, Zidan, Jamal, Friedman, Eitan, Ehrencrona, Hans, Stenmark-Askmalm, Marie, Einbeigi, Zakaria, Loman, Niklas, Harbst, Katja, Rantala, Johanna, Melin, Beatrice, Huo, Dezheng, Olopade, Olufunmilayo I, Seldon, Joyce, Ganz, Patricia A, Nussbaum, Robert L, Chan, Salina B, Odunsi, Kunle, Gayther, Simon A, Domchek, Susan M, Arun, Banu K, Lu, Karen H, Mitchell, Gillian, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Godwin, Andrew K, Pathak, Harsh, Ross, Eric, Daly, Mary B, Whittemore, Alice S, John, Esther M, Miron, Alexander, Terry, Mary Beth, Chung, Wendy K, Goldgar, David E, Buys, Saundra S, Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Steele, Linda, Neuhausen, Susan L, Ding, Yuan Chun, Ejlertsen, Bent, Gerdes, Anne-Marie, Hansen, Thomas VO, Ramón y Cajal, Teresa, Osorio, Ana, Benitez, Javier, Godino, Javier, Tejada, Maria-Isabel, Duran, Mercedes, Weitzel, Jeffrey N, Bobolis, Kristie A, Sand, Sharon R, Fontaine, Annette, Savarese, Antonella, Pasini, Barbara, Peissel, Bernard, Bonanni, Bernardo, Zaffaroni, Daniela, Vignolo-Lutati, Francesca, Scuvera, Giulietta, Giannini, Giuseppe, Bernard, Loris, Genuardi, Maurizio, Radice, Paolo, Dolcetti, Riccardo, Manoukian, Siranoush, Pensotti, Valeria, Gismondi, Viviana, Yannoukakos, Drakoulis, Fostira, Florentia, Garber, Judy, Torres, Diana, Rashid, Muhammad Usman, Hamann, Ute, Peock, Susan, Frost, Debra, Platte, Radka, Evans, D Gareth, Eeles, Rosalind, Davidson, Rosemarie, and Eccles, Diana
Subjects: CIMBA Consortium, Humans, Breast Neoplasms, Ovarian Neoplasms, Genetic Predisposition to Disease, Nucleotides, Risk Factors, Age of Onset, Heterozygote, Mutation, Genes, BRCA1, Genes, BRCA2, Adult, Middle Aged, Female, Clinical Research, Prevention, Cancer, Breast Cancer, Ovarian Cancer, Rare Diseases, Medical and Health Sciences, General & Internal Medicine
Abstract: ImportanceLimited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.ObjectiveTo identify mutation-specific cancer risks for carriers of BRCA1/2.Design, setting, and participantsObservational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.ExposuresMutations of BRCA1 or BRCA2.Main outcomes and measuresBreast and ovarian cancer risks.ResultsAmong BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.Conclusions and relevanceBreast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
Published: 2015

8. 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: EMBRACE, GEMO Study Collaborators, Breast Cancer Family Registry, HEBON, KConFab Investigators, Australian Cancer Study, Australian Ovarian Cancer Study Group, Consortium of Investigators of Modifiers of BRCA1 and BRCA2, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, BRCA2 Protein, Risk, Genotype, Heterozygote, Mutation, Polymorphism, Single Nucleotide, Alleles, Genes, Reporter, Quantitative Trait Loci, Adolescent, Adult, Female, Genome-Wide Association Study, Young Adult, Carcinoma, Ovarian Epithelial, Human Genome, Rare Diseases, Genetics, Cancer, Prevention, Ovarian Cancer, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, 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

9. 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: EMBRACE, GEMO Study Collaborators, Breast Cancer Family Registry, HEBON, KConFab Investigators, Australian Cancer Study, Australian Ovarian Cancer Study Group, Consortium of Investigators of Modifiers of BRCA1 and BRCA2, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, BRCA2 Protein, Risk, Genotype, Heterozygote, Mutation, Polymorphism, Single Nucleotide, Alleles, Genes, Reporter, Quantitative Trait Loci, Adolescent, Adult, Female, Genome-Wide Association Study, Young Adult, Carcinoma, Ovarian Epithelial, Genetic Testing, Human Genome, Ovarian Cancer, Genetics, Prevention, Cancer, Rare Diseases, 2.1 Biological and endogenous factors, Developmental Biology, Biological Sciences, Medical and Health Sciences
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

10. Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Peterlongo, Paolo, Chang-Claude, Jenny, Moysich, Kirsten B, Rudolph, Anja, Schmutzler, Rita K, Simard, Jacques, Soucy, Penny, Eeles, Rosalind A, Easton, Douglas F, Hamann, Ute, Wilkening, Stefan, Chen, Bowang, Rookus, Matti A, Schmidt, Marjanka K, van der Baan, Frederieke H, Spurdle, Amanda B, Walker, Logan C, Lose, Felicity, Maia, Ana-Teresa, Montagna, Marco, Matricardi, Laura, Lubinski, Jan, Jakubowska, Anna, Garcia, Encarna B Gómez, Olopade, Olufunmilayo I, Nussbaum, Robert L, Nathanson, Katherine L, Domchek, Susan M, Rebbeck, Timothy R, Arun, Banu K, Karlan, Beth Y, Orsulic, Sandra, Lester, Jenny, Chung, Wendy K, Miron, Alex, Southey, Melissa C, Goldgar, David E, Buys, Saundra S, Janavicius, Ramunas, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Ding, Yuan Chun, Neuhausen, Susan L, Hansen, Thomas VO, Gerdes, Anne-Marie, Ejlertsen, Bent, Jønson, Lars, Osorio, Ana, Martínez-Bouzas, Cristina, Benitez, Javier, Conway, Edye E, Blazer, Kathleen R, Weitzel, Jeffrey N, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, 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 E, Donaldson, Alan, Brewer, Carole, Foo, Claire, Evans, D Gareth R, Frost, Debra, Eccles, Diana, Brady, Angela, Cook, Jackie, Tischkowitz, Marc, Adlard, Julian, Barwell, Julian, Walker, Lisa, Izatt, Louise, Side, Lucy E, Kennedy, M John, Rogers, Mark T, Porteous, Mary E, Morrison, Patrick J, Platte, Radka, Davidson, Rosemarie, Hodgson, Shirley V, Ellis, Steve, Cole, Trevor, behalf of EMBRACE, on, Godwin, Andrew K, Claes, Kathleen, Van Maerken, Tom, Meindl, Alfons, Gehrig, Andrea, and Sutter, Christian
Subjects: Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Cancer, Women's Health, Rare Diseases, Human Genome, Breast Cancer, Genetic Testing, Prevention, Genetics, Ovarian Cancer, 2.1 Biological and endogenous factors, Aetiology, Adult, Breast Neoplasms, Cohort Studies, Female, Genes, BRCA1, Genes, BRCA2, Humans, Mutation, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Retrospective Studies, Young Adult, EMBRACE, GEMO Study Collaborators, HEBON, KConFab Investigators, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract: BackgroundBRCA1 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.MethodsGenotyping 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.ResultsThe 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.ConclusionThere 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.ImpactGenome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
Published: 2015

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

Author: Peterlongo, Paolo, Chang-Claude, Jenny, Moysich, Kirsten B, Rudolph, Anja, Schmutzler, Rita K, Simard, Jacques, Soucy, Penny, Eeles, Rosalind A, Easton, Douglas F, Hamann, Ute, Wilkening, Stefan, Chen, Bowang, Rookus, Matti A, Schmidt, Marjanka K, van der Baan, Frederieke H, Spurdle, Amanda B, Walker, Logan C, Lose, Felicity, Maia, Ana-Teresa, Montagna, Marco, Matricardi, Laura, Lubinski, Jan, Jakubowska, Anna, Gómez Garcia, Encarna B, Olopade, Olufunmilayo I, Nussbaum, Robert L, Nathanson, Katherine L, Domchek, Susan M, Rebbeck, Timothy R, Arun, Banu K, Karlan, Beth Y, Orsulic, Sandra, Lester, Jenny, Chung, Wendy K, Miron, Alex, Southey, Melissa C, Goldgar, David E, Buys, Saundra S, Janavicius, Ramunas, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Ding, Yuan Chun, Neuhausen, Susan L, Hansen, Thomas VO, Gerdes, Anne-Marie, Ejlertsen, Bent, Jønson, Lars, Osorio, Ana, Martínez-Bouzas, Cristina, Benitez, Javier, Conway, Edye E, Blazer, Kathleen R, Weitzel, Jeffrey N, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, 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 E, Donaldson, Alan, Brewer, Carole, Foo, Claire, Evans, D Gareth R, Frost, Debra, Eccles, Diana, Brady, Angela, Cook, Jackie, Tischkowitz, Marc, Adlard, Julian, Barwell, Julian, Walker, Lisa, Izatt, Louise, Side, Lucy E, Kennedy, M John, Rogers, Mark T, Porteous, Mary E, Morrison, Patrick J, Platte, Radka, Davidson, Rosemarie, Hodgson, Shirley V, Ellis, Steve, Cole, Trevor, EMBRACE, Godwin, Andrew K, Claes, Kathleen, Van Maerken, Tom, Meindl, Alfons, Gehrig, Andrea, and Sutter, Christian
Subjects: EMBRACE, GEMO Study Collaborators, HEBON, KConFab Investigators, Humans, Breast Neoplasms, Ovarian Neoplasms, Retrospective Studies, Cohort Studies, Mutation, Polymorphism, Single Nucleotide, Genes, BRCA1, Genes, BRCA2, Adult, Female, Young Adult, Polymorphism, Single Nucleotide, Genes, BRCA1, BRCA2, Prevention, Genetics, Human Genome, Breast Cancer, Cancer, Genetic Testing, Aging, Clinical Research, Rare Diseases, Ovarian Cancer, 2.1 Biological and endogenous factors, Epidemiology, Medical and Health Sciences
Abstract: BackgroundBRCA1 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.MethodsGenotyping 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.ResultsThe 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.ConclusionThere 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.ImpactGenome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
Published: 2015

12. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers.

Author: Kuchenbaecker, Karoline B, Neuhausen, Susan L, Robson, Mark, Barrowdale, Daniel, McGuffog, Lesley, Mulligan, Anna Marie, Andrulis, Irene L, Spurdle, Amanda B, Schmidt, Marjanka K, Schmutzler, Rita K, Engel, Christoph, Wappenschmidt, Barbara, Nevanlinna, Heli, Thomassen, Mads, Southey, Melissa, Radice, Paolo, Ramus, Susan J, Domchek, Susan M, Nathanson, Katherine L, Lee, Andrew, Healey, Sue, Nussbaum, Robert L, Rebbeck, Timothy R, Arun, Banu K, James, Paul, Karlan, Beth Y, Lester, Jenny, Cass, Ilana, Breast Cancer Family Registry, Terry, Mary Beth, Daly, Mary B, Goldgar, David E, Buys, Saundra S, Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Steele, Linda, v O Hansen, Thomas, Ejlertsen, Bent, Gerdes, Anne-Marie, Nielsen, Finn C, Dennis, Joe, Cunningham, Julie, Hart, Steven, Slager, Susan, Osorio, Ana, Benitez, Javier, Duran, Mercedes, Weitzel, Jeffrey N, Tafur, Isaac, Hander, Mary, Peterlongo, Paolo, Manoukian, Siranoush, Peissel, Bernard, Roversi, Gaia, Scuvera, Giulietta, Bonanni, Bernardo, Mariani, Paolo, Volorio, Sara, Dolcetti, Riccardo, Varesco, Liliana, Papi, Laura, Tibiletti, Maria Grazia, Giannini, Giuseppe, Fostira, Florentia, Konstantopoulou, Irene, Garber, Judy, Hamann, Ute, Donaldson, Alan, Brewer, Carole, Foo, Claire, Evans, D Gareth, Frost, Debra, Eccles, Diana, EMBRACE Study, Douglas, Fiona, Brady, Angela, Cook, Jackie, Tischkowitz, Marc, Adlard, Julian, Barwell, Julian, Ong, Kai-ren, Walker, Lisa, Izatt, Louise, Side, Lucy E, Kennedy, M John, Rogers, Mark T, Porteous, Mary E, Morrison, Patrick J, Platte, Radka, Eeles, Ros, Davidson, Rosemarie, Hodgson, Shirley, Ellis, Steve, Godwin, Andrew K, Rhiem, Kerstin, Meindl, Alfons, and Ditsch, Nina
Subjects: Breast Cancer Family Registry, EMBRACE Study, GEMO Study Collaborators, HEBON, KConFab Investigators, CIMBA, Humans, Carcinoma, Carcinoma, Ductal, Breast, Carcinoma, Lobular, Breast Neoplasms, Genetic Predisposition to Disease, Receptor, erbB-2, Receptors, Estrogen, Receptors, Progesterone, Neoplasm Staging, Heterozygote, Alleles, Genes, BRCA1, Genes, BRCA2, Adult, Aged, Middle Aged, Female, Neoplasm Grading, Receptor, ErbB-2, Ductal, Breast, Lobular, Receptor, erbB-2, Receptors, Estrogen, Progesterone, Genes, BRCA1, BRCA2, ErbB-2, Prevention, Breast Cancer, Clinical Research, Genetics, Cancer, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract: IntroductionMore than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers.MethodsWe used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement.ResultsThe estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P
Published: 2014

13. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia.

Author: Spurdle, Amanda B, Couch, Fergus J, Parsons, Michael T, McGuffog, Lesley, Barrowdale, Daniel, Bolla, Manjeet K, Wang, Qin, Healey, Sue, Schmutzler, Rita, Wappenschmidt, Barbara, Rhiem, Kerstin, Hahnen, Eric, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hansjoerg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Ellis, Steve, Frost, Debra, Platte, Radka, Perkins, Jo, Evans, D Gareth, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Scuvera, Giulietta, Manoukian, Siranoush, Bonanni, Bernardo, Mariette, Frederique, Fortuzzi, Stefano, Viel, Alessandra, Pasini, Barbara, Papi, Laura, Varesco, Liliana, Balleine, Rosemary, Nathanson, Katherine L, Domchek, Susan M, Offitt, Kenneth, Jakubowska, Anna, Lindor, Noralane, Thomassen, Mads, Jensen, Uffe Birk, Rantala, Johanna, Borg, Åke, Andrulis, Irene L, Miron, Alexander, Hansen, Thomas VO, Caldes, Trinidad, Neuhausen, Susan L, Toland, Amanda E, Nevanlinna, Heli, Montagna, Marco, Garber, Judy, Godwin, Andrew K, Osorio, Ana, Factor, Rachel E, Terry, Mary B, Rebbeck, Timothy R, Karlan, Beth Y, Southey, Melissa, Rashid, Muhammad Usman, Tung, Nadine, Pharoah, Paul DP, Blows, Fiona M, Dunning, Alison M, Provenzano, Elena, Hall, Per, Czene, Kamila, Schmidt, Marjanka K, Broeks, Annegien, Cornelissen, Sten, Verhoef, Senno, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Slamon, Dennis J, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, Aittomäki, Kristiina, Muranen, Taru A, Heikkilä, Päivi, Blomqvist, Carl, Figueroa, Jonine, Chanock, Stephen J, and Brinton, Louise
Subjects: ABCTB Investigators, EMBRACE Group, GENICA Network, HEBON Group, kConFab Investigators, Humans, Carcinoma, Breast Neoplasms, Receptor, erbB-2, Receptors, Estrogen, Receptors, Progesterone, Neoplasm Staging, Likelihood Functions, Age Factors, Mutation, Genes, BRCA1, Genes, BRCA2, Adult, Aged, Middle Aged, Female, Neoplasm Grading, Triple Negative Breast Neoplasms, Receptor, ErbB-2, Receptor, erbB-2, Receptors, Estrogen, Progesterone, Genes, BRCA1, BRCA2, ErbB-2, Prevention, Breast Cancer, Cancer, Genetics, 4.2 Evaluation of markers and technologies, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract: IntroductionThe distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling.MethodsSelection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach.ResultsER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)).ConclusionsThese results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
Published: 2014

14. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Author: Kuchenbaecker, Karoline B, Neuhausen, Susan L, Robson, Mark, Barrowdale, Daniel, McGuffog, Lesley, Mulligan, Anna Marie, Andrulis, Irene L, Spurdle, Amanda B, Schmidt, Marjanka K, Schmutzler, Rita K, Engel, Christoph, Wappenschmidt, Barbara, Nevanlinna, Heli, Thomassen, Mads, Southey, Melissa, Radice, Paolo, Ramus, Susan J, Domchek, Susan M, Nathanson, Katherine L, Lee, Andrew, Healey, Sue, Nussbaum, Robert L, Rebbeck, Timothy R, Arun, Banu K, James, Paul, Karlan, Beth Y, Lester, Jenny, Cass, Ilana, Registry, Breast Cancer Family, Terry, Mary Beth, Daly, Mary B, Goldgar, David E, Buys, Saundra S, Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Steele, Linda, v O Hansen, Thomas, Ejlertsen, Bent, Gerdes, Anne-Marie, Nielsen, Finn C, Dennis, Joe, Cunningham, Julie, Hart, Steven, Slager, Susan, Osorio, Ana, Benitez, Javier, Duran, Mercedes, Weitzel, Jeffrey N, Tafur, Isaac, Hander, Mary, Peterlongo, Paolo, Manoukian, Siranoush, Peissel, Bernard, Roversi, Gaia, Scuvera, Giulietta, Bonanni, Bernardo, Mariani, Paolo, Volorio, Sara, Dolcetti, Riccardo, Varesco, Liliana, Papi, Laura, Tibiletti, Maria Grazia, Giannini, Giuseppe, Fostira, Florentia, Konstantopoulou, Irene, Garber, Judy, Hamann, Ute, Donaldson, Alan, Brewer, Carole, Foo, Claire, Evans, D Gareth, Frost, Debra, Eccles, Diana, Douglas, Fiona, Brady, Angela, Cook, Jackie, Tischkowitz, Marc, Adlard, Julian, Barwell, Julian, Ong, Kai-ren, Walker, Lisa, Izatt, Louise, Side, Lucy E, Kennedy, M John, Rogers, Mark T, Porteous, Mary E, Morrison, Patrick J, Platte, Radka, Eeles, Ros, Davidson, Rosemarie, Hodgson, Shirley, Ellis, Steve, Godwin, Andrew K, Rhiem, Kerstin, Meindl, Alfons, Ditsch, Nina, and Arnold, Norbert
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Prevention, Breast Cancer, Clinical Research, Cancer, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Alleles, Breast Neoplasms, Carcinoma, Carcinoma, Ductal, Breast, Carcinoma, Lobular, Female, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Heterozygote, Humans, Middle Aged, Neoplasm Grading, Neoplasm Staging, Receptor, ErbB-2, Receptors, Estrogen, Receptors, Progesterone, Breast Cancer Family Registry, EMBRACE Study, GEMO Study Collaborators, HEBON, KConFab Investigators, CIMBA, Receptor, erbB-2, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: IntroductionMore than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers.MethodsWe used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement.ResultsThe estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P
Published: 2014

15. Refined histopathological predictors of BRCA1 and BRCA2mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Author: Spurdle, Amanda B, Couch, Fergus J, Parsons, Michael T, McGuffog, Lesley, Barrowdale, Daniel, Bolla, Manjeet K, Wang, Qin, Healey, Sue, Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Hahnen, Eric, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hansjoerg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Ellis, Steve, Frost, Debra, Platte, Radka, Perkins, Jo, Evans, D Gareth, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Scuvera, Giulietta, Manoukian, Siranoush, Bonanni, Bernardo, Mariette, Frederique, Fortuzzi, Stefano, Viel, Alessandra, Pasini, Barbara, Papi, Laura, Varesco, Liliana, Balleine, Rosemary, Nathanson, Katherine L, Domchek, Susan M, Offitt, Kenneth, Jakubowska, Anna, Lindor, Noralane, Thomassen, Mads, Jensen, Uffe Birk, Rantala, Johanna, Borg, Åke, Andrulis, Irene L, Miron, Alexander, Hansen, Thomas VO, Caldes, Trinidad, Neuhausen, Susan L, Toland, Amanda E, Nevanlinna, Heli, Montagna, Marco, Garber, Judy, Godwin, Andrew K, Osorio, Ana, Factor, Rachel E, Terry, Mary B, Rebbeck, Timothy R, Karlan, Beth Y, Southey, Melissa, Rashid, Muhammad Usman, Tung, Nadine, Pharoah, Paul DP, Blows, Fiona M, Dunning, Alison M, Provenzano, Elena, Hall, Per, Czene, Kamila, Schmidt, Marjanka K, Broeks, Annegien, Cornelissen, Sten, Verhoef, Senno, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Slamon, Dennis J, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, Aittomäki, Kristiina, Muranen, Taru A, Heikkilä, Päivi, Blomqvist, Carl, Figueroa, Jonine, Chanock, Stephen J, and Brinton, Louise
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Cancer, Prevention, Genetics, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Adult, Age Factors, Aged, Breast Neoplasms, Carcinoma, Female, Genes, BRCA1, Genes, BRCA2, Humans, Likelihood Functions, Middle Aged, Mutation, Neoplasm Grading, Neoplasm Staging, Receptor, ErbB-2, Receptors, Estrogen, Receptors, Progesterone, Triple Negative Breast Neoplasms, ABCTB Investigators, EMBRACE Group, GENICA Network, HEBON Group, kConFab Investigators, Receptor, erbB-2, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
Published: 2014

16. 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, and Engel, Christoph
Subjects: SWE-BRCA, HEBON, KConFab Investigators, Humans, Breast Neoplasms, Ovarian Neoplasms, Genetic Predisposition to Disease, DNA Glycosylases, BRCA1 Protein, BRCA2 Protein, Risk, DNA Repair, Genotype, Polymorphism, Single Nucleotide, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Polymorphism, Single Nucleotide, and over, Developmental Biology, Genetics
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

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

Author: Osorio, Ana, Milne, Roger, 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, Arver, Brita, Rantala, Johanna, Loman, Niklas, Ehrencrona, Hans, Olopade, Olufunmilayo, Beattie, Mary, Domchek, Susan, Nathanson, Katherine, Rebbeck, Timothy, Arun, Banu, Walsh, Christine, Lester, Jenny, John, Esther, Whittemore, Alice, Daly, Mary, Southey, Melissa, Hopper, John, Terry, Mary, Buys, Saundra, Janavicius, Ramunas, Dorfling, Cecilia, van Rensburg, Elizabeth, Steele, Linda, Neuhausen, Susan, Ding, Yuan, Hansen, Thomas, Jønson, Lars, Ejlertsen, Bent, Gerdes, Anne-Marie, Infante, Mar, Herráez, Belén, Moreno, Leticia, Weitzel, Jeffrey, 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, 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, Schmutzler, Rita, Wappenschmidt, Barbara, Rhiem, Kerstin, Engel, Christoph, Meindl, Alfons, and Ditsch, Nina
Subjects: Adolescent, Adult, Aged, Aged, 80 and over, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, DNA Glycosylases, DNA Repair, Female, Genetic Predisposition to Disease, Genotype, Humans, Middle Aged, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk
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

18. 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, and Engel, Christoph
Subjects: Biological Sciences, Genetics, Cancer, Genetic Testing, Rare Diseases, Breast Cancer, Prevention, Ovarian Cancer, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Adult, Aged, Aged, 80 and over, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, DNA Glycosylases, DNA Repair, Female, Genetic Predisposition to Disease, Genotype, Humans, Middle Aged, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk, SWE-BRCA, HEBON, 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

19. 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 BL, Peock, Susan, Stoppa-Lyonnet, Dominique, Jakubowska, Anna, kConFab Investigators, Radice, Paolo, Schmutzler, Rita Katharina, SWE-BRCA, Domchek, Susan M, Piedmonte, Marion, Singer, Christian F, Friedman, Eitan, Thomassen, Mads, Ontario Cancer Genetics Network, Hansen, Thomas VO, 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 HM, Seynaeve, Caroline, Gómez Garcia, Encarna B, van Leeuwen, Flora E, Meijers-Heijboer, Hanne EJ, Gille, Johannes JP, Ausems, Margreet GEM, Blok, Marinus J, Ligtenberg, Marjolijn JL, Rookus, Matti A, Devilee, Peter, Verhoef, Senno, van Os, Theo AM, Wijnen, Juul T, HEBON, EMBRACE, Frost, Debra, Ellis, Steve, Fineberg, Elena, Platte, Radka, Evans, D Gareth, Izatt, Louise, Eeles, Rosalind A, and Adlard, Julian
Subjects: kConFab Investigators, SWE-BRCA, Ontario Cancer Genetics Network, HEBON, EMBRACE, GEMO Study Collaborators, BCFR, CIMBA, Humans, Breast Neoplasms, Ovarian Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, BRCA2 Protein, Prognosis, Risk Factors, Genotype, Heterozygote, Mutation, Polymorphism, Single Nucleotide, Middle Aged, Female, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Developmental Biology, Genetics
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.
Published: 2013

20. 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 BL, Peock, Susan, Stoppa-Lyonnet, Dominique, Jakubowska, Anna, Investigators, kConFab, Radice, Paolo, Schmutzler, Rita Katharina, Domchek, Susan M, Piedmonte, Marion, Singer, Christian F, Friedman, Eitan, Thomassen, Mads, Hansen, Thomas VO, 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, Ewart Toland, Amanda, 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 HM, Seynaeve, Caroline, Gómez Garcia, Encarna B, van Leeuwen, Flora E, Meijers-Heijboer, Hanne EJ, Gille, Johannes JP, Ausems, Margreet GEM, Blok, Marinus J, Ligtenberg, Marjolijn JL, Rookus, Matti A, Devilee, Peter, Verhoef, Senno, van Os, Theo AM, Wijnen, Juul T, Frost, Debra, Ellis, Steve, Fineberg, Elena, Platte, Radka, Evans, D Gareth, Izatt, Louise, Eeles, Rosalind A, Adlard, Julian, Eccles, Diana M, Cook, Jackie, Brewer, Carole, and Douglas, Fiona
Subjects: Biological Sciences, Genetics, Human Genome, Cancer, Prevention, Breast Cancer, Rare Diseases, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heterozygote, Humans, Middle Aged, Mutation, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Prognosis, Risk Factors, kConFab Investigators, SWE-BRCA, Ontario Cancer Genetics Network, HEBON, EMBRACE, GEMO Study Collaborators, BCFR, CIMBA, Developmental Biology
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.
Published: 2013

21. 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 C, Kuchenbaecker, Karoline B, Soucy, Penny, Beesley, Jonathan, Chen, Xiaoqing, McGuffog, Lesley, Lee, Andrew, Barrowdale, Daniel, Healey, Sue, Sinilnikova, Olga M, Caligo, Maria A, 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 B, van Os, Theo A, Verhoef, Senno, Meijers-Heijboer, Hanne EJ, Wijnen, Juul, Gómez Garcia, Encarna B, Ligtenberg, Marjolijn J, Kriege, Mieke, Collée, J Margriet, Ausems, Margreet GEM, Oosterwijk, Jan C, Peock, Susan, Frost, Debra, Ellis, Steve D, 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 J, Walker, Lisa, Rogers, Mark T, Donaldson, Alan, Dorkins, Huw, Godwin, Andrew K, 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, Hopper, John L, John, Esther M, Southey, Melissa, Goldgar, David, Singer, Christian F, Fink-Retter, Anneliese, Tea, Muy-Kheng, Kaulich, Daphne, Hansen, Thomas VO, Nielsen, Finn C, Barkardottir, Rosa B, Gaudet, Mia, Kirchhoff, Tomas, Joseph, Vijai, Dutra-Clarke, Ana, Offit, Kenneth, and Piedmonte, Marion
Abstract: AbstractIntroductionSeveral 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). MethodsTo evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12599 BRCA1 and 7132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. ResultsOnly SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele Hazard Ratio (HR)= 0.87, 95%CI:0.81-0.94, P-trend=3x10^-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR=0.82, 95%CI:0.74-0.90, P-trend=3.1x10^-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: 0.74-0.90, P-trend=4x10^-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR=0.78, 95%CI:0.62-1.00, P-trend=0.049). ConclusionsThe 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.
Published: 2012

22. 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, AC, Kuchenbaecker, KB, Soucy, P, Beesley, J, Chen, X, McGuffog, L, Lee, A, Barrowdale, D, Healey, S, Sinilnikova, OM, Caligo, MA, Loman, N, Harbst, K, Lindblom, A, Arver, B, Rosenquist, R, Karlsson, P, Nathanson, K, Domchek, S, Rebbeck, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Zlowowcka-Perlowska, E, Osorio, A, Duran, M, Andres, R, Benitez, J, Hamann, U, Hogervorst, FB, van Os, TA, Verhoef, S, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Ligtenberg, MJ, Kriege, M, Collee, M, Ausems, MGEM, Oosterwijk, JC, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Jacobs, C, Eeles, R, Adlard, J, Davidson, R, Cole, T, Cook, J, Paterson, J, Douglas, F, Brewer, C, Hodgson, S, Morrison, PJ, Walker, L, Rogers, MT, Donaldson, A, Dorkins, H, Godwin, AK, Bove, B, Stoppa-Lyonnet, D, Houdayer, C, Buecher, B, de Pauw, A, Mazoyer, S, Calender, A, Leone, M, Bressac-de Paillerets, B, Caron, O, Sobol, H, Frenay, M, Prieur, F, Ferrer, SF, Mortemousque, I, Buys, S, Daly, M, Miron, A, Terry, MB, Hopper, JL, John, EM, Southey, M, Goldgar, D, Singer, CF, Fink-Retter, A, Tea, M-K, Kaulich, DG, Hansen, TVO, Nielsen, FC, Barkardottir, RB, Gaudet, M, Kirchhoff, T, Joseph, V, Dutra-Clarke, A, Offit, K, and Piedmonte, M
Published: 2012

23. Risk of Estrogen Receptor–Positive and –Negative Breast Cancer and Single–Nucleotide Polymorphism 2q35-rs13387042

Author: Milne, Roger L, Benítez, Javier, Nevanlinna, Heli, Heikkinen, Tuomas, Aittomäki, Kristiina, Blomqvist, Carl, Arias, José Ignacio, Zamora, M Pilar, Burwinkel, Barbara, Bartram, Claus R, Meindl, Alfons, Schmutzler, Rita K, Cox, Angela, Brock, Ian, Elliott, Graeme, Reed, Malcolm WR, Southey, Melissa C, Smith, Letitia, Spurdle, Amanda B, Hopper, John L, Couch, Fergus J, Olson, Janet E, Wang, Xianshu, Fredericksen, Zachary, Schürmann, Peter, Bremer, Michael, Hillemanns, Peter, Dörk, Thilo, Devilee, Peter, van Asperen, Christie J, Tollenaar, Rob AEM, Seynaeve, Caroline, Hall, Per, Czene, Kamila, Liu, Jianjun, Li, Yuqing, Ahmed, Shahana, Dunning, Alison M, Maranian, Melanie, Pharoah, Paul DP, Chenevix-Trench, Georgia, Beesley, Jonathan, Investigators, kConFab, Group, AOCS, Bogdanova, Natalia V, Antonenkova, Natalia N, Zalutsky, Iosif V, Anton-Culver, Hoda, Ziogas, Argyrios, Brauch, Hiltrud, Justenhoven, Christina, Ko, Yon-Dschun, Haas, Susanne, Fasching, Peter A, Strick, Reiner, Ekici, Arif B, Beckmann, Matthias W, Giles, Graham G, Severi, Gianluca, Baglietto, Laura, English, Dallas R, Fletcher, Olivia, Johnson, Nichola, dos Santos Silva, Isabel, Peto, Julian, Turnbull, Clare, Hines, Sarah, Renwick, Anthony, Rahman, Nazneen, Nordestgaard, Børge G, Bojesen, Stig E, Flyger, Henrik, Kang, Daehee, Yoo, Keun-Young, Noh, Dong-Young, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, García-Closas, Montserrat, Chanock, Stephen, Lissowska, Jolanta, Brinton, Louise A, Chang-Claude, Jenny, Wang-Gohrke, Shan, Shen, Chen-Yang, Wang, Hui-Chun, Yu, Jyh-Cherng, Chen, Sou-Tong, Bermisheva, Marina, Nikolaeva, Tatjana, Khusnutdinova, Elza, Humphreys, Manjeet K, Morrison, Jonathan, Platte, Radka, Easton, Douglas F, and Consortium, on behalf of the Breast Cancer Association
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Breast Cancer, Clinical Research, Cancer, Human Genome, Estrogen, Adult, Aged, Asian People, Biomarkers, Tumor, Breast Neoplasms, Carcinoma, Ductal, Breast, Carcinoma, Intraductal, Noninfiltrating, Case-Control Studies, Confidence Intervals, Confounding Factors, Epidemiologic, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Linkage Disequilibrium, Middle Aged, Neoplasms, Hormone-Dependent, Odds Ratio, Polymorphism, Single Nucleotide, Receptors, Estrogen, Receptors, Progesterone, White People, kConFab Investigators, AOCS Group, Breast Cancer Association Consortium, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: BackgroundA recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)-positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium.Methods2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided.ResultsWe found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; P(trend) = 1.0 x 10(-19)). The odds ratio was lower than that previously reported (P = .02) and did not vary by age or ethnicity (all P > or = .2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P = .02). An association was observed for both ER-positive (OR = 1.14, 95% CI = 1.10 to 1.17; P = 10(-15)) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P = .0003) and both progesterone receptor (PR)-positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 x 10(-14)) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P = .00002).ConclusionThe rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women.
Published: 2009

24. Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042.

Author: Milne, Roger L, Benítez, Javier, Nevanlinna, Heli, Heikkinen, Tuomas, Aittomäki, Kristiina, Blomqvist, Carl, Arias, José Ignacio, Zamora, M Pilar, Burwinkel, Barbara, Bartram, Claus R, Meindl, Alfons, Schmutzler, Rita K, Cox, Angela, Brock, Ian, Elliott, Graeme, Reed, Malcolm WR, Southey, Melissa C, Smith, Letitia, Spurdle, Amanda B, Hopper, John L, Couch, Fergus J, Olson, Janet E, Wang, Xianshu, Fredericksen, Zachary, Schürmann, Peter, Bremer, Michael, Hillemanns, Peter, Dörk, Thilo, Devilee, Peter, van Asperen, Christie J, Tollenaar, Rob AEM, Seynaeve, Caroline, Hall, Per, Czene, Kamila, Liu, Jianjun, Li, Yuqing, Ahmed, Shahana, Dunning, Alison M, Maranian, Melanie, Pharoah, Paul DP, Chenevix-Trench, Georgia, Beesley, Jonathan, kConFab Investigators, AOCS Group, Bogdanova, Natalia V, Antonenkova, Natalia N, Zalutsky, Iosif V, Anton-Culver, Hoda, Ziogas, Argyrios, Brauch, Hiltrud, Justenhoven, Christina, Ko, Yon-Dschun, Haas, Susanne, Fasching, Peter A, Strick, Reiner, Ekici, Arif B, Beckmann, Matthias W, Giles, Graham G, Severi, Gianluca, Baglietto, Laura, English, Dallas R, Fletcher, Olivia, Johnson, Nichola, dos Santos Silva, Isabel, Peto, Julian, Turnbull, Clare, Hines, Sarah, Renwick, Anthony, Rahman, Nazneen, Nordestgaard, Børge G, Bojesen, Stig E, Flyger, Henrik, Kang, Daehee, Yoo, Keun-Young, Noh, Dong-Young, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, García-Closas, Montserrat, Chanock, Stephen, Lissowska, Jolanta, Brinton, Louise A, Chang-Claude, Jenny, Wang-Gohrke, Shan, Shen, Chen-Yang, Wang, Hui-Chun, Yu, Jyh-Cherng, Chen, Sou-Tong, Bermisheva, Marina, Nikolaeva, Tatjana, Khusnutdinova, Elza, Humphreys, Manjeet K, Morrison, Jonathan, Platte, Radka, Easton, Douglas F, and Breast Cancer Association Consortium
Subjects: kConFab Investigators, AOCS Group, Breast Cancer Association Consortium, Humans, Carcinoma, Ductal, Breast, Carcinoma, Intraductal, Noninfiltrating, Breast Neoplasms, Neoplasms, Hormone-Dependent, Genetic Predisposition to Disease, Receptors, Estrogen, Receptors, Progesterone, Confidence Intervals, Odds Ratio, Case-Control Studies, Gene Frequency, Genotype, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Asian Continental Ancestry Group, European Continental Ancestry Group, Female, Biomarkers, Tumor, Confounding Factors, Epidemiologic, Carcinoma, Ductal, Breast, Intraductal, Noninfiltrating, Neoplasms, Hormone-Dependent, Receptors, Estrogen, Progesterone, Polymorphism, Single Nucleotide, Biomarkers, Tumor, Confounding Factors, Epidemiologic, Clinical Research, Breast Cancer, Human Genome, Cancer, Genetics, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: BackgroundA recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)-positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium.Methods2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided.ResultsWe found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; P(trend) = 1.0 x 10(-19)). The odds ratio was lower than that previously reported (P = .02) and did not vary by age or ethnicity (all P > or = .2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P = .02). An association was observed for both ER-positive (OR = 1.14, 95% CI = 1.10 to 1.17; P = 10(-15)) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P = .0003) and both progesterone receptor (PR)-positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 x 10(-14)) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P = .00002).ConclusionThe rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women.
Published: 2009

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24 results on '"Platte P"'

1. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

2. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2.

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

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

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

6. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

7. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

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

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

10. Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

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

12. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers.

13. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia.

14. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

15. Refined histopathological predictors of BRCA1 and BRCA2mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

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

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

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

19. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

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

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

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

23. Risk of Estrogen Receptor–Positive and –Negative Breast Cancer and Single–Nucleotide Polymorphism 2q35-rs13387042

24. Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042.

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