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5 results on '"Guenel, Pascal"'

1. Fine‐scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer

Author

Shi, Jiajun, Zhang, Yanfeng, Zheng, Wei, Michailidou, Kyriaki, Ghoussaini, Maya, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Lush, Michael, Milne, Roger L, Shu, Xiao‐Ou, Beesley, Jonathan, Kar, Siddhartha, Andrulis, Irene L, Anton‐Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Zhao, Zhiguo, Guo, Xingyi, Benitez, Javier, Beeghly‐Fadiel, Alicia, Blot, William, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Hui, Canisius, Sander, Chang‐Claude, Jenny, Choi, Ji‐Yeob, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Darabi, Hatef, Devilee, Peter, Droit, Arnaud, Dork, Thilo, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gaborieau, Valerie, García‐Closas, Montserrat, Giles, Graham G, Grip, Mervi, Guenel, Pascal, Haiman, Christopher A, Hamann, Ute, Hartman, Mikael, Miao, Hui, Hollestelle, Antoinette, Hopper, John L, Hsiung, Chia‐Ni, Investigators, kConFab, Ito, Hidemi, Jakubowska, Anna, Johnson, Nichola, Torres, Diana, Kabisch, Maria, Kang, Daehee, Khan, Sofia, Knight, Julia A, Kosma, Veli‐Matti, Lambrechts, Diether, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Le Marchand, Loic, Margolin, Sara, Marme, Frederik, Matsuo, Keitaro, McLean, Catriona, Meindl, Alfons, Muir, Kenneth, Neuhausen, Susan L, Nevanlinna, Heli, Nord, Silje, Børresen‐Dale, Anne‐Lise, Olson, Janet E, Orr, Nick, van den Ouweland, Ans MW, Peterlongo, Paolo, Putti, Thomas Choudary, Rudolph, Anja, Sangrajrang, Suleeporn, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Shen, Chen‐Yang, Hou, Ming‐Feng, Shrubsole, Matha J, and Southey, Melissa C

Subjects
Genetics, Cancer, Breast Cancer, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Alleles, Breast Neoplasms, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 8, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Linkage Disequilibrium, Odds Ratio, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, White People, breast cancer, genetic susceptibility, 8q24, fine-mapping, single nucleotide polymorphism, Mervi Grip, kConFab Investigators, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2)  = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.

Published
2016

2. Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent

Author

Guo, Yan, Warren Andersen, Shaneda, Shu, Xiao-Ou, Michailidou, Kyriaki, Bolla, Manjeet K., Wang, Qin, Garcia-Closas, Montserrat, Milne, Roger L., Schmidt, Marjanka K., Chang-Claude, Jenny, Dunning, Allison, Bojesen, Stig E., Ahsan, Habibul, Aittomäki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bogdanova, Natalia V., Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brand, Judith, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Casey, Graham, Chenevix-Trench, Georgia, Couch, Fergus J., Cox, Angela, Cross, Simon S., Czene, Kamila, Devilee, Peter, Dörk, Thilo, Dumont, Martine, Fasching, Peter A., Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gammon, Marilie, Giles, Graham G., Guénel, Pascal, Haiman, Christopher A., Hamann, Ute, Hooning, Maartje J., Hopper, John L., Jakubowska, Anna, Jasmine, Farzana, Jenkins, Mark, John, Esther M., Johnson, Nichola, Jones, Michael E., Kabisch, Maria, Kibriya, Muhammad, Knight, Julia A., Koppert, Linetta B., Kosma, Veli-Matti, Kristensen, Vessela, Le Marchand, Loic, Lee, Eunjung, Li, Jingmei, Lindblom, Annika, Luben, Robert, Lubinski, Jan, Malone, Kathi E., Mannermaa, Arto, Margolin, Sara, Marme, Frederik, McLean, Catriona, Meijers-Heijboer, Hanne, Meindl, Alfons, Neuhausen, Susan L., Nevanlinna, Heli, Neven, Patrick, Olson, Janet E., Perez, Jose I. A., Perkins, Barbara, Peterlongo, Paolo, Phillips, Kelly-Anne, Pylkäs, Katri, Rudolph, Anja, Santella, Regina, Sawyer, Elinor J., Schmutzler, Rita K., Seynaeve, Caroline, Shah, Mitul, Shrubsole, Martha J., Southey, Melissa C., Swerdlow, Anthony J., Toland, Amanda E., Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Ursin, Giske, Van Der Luijt, Rob B., Verhoef, Senno, Whittemore, Alice S., Winqvist, Robert, Zhao, Hui, Zhao, Shilin, Hall, Per, Simard, Jacques, Kraft, Peter, Pharoah, Paul, Hunter, David, Easton, Douglas F., and Zheng, Wei

Subjects
Medicine and Health Sciences, Oncology, Cancers and Neoplasms, Breast Tumors, Breast Cancer, Biology and Life Sciences, Genetics, Human Genetics, Physiology, Physiological Parameters, Body Weight, Body Mass Index, Cancer Risk Factors, Social Sciences, Sociology, Consortia, Computational Biology, Genome Analysis, Genome-Wide Association Studies, Genomics, Epidemiology, Genetic Epidemiology, Endocrinology, Endocrine Physiology, Menstrual Cycle, Menarche, Reproductive Physiology
Abstract

Background: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. Methods: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. Results: In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56–0.75, p = 3.32 × 10−10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31–0.62, p = 9.91 × 10−8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46–0.71, p = 1.88 × 10−8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60–0.84, p = 1.64 × 10−7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. Conclusions: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

Published
2016
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3. MicroRNA Related Polymorphisms and Breast Cancer Risk

Author

Khan, Sofia, Greco, Dario, Michailidou, Kyriaki, Milne, Roger L., Muranen, Taru A., Heikkinen, Tuomas, Aaltonen, Kirsimari, Dennis, Joe, Bolla, Manjeet K., Liu, Jianjun, Hall, Per, Irwanto, Astrid, Humphreys, Keith, Li, Jingmei, Czene, Kamila, Chang-Claude, Jenny, Hein, Rebecca, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Fletcher, Olivia, Peto, Julian, dos Santos Silva, Isabel, Johnson, Nichola, Gibson, Lorna, Aitken, Zoe, Hopper, John L., Tsimiklis, Helen, Bui, Minh, Makalic, Enes, Schmidt, Daniel F., Southey, Melissa C., Apicella, Carmel, Stone, Jennifer, Waisfisz, Quinten, Meijers-Heijboer, Hanne, Adank, Muriel A., van der Luijt, Rob B., Meindl, Alfons, Schmutzler, Rita K., Müller-Myhsok, Bertram, Lichtner, Peter, Turnbull, Clare, Rahman, Nazneen, Chanock, Stephen J., Hunter, David J., Cox, Angela, Cross, Simon S., Reed, Malcolm W. R., Schmidt, Marjanka K., Broeks, Annegien, Veer, Laura J. V. a. n't., Hogervorst, Frans B., Fasching, Peter A., Schrauder, Michael G., Ekici, Arif B., Beckmann, Matthias W., Bojesen, Stig E., Nordestgaard, Børge G., Nielsen, Sune F., Flyger, Henrik, Benitez, Javier, Zamora, Pilar M., Perez, Jose I. A., Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Pharoah, Paul D. P., Dunning, Alison M., Shah, Mitul, Luben, Robert, Brown, Judith, Couch, Fergus J., Wang, Xianshu, Vachon, Celine, Olson, Janet E., Lambrechts, Diether, Moisse, Matthieu, Paridaens, Robert, Christiaens, Marie-Rose, Guénel, Pascal, Truong, Thérèse, Laurent-Puig, Pierre, Mulot, Claire, Marme, Frederick, Burwinkel, Barbara, Schneeweiss, Andreas, Sohn, Christof, Sawyer, Elinor J., Tomlinson, Ian, Kerin, Michael J., Miller, Nicola, Andrulis, Irene L., Knight, Julia A., Tchatchou, Sandrine, Mulligan, Anna Marie, Dörk, Thilo, Bogdanova, Natalia V., Antonenkova, Natalia N., Anton-Culver, Hoda, Darabi, Hatef, Eriksson, Mikael, Garcia-Closas, Montserrat, Figueroa, Jonine, Lissowska, Jolanta, Brinton, Louise, Devilee, Peter, Tollenaar, Robert A. E. M., Seynaeve, Caroline, van Asperen, Christi J., Kristensen, Vessela N., Slager, Susan, Toland, Amanda E., Ambrosone, Christine B., Yannoukakos, Drakoulis, Lindblom, Annika, Margolin, Sara, Radice, Paolo, Peterlongo, Paolo, Barile, Monica, Mariani, Paolo, Hooning, Maartje J., Martens, John W. M., Collée, J. Margriet, Jager, Agnes, Jakubowska, Anna, Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Giles, Graham G., McLean, Catriona, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Jones, Michael, Simard, Jacques, Goldberg, Mark S., Labrèche, France, Dumont, Martine, Winqvist, Robert, Pylkäs, Katri, Jukkola-Vuorinen, Arja, Grip, Mervi, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Mannermaa, Arto, Hamann, Ute, Chenevix-Trench, Georgia, Blomqvist, Carl, Aittomäki, Kristiina, Easton, Douglas F., and Nevanlinna, Heli

Subjects
Biology and Life Sciences, Genetics, Genetics of Disease, Genetic Predisposition, Heredity, Complex Traits, Human Genetics, Genetic Association Studies, Cancer Genetics
Abstract

Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88–0.96), rs1052532 (OR 0.97; 95% CI: 0.95–0.99), rs10719 (OR 0.97; 95% CI: 0.94–0.99), rs4687554 (OR 0.97; 95% CI: 0.95–0.99, and rs3134615 (OR 1.03; 95% CI: 1.01–1.05) located in the 3′ UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.

Published
2014
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4. Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium

Author

Lei, Jieping, Rudolph, Anja, Moysich, Kirsten B., Behrens, Sabine, Goode, Ellen L., Bolla, Manjeet K., Dennis, Joe, Dunning, Alison M., Easton, Douglas F., Wang, Qin, Benitez, Javier, Hopper, John L., Southey, Melissa C., Schmidt, Marjanka K., Broeks, Annegien, Fasching, Peter A., Haeberle, Lothar, Peto, Julian, dos-Santos-Silva, Isabel, Sawyer, Elinor J., Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guenel, Pascal, Truong, Therese, Bojesen, Stig E., Flyger, Henrik, Nielsen, Sune F., Nordestgaard, Borge G., Gonzalez-Neira, Anna, Menendez, Primitiva, Anton-Culver, Hoda, Neuhausen, Susan L., Brenner, Hermann, Arndt, Volker, Meindl, Alfons, Schmutzler, Rita K., Brauch, Hiltrud, Hamann, Ute, Nevanlinna, Heli, Fagerholm, Rainer, Doerk, Thilo, Bogdanova, Natalia V., Mannermaa, Arto, Hartikainen, Jaana M., Van Dijck, Laurien, Smeets, Ann, Flesch-Janys, Dieter, Eilber, Ursula, Radice, Paolo, Peterlongo, Paolo, Couch, Fergus J., Hallberg, Emily, Giles, Graham G., Milne, Roger L., Haiman, Christopher A., Schumacher, Fredrick, Simard, Jacques, Goldberg, Mark S., Kristensen, Vessela, Borresen-Dale, Anne-Lise, Zheng, Wei, Beeghly-Fadiel, Alicia, Winqvist, Robert, Grip, Mervi, Andrulis, Irene L., Glendon, Gord, Garcia-Closas, Montserrat, Figueroa, Jonine, Czene, Kamila, Brand, Judith S., Darabi, Hatef, Eriksson, Mikael, Hall, Per, Li, Jingmei, Cox, Angela, Cross, Simon S., Pharoah, Paul D. P., Shah, Mitul, Kabisch, Maria, Torres, Diana, Jakubowska, Anna, Lubinski, Jan, Ademuyiwa, Foluso, Ambrosone, Christine B., Swerdlow, Anthony, Jones, Michael, Chang-Claude, Jenny, Department of Obstetrics and Gynecology, and Clinicum

Subjects
3122 Cancers, LOCI, Breast Neoplasms, MULTIPLE-SCLEROSIS, Polymorphism, Single Nucleotide, CROHNS-DISEASE, STAT3, Case-Control Studies, ANTITUMOR IMMUNITY, Immune Tolerance, Genetics, SUPPRESSOR-CELLS, Humans, JAPANESE POPULATION, Female, Genetic Predisposition to Disease, Genetics(clinical), REGULATORY T-CELLS, 3111 Biomedicine, GENOME-WIDE ASSOCIATION, TUMOR MICROENVIRONMENT, Original Investigation
Abstract

Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03–1.08; p value = 1.4 × 10−6). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10−3 and 7.0 × 10−3, respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10−3, 4.5 × 10−4 and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3,IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry. Electronic supplementary material The online version of this article (doi:10.1007/s00439-015-1616-8) contains supplementary material, which is available to authorized users.

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5. Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

Author

Gaudet, Mia M., Kuchenbaecker, Karoline B., Vijai, Joseph, Klein, Robert J., Kirchhoff, Tomas, McGuffog, Lesley, Barrowdale, Daniel, Dunning, Alison M., Dennis, Joe, Healey, Sue, Dicks, Ed, Soucy, Penny, Sinilnikova, Olga M., Pankratz, Vernon S., Wang, Xianshu, Eldridge, Ronald C., Tessier, Daniel C., Vincent, Daniel, Bacot, Francois, Hogervorst, Frans B. L., Peock, Susan, Stoppa-Lyonnet, Dominique, Peterlongo, Paolo, Schmutzler, Rita K., Nathanson, Katherine L., Piedmonte, Marion, Singer, Christian F., Thomassen, Mads, Hansen, Thomas v. O., Neuhausen, Susan L., Blanco, Ignacio, Greene, Mark H., Weitzel, Jeffrey N., Andrulis, Irene L., Goldgar, David E., D'Andrea, Emma, Caldes, Trinidad, Nevanlinna, Heli, Osorio, Ana, van Rensburg, Elizabeth J., Arason, Adalgeir, Rennert, Gad, van den Ouweland, Ans M. W., van der Hout, Annemarie H., Kets, Carolien M., Aalfs, Cora M., Wijnen, Juul T., Ausems, Margreet G. E. M., Frost, Debra, Ellis, Steve, Fineberg, Elena, Platte, Radka, Adlard, Julian, Tischkowitz, Marc, Porteous, Mary E., Damiola, Francesca, Golmard, Lisa, Barjhoux, Laure, Longy, Michel, Belotti, Muriel, Ferrer, Sandra Fert, Mazoyer, Sylvie, Spurdle, Amanda B., Manoukian, Siranoush, Barile, Monica, Genuardi, Maurizio, Arnold, Norbert, Meindl, Alfons, Sutter, Christian, Wappenschmidt, Barbara, Domchek, Susan M., Pfeiler, Georg, Friedman, Eitan, Jensen, Uffe Birk, Robson, Mark, Shah, Sohela, Lazaro, Conxi, Benitez, Javier, Southey, Melissa C., Schmidt, Marjanka K., Fasching, Peter A., Peto, Julian, Humphreys, Manjeet K., Michailidou, Kyriaki, Sawyer, Elinor J., Burwinkel, Barbara, Guénel, Pascal, Bojesen, Stig E., Milne, Roger L., Brenner, Hermann, Lochmann, Magdalena, Aittomäki, Kristiina, Dörk, Thilo, Margolin, Sara, Mannermaa, Arto, Lambrechts, Diether, Chang-Claude, Jenny, Radice, Paolo, Giles, Graham G., Haiman, Christopher A., Winqvist, Robert, Devillee, Peter, García-Closas, Montserrat, Schoof, Nils, Hooning, Maartje J., Cox, Angela, Pharoah, Paul D. P., Jakubowska, Anna, Orr, Nick, González-Neira, Anna, Pita, Guillermo, Alonso, M. Rosario, Hall, Per, Couch, Fergus J., Simard, Jacques, Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., Offit, Kenneth, Lee, Andrew, Evans, D. Gareth, Jacobs, Chris, Mai, Phuong L., Wang, Qin, Altshuler, David Matthew, and Garber, Judy Ellen

Subjects
Biology, Genetics, Cancer Genetics, Genome-Wide Association Studies
Abstract

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80–0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

Published
2013
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