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1. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Author

Kenneth Offit, Hoda Anton-Culver, Ans M.W. van den Ouweland, Siranoush Manoukian, Christine L. Clarke, Kyriaki Michailidou, Antonis C. Antoniou, Maria Kabisch, Isabel dos-Santos-Silva, Douglas F. Easton, Curtis Olswold, Graham G. Giles, Tien Yin Wong, Ursula Eilber, Mads Thomassen, Christopher A. Haiman, Alice J. Sigurdson, Lothar Haeberle, Florence Menegaux, Ana Osorio, Marco Montagna, Katarzyna Jaworska-Bieniek, Eitan Friedman, Simon S. Cross, Daniel Barrowdale, Elinor J. Sawyer, Adam N. Freeman, Caroline Seynaeve, Min Hyuk Lee, Arnaud Droit, Per Hall, Minouk J. Schoemaker, Trinidad Caldés, Peter Hillemanns, Frederik Marmé, Jenny Lester, Michele M. Doody, Bernard Peissel, Peter Kraft, Elza Khusnutdinova, Anna H. Wu, Stéphanie Peeters, Georg Pfeiler, Pascal Guénel, Hidemi Ito, Xingyi Guo, Antoinette Hollestelle, Heli Nevanlinna, Kathleen Claes, Ylva Paulsson-Karlsson, Cecilia M. Dorfling, Roger L. Milne, Daehee Kang, Judith S. Brand, Diether Lambrechts, Olufunmilayo I. Olopade, Simona Agata, Saundra S. Buys, Muhammad Usman Rashid, Fabienne Lesueur, Alicia Beeghly-Fadiel, Peter Devilee, Manjeet K. Bolla, Natalia Antonenkova, Irene Konstantopoulou, Claudine Isaacs, Anja Rudolph, Carl Blomqvist, Tjoung Won Park-Simon, Judy Garber, Csilla Szabo, Francois Bacot, Arto Mannermaa, Yu-Tang Gao, Stig E. Bojesen, Susan L. Neuhausen, Marina Bermisheva, Qiuyin Cai, Zakaria Einbeigi, Christian F. Singer, Qin Wang, Kerstin Rhiem, Sofia Khan, Fiona Lalloo, Robert L. Nussbaum, Thilo Dörk, William J. Blot, Sylvie Mazoyer, Julia A. Knight, Katherine L. Nathanson, Clare Turnbull, Nazneen Rahman, Anne Lise Børresen-Dale, Chuen Neng Lee, Annegien Broeks, Martha J. Shrubsole, Ava Kwong, Jirong Long, Ian G. Campbell, Sara Margolin, Fergus J. Couch, Laima Tihomirova, Mary Beth Terry, Jenny Chang-Claude, Alice S. Whittemore, Joseph Vijai, Alfons Meindl, Xiao-Ou Shu, Shan Wang-Gohrke, Wei Zheng, Beth Y. Karlan, Jacques Simard, Angela Cox, Shahana Ahmed, Polly A. Newcomb, Ritu Salani, Chen-Yang Shen, Adalgeir Arason, Sandrine Tchatchou, Ute Hamann, Elizabeth J. van Rensburg, Michael Jones, Mark H. Greene, Anthony J. Swerdlow, Senno Verhoef, Jonine Figueroa, Hermann Brenner, Volker Arndt, Charles Joly Beauparlant, Esther M. John, Nadege Presneau, Jingmei Li, Laura Papi, Marjanka K. Schmidt, Montserrat Garcia-Closas, Uffe Birk Jensen, Georgia Chenevix-Trench, Paolo Peterlongo, Penny Soucy, Thomas Brüning, Jaana M. Hartikainen, Siddhartha Kar, Ji Yeob Choi, Manuel R. Teixeira, Phuong L. Mai, Alex Teulé, Jyh Cherng Yu, Paul Brennan, Maya Ghoussaini, Edith Olah, Henrik Flyger, Michael Friedlander, Soo Hwang Teo, Frans B. L. Hogervorst, Kathleen M. Egan, David J. Hunter, Kristiina Aittomäki, Joe Dennis, Anna González-Neira, Mikael Hartman, Alison M. Dunning, Doris Steinemann, Debra Frost, Melissa C. Southey, Ramunas Janavicius, Evgeny N. Imyanitov, Catherine M. Phelan, Amanda E. Toland, Anna Marie Mulligan, David ven den Berg, Rita K. Schmutzler, Julian Peto, Irene L. Andrulis, Chenjie Zeng, Kenneth Muir, Peter Schürmann, Saila Kauppila, Banu Arun, Jane Carpenter, Jeffrey N. Weitzel, Yael Laitman, Susan M. Domchek, Robert Winqvist, Caroline Baynes, Brita Arver, Marc Tischkowitz, Kamila Czene, Keitaro Matsuo, Barbara Burwinkel, Miriam Dwek, Kim De Leeneer, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Peter A. Fasching, Bernd Dworniczak, Susan J. Ramus, Lesley McGuffog, Andrea Gehrig, Michael J. Kerin, Thomas Hansen, Francesca Damiola, John L. Hopper, Loic Le Marchand, Peter J. Hulick, Annika Lindblom, Emily Hallberg, Miguel de la Hoya, Gaetana Gambino, Martine Dumont, Susan L. Slager, Bernardo Bonanni, Bent Ejlertsen, Norhashimah Hassan, Sue Healey, Orland Diez, Mary B. Daly, Carolyn B. Hendricks, Artitaya Lophatananon, Annelie Liljegren, Steven N. Hart, Jan Lubinski, Natalia Bogdanova, Drakoulis Yannoukakos, Steve Ellis, Silje Nord, Hiltrud Brauch, Gad Rennert, Conxi Lázaro, Daniel C. Tessier, Paolo Radice, Dominique Stoppa-Lyonnet, Nadine Tung, Andrew K. Godwin, Suleeporn Sangrajrang, Karoline Kuchenbaecker, Javier Benitez, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Obstetrics and Gynecology, School of Medicine / Clinical Medicine, Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Tischkowitz, Marc [0000-0002-7880-0628], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Clinical Genetics, Medical Oncology, and Obstetrics & Gynecology

Subjects
0301 basic medicine, Fine-scale mapping, Genome-wide association study, HORMONE-RELATED PROTEIN, Epigenesis, Genetic, Breast cancer, Medizinische Fakultät, Databases, Genetic, Genotype, BRCA2 MUTATION CARRIERS, Odds Ratio, Medicine and Health Sciences, Pair 12, Medicine, Genetic risk factor, Promoter Regions, Genetic, Medicine(all), Genetics, BRCA1 Protein, PTHLH-CCDC91, Chromosome Mapping, LOCALIZATION, Single Nucleotide, PTHLH, 3. Good health, Enhancer Elements, Genetic, Population Surveillance, Female, Medical Genetics, BRAC1 mutation carriers, CCDC91, Alleles, Breast Neoplasms, Case-Control Studies, Computational Biology, European Continental Ancestry Group, Haplotypes, Heterozygote, Humans, Mutation, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Chromosomes, Human, Pair 12, Genetic Predisposition to Disease, Genome-Wide Association Study, Human, Research Article, EXPRESSION, Enhancer Elements, SUSCEPTIBILITY LOCI, 3122 Cancers, Single-nucleotide polymorphism, Chromosomes, White People, OVARIAN-CANCER, Càncer de mama, Promoter Regions, Databases, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, Genetic, Journal Article, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Medicinsk genetik, Genetic association, Cancer och onkologi, business.industry, Haplotype, Case-control study, Biology and Life Sciences, Odds ratio, medicine.disease, ENHANCERS, 030104 developmental biology, Cancer and Oncology, METASTASIS, 3111 Biomedicine, GENETIC MODIFIERS, business, Genètica, Epigenesis
Abstract

Article, Background Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P, published version, peerReviewed

Published
2016
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2. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Author

Zeng, Chenjie, Guo, Xingyi, Long, Jirong, Kuchenbaecker, Karoline B., Droit, Arnaud, Michailidou, Kyriaki, Ghoussaini, Maya, Kar, Siddhartha, Freeman, Adam, Hopper, John L., Milne, Roger L., Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Agata, Simona, Ahmed, Shahana, Aittomaki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Arason, Adalgeir, Arndt, Volker, Arun, Banu K., Arver, Brita, Bacot, Francois, Barrowdale, Daniel, Baynes, Caroline, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Blot, William J., Bogdanova, Natalia V., Bojesen, Stig E., Bonanni, Bernardo, Borresen-Dale, Anne-Lise, Brand, Judith S., Brauch, Hiltrud, Brennan, Paul, Brenner, Hermann, Broeks, Annegien, Bruening, Thomas, Burwinkel, Barbara, Buys, Saundra S., Cai, Qiuyin, Caldes, Trinidad, Campbell, Ian, Carpenter, Jane, Chang-Claude, Jenny, Choi, Ji-Yeob, Claes, Kathleen B. M., Clarke, Christine, Cox, Angela, Cross, Simon S., Czene, Kamila, Daly, Mary B., de la Hoya, Miguel, De Leeneer, Kim, Devilee, Peter, Diez, Orland, Domchek, Susan M., Doody, Michele, Dorfling, Cecilia M., Doerk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Dwek, Miriam, Dworniczak, Bernd, Egan, Kathleen, Eilber, Ursula, Einbeigi, Zakaria, Ejlertsen, Bent, Ellis, Steve, Frost, Debra, Lalloo, Fiona, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Friedlander, Michael, Friedman, Eitan, Gambino, Gaetana, Gao, Yu-Tang, Garber, Judy, Garcia-Closas, Montserrat, Gehrig, Andrea, Damiola, Francesca, Lesueur, Fabienne, Mazoyer, Sylvie, Stoppa-Lyonnet, Dominique, Giles, Graham G., Godwin, Andrew K., Goldgar, David E., Gonzalez-Neira, Anna, Greene, Mark H., Guenel, Pascal, Haeberle, Lothar, Haiman, Christopher A., Hallberg, Emily, Hamann, Ute, Hansen, Thomas V. O., Hart, Steven, Hartikainen, Jaana M., Hartman, Mikael, Hassan, Norhashimah, Healey, Sue, Hogervorst, Frans B. L., Verhoef, Senno, Hendricks, Carolyn B., Hillemanns, Peter, Hollestelle, Antoinette, Hulick, Peter J., Hunter, David J., Imyanitov, Evgeny N., Isaacs, Claudine, Ito, Hidemi, Jakubowska, Anna, Janavicius, Ramunas, Jaworska-Bieniek, Katarzyna, Jensen, Uffe Birk, John, Esther M., Beauparlant, Charles Joly, Jones, Michael, Kabisch, Maria, Kang, Daehee, Karlan, Beth Y., Kauppila, Saila, Kerin, Michael J., Khan, Sofia, Khusnutdinova, Elza, Knight, Julia A., Konstantopoulou, Irene, Kraft, Peter, Kwong, Ava, Laitman, Yael, Lambrechts, Diether, Lazaro, Conxi, Le Marchand, Loic, Lee, Chuen Neng, Lee, Min Hyuk, Lester, Jenny, Li, Jingmei, Liljegren, Annelie, Lindblom, Annika, Lophatananon, Artitaya, Lubinski, Jan, Mai, Phuong L., Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Marme, Frederik, Matsuo, Keitaro, McGuffog, Lesley, Meindl, Alfons, Menegaux, Florence, Montagna, Marco, Muir, Kenneth, Mulligan, Anna Marie, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Newcomb, Polly A., Nord, Silje, Nussbaum, Robert L., Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olswold, Curtis, Osorio, Ana, Papi, Laura, Park-Simon, Tjoung-Won, Paulsson-Karlsson, Ylva, Peeters, Stephanie, Peissel, Bernard, Peterlongo, Paolo, Peto, Julian, Pfeiler, Georg, Phelan, Catherine M., Presneau, Nadege, Radice, Paolo, Rahman, Nazneen, Ramus, Susan J., Rashid, Muhammad Usman, Rennert, Gad, Rhiem, Kerstin, Rudolph, Anja, Salani, Ritu, Sangrajrang, Suleeporn, Sawyer, Elinor J., Schmidt, Marjanka K., Schmutzler, Rita K., Schoemaker, Minouk J., Schuermann, Peter, Seynaeve, Caroline, Shen, Chen-Yang, Shrubsole, Martha J., Shu, Xiao-Ou, Sigurdson, Alice, Singer, Christian F., Slager, Susan, Soucy, Penny, Southey, Melissa, Steinemann, Doris, Swerdlow, Anthony, Szabo, Csilla I., Tchatchou, Sandrine, Teixeira, Manuel R., Teo, Soo H., Terry, Mary Beth, Tessier, Daniel C., Teule, Alex, Thomassen, Mads, Tihomirova, Laima, Tischkowitz, Marc, Toland, Amanda E., Tung, Nadine, Turnbull, Clare, van den Ouweland, Ans M. W., van Rensburg, Elizabeth J., ven den Berg, David, Vijai, Joseph, Wang-Gohrke, Shan, Weitzel, Jeffrey N., Whittemore, Alice S., Winqvist, Robert, Wong, Tien Y., Wu, Anna H., Yannoukakos, Drakoulis, Yu, Jyh-Cherng, Pharoah, Paul D. P., Hall, Per, Chenevix-Trench, Georgia, Dunning, Alison M., Simard, Jacques, Couch, Fergus J., Antoniou, Antonis C., Easton, Douglas F., Zheng, Wei, Zeng, Chenjie, Guo, Xingyi, Long, Jirong, Kuchenbaecker, Karoline B., Droit, Arnaud, Michailidou, Kyriaki, Ghoussaini, Maya, Kar, Siddhartha, Freeman, Adam, Hopper, John L., Milne, Roger L., Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Agata, Simona, Ahmed, Shahana, Aittomaki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Arason, Adalgeir, Arndt, Volker, Arun, Banu K., Arver, Brita, Bacot, Francois, Barrowdale, Daniel, Baynes, Caroline, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Blot, William J., Bogdanova, Natalia V., Bojesen, Stig E., Bonanni, Bernardo, Borresen-Dale, Anne-Lise, Brand, Judith S., Brauch, Hiltrud, Brennan, Paul, Brenner, Hermann, Broeks, Annegien, Bruening, Thomas, Burwinkel, Barbara, Buys, Saundra S., Cai, Qiuyin, Caldes, Trinidad, Campbell, Ian, Carpenter, Jane, Chang-Claude, Jenny, Choi, Ji-Yeob, Claes, Kathleen B. M., Clarke, Christine, Cox, Angela, Cross, Simon S., Czene, Kamila, Daly, Mary B., de la Hoya, Miguel, De Leeneer, Kim, Devilee, Peter, Diez, Orland, Domchek, Susan M., Doody, Michele, Dorfling, Cecilia M., Doerk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Dwek, Miriam, Dworniczak, Bernd, Egan, Kathleen, Eilber, Ursula, Einbeigi, Zakaria, Ejlertsen, Bent, Ellis, Steve, Frost, Debra, Lalloo, Fiona, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Friedlander, Michael, Friedman, Eitan, Gambino, Gaetana, Gao, Yu-Tang, Garber, Judy, Garcia-Closas, Montserrat, Gehrig, Andrea, Damiola, Francesca, Lesueur, Fabienne, Mazoyer, Sylvie, Stoppa-Lyonnet, Dominique, Giles, Graham G., Godwin, Andrew K., Goldgar, David E., Gonzalez-Neira, Anna, Greene, Mark H., Guenel, Pascal, Haeberle, Lothar, Haiman, Christopher A., Hallberg, Emily, Hamann, Ute, Hansen, Thomas V. O., Hart, Steven, Hartikainen, Jaana M., Hartman, Mikael, Hassan, Norhashimah, Healey, Sue, Hogervorst, Frans B. L., Verhoef, Senno, Hendricks, Carolyn B., Hillemanns, Peter, Hollestelle, Antoinette, Hulick, Peter J., Hunter, David J., Imyanitov, Evgeny N., Isaacs, Claudine, Ito, Hidemi, Jakubowska, Anna, Janavicius, Ramunas, Jaworska-Bieniek, Katarzyna, Jensen, Uffe Birk, John, Esther M., Beauparlant, Charles Joly, Jones, Michael, Kabisch, Maria, Kang, Daehee, Karlan, Beth Y., Kauppila, Saila, Kerin, Michael J., Khan, Sofia, Khusnutdinova, Elza, Knight, Julia A., Konstantopoulou, Irene, Kraft, Peter, Kwong, Ava, Laitman, Yael, Lambrechts, Diether, Lazaro, Conxi, Le Marchand, Loic, Lee, Chuen Neng, Lee, Min Hyuk, Lester, Jenny, Li, Jingmei, Liljegren, Annelie, Lindblom, Annika, Lophatananon, Artitaya, Lubinski, Jan, Mai, Phuong L., Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Marme, Frederik, Matsuo, Keitaro, McGuffog, Lesley, Meindl, Alfons, Menegaux, Florence, Montagna, Marco, Muir, Kenneth, Mulligan, Anna Marie, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Newcomb, Polly A., Nord, Silje, Nussbaum, Robert L., Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olswold, Curtis, Osorio, Ana, Papi, Laura, Park-Simon, Tjoung-Won, Paulsson-Karlsson, Ylva, Peeters, Stephanie, Peissel, Bernard, Peterlongo, Paolo, Peto, Julian, Pfeiler, Georg, Phelan, Catherine M., Presneau, Nadege, Radice, Paolo, Rahman, Nazneen, Ramus, Susan J., Rashid, Muhammad Usman, Rennert, Gad, Rhiem, Kerstin, Rudolph, Anja, Salani, Ritu, Sangrajrang, Suleeporn, Sawyer, Elinor J., Schmidt, Marjanka K., Schmutzler, Rita K., Schoemaker, Minouk J., Schuermann, Peter, Seynaeve, Caroline, Shen, Chen-Yang, Shrubsole, Martha J., Shu, Xiao-Ou, Sigurdson, Alice, Singer, Christian F., Slager, Susan, Soucy, Penny, Southey, Melissa, Steinemann, Doris, Swerdlow, Anthony, Szabo, Csilla I., Tchatchou, Sandrine, Teixeira, Manuel R., Teo, Soo H., Terry, Mary Beth, Tessier, Daniel C., Teule, Alex, Thomassen, Mads, Tihomirova, Laima, Tischkowitz, Marc, Toland, Amanda E., Tung, Nadine, Turnbull, Clare, van den Ouweland, Ans M. W., van Rensburg, Elizabeth J., ven den Berg, David, Vijai, Joseph, Wang-Gohrke, Shan, Weitzel, Jeffrey N., Whittemore, Alice S., Winqvist, Robert, Wong, Tien Y., Wu, Anna H., Yannoukakos, Drakoulis, Yu, Jyh-Cherng, Pharoah, Paul D. P., Hall, Per, Chenevix-Trench, Georgia, Dunning, Alison M., Simard, Jacques, Couch, Fergus J., Antoniou, Antonis C., Easton, Douglas F., and Zheng, Wei

Abstract

Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion

Published
2016
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3. Mutagen Sensitivity and DNA Repair Gene Polymorphisms in Hereditary and Sporadic Breast Cancer

Author

GEORGETOWN UNIV WASHINGTON DC MEDICAL CENTER, Santi-Ruiz, Luisel J., GEORGETOWN UNIV WASHINGTON DC MEDICAL CENTER, and Santi-Ruiz, Luisel J.

Abstract

Breast cancer risk for both sporadic and familial breast cancer can better be elucidated in studies in women with BRCA1 mutations. Since the BRCA1 protein is involved in DNA repair, genotype-phenotype relationships can be established by the assessment of DNA repair efficiency and the identification of genetic polymorphisms in the BRCA1 DNA repair pathway. To study risks associated with certain polymorphisms in DNA repair genes, EBV-immortalized cells from women in the LCC Registry were used in both a phenotypic assay that measures DNA repair capacity and genotypic assays that determined genotypes that increased susceptibility to breast cancer. Ninety-five affected and 65 healthy BRCA1 mutation carriers are being analyzed in this study. Gamma radiation was used to induce chromosomal breaks and those chromosomal breaks were scored, counted and compared within each patient and between patients. Also, the BRCA1, BRCA2, and Rad51 genes are being sequenced and the genotypes whose polymorphisms code for amino acid changes in conserved and functional areas are being analyzed. We predict that polymorphisms in these genes will be highly correlated with deficient DNA repair in high risk breast cancer families. Several BRCA1 and BRCA2 polymorphisms appear to be associated with decreased DNA repair efficiency. Specifically, the N372H (OR: 7.0 CI: 0.3-140.0) polymorphism in BRCA2,the K1183R (OR: 1.8 CI:0.1-17.7) polymorphism in BRCA1, and the 5382inC mutation (OR:3.0 C1:0.3-29.8), appear to be correlated with mutagen sensitivity, but a larger sample size is needed for odds ratios to be significant In addition, we have a large population of 187delAG (n=54) and 5382insC (n=21) mutation carriers, so we can begin to look at what polymorphisms will affect risk within those mutation carriers. Ultimately, the study of the high risk families can inform, and set priorities for the study of genetic polymorphisms in sporadic breast cancer studies.

Published
2005

4. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

Author

Zeng C, Guo X, Long J, Kuchenbaecker KB, Droit A, Michailidou K, Ghoussaini M, Kar S, Freeman A, Hopper JL, Milne RL, Bolla MK, Wang Q, Dennis J, Agata S, Ahmed S, Aittomäki K, Andrulis IL, Anton-Culver H, Antonenkova NN, Arason A, Arndt V, Arun BK, Arver B, Bacot F, Barrowdale D, Baynes C, Beeghly-Fadiel A, Benitez J, Bermisheva M, Blomqvist C, Blot WJ, Bogdanova NV, Bojesen SE, Bonanni B, Borresen-Dale AL, Brand JS, Brauch H, Brennan P, Brenner H, Broeks A, Brüning T, Burwinkel B, Buys SS, Cai Q, Caldes T, Campbell I, Carpenter J, Chang-Claude J, Choi JY, Claes KB, Clarke C, Cox A, Cross SS, Czene K, Daly MB, de la Hoya M, De Leeneer K, Devilee P, Diez O, Domchek SM, Doody M, Dorfling CM, Dörk T, Dos-Santos-Silva I, Dumont M, Dwek M, Dworniczak B, Egan K, Eilber U, Einbeigi Z, Ejlertsen B, Ellis S, Frost D, Lalloo F, Fasching PA, Figueroa J, Flyger H, Friedlander M, Friedman E, Gambino G, Gao YT, Garber J, García-Closas M, Gehrig A, Damiola F, Lesueur F, Mazoyer S, Stoppa-Lyonnet D, Giles GG, Godwin AK, Goldgar DE, González-Neira A, Greene MH, Guénel P, Haeberle L, Haiman CA, Hallberg E, Hamann U, Hansen TV, Hart S, Hartikainen JM, Hartman M, Hassan N, Healey S, Hogervorst FB, Verhoef S, Hendricks CB, Hillemanns P, Hollestelle A, Hulick PJ, Hunter DJ, Imyanitov EN, Isaacs C, Ito H, Jakubowska A, Janavicius R, Jaworska-Bieniek K, Jensen UB, John EM, Joly Beauparlant C, Jones M, Kabisch M, Kang D, Karlan BY, Kauppila S, Kerin MJ, Khan S, Khusnutdinova E, Knight JA, Konstantopoulou I, Kraft P, Kwong A, Laitman Y, Lambrechts D, Lazaro C, Le Marchand L, Lee CN, Lee MH, Lester J, Li J, Liljegren A, Lindblom A, Lophatananon A, Lubinski J, Mai PL, Mannermaa A, Manoukian S, Margolin S, Marme F, Matsuo K, McGuffog L, Meindl A, Menegaux F, Montagna M, Muir K, Mulligan AM, Nathanson KL, Neuhausen SL, Nevanlinna H, Newcomb PA, Nord S, Nussbaum RL, Offit K, Olah E, Olopade OI, Olswold C, Osorio A, Papi L, Park-Simon TW, Paulsson-Karlsson Y, Peeters S, Peissel B, Peterlongo P, Peto J, Pfeiler G, Phelan CM, Presneau N, Radice P, Rahman N, Ramus SJ, Rashid MU, Rennert G, Rhiem K, Rudolph A, Salani R, Sangrajrang S, Sawyer EJ, Schmidt MK, Schmutzler RK, Schoemaker MJ, Schürmann P, Seynaeve C, Shen CY, Shrubsole MJ, Shu XO, Sigurdson A, Singer CF, Slager S, Soucy P, Southey M, Steinemann D, Swerdlow A, Szabo CI, Tchatchou S, Teixeira MR, Teo SH, Terry MB, Tessier DC, Teulé A, Thomassen M, Tihomirova L, Tischkowitz M, Toland AE, Tung N, Turnbull C, van den Ouweland AM, van Rensburg EJ, Ven den Berg D, Vijai J, Wang-Gohrke S, Weitzel JN, Whittemore AS, Winqvist R, Wong TY, Wu AH, Yannoukakos D, Yu JC, Pharoah PD, Hall P, Chenevix-Trench G, Dunning AM, Simard J, Couch FJ, Antoniou AC, Easton DF, and Zheng W

Subjects
Alleles, BRCA1 Protein genetics, Case-Control Studies, Computational Biology methods, Databases, Genetic, Enhancer Elements, Genetic, Epigenesis, Genetic, Female, Genotype, Haplotypes, Heterozygote, Humans, Mutation, Odds Ratio, Polymorphism, Single Nucleotide, Population Surveillance, Promoter Regions, Genetic, Quantitative Trait Loci, Risk, White People genetics, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Chromosome Mapping, Chromosomes, Human, Pair 12, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk., Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation., Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05., Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.

Published
2016
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