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1. Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.

Author

Fehringer G, Kraft P, Pharoah PD, Eeles RA, Chatterjee N, Schumacher FR, Schildkraut JM, Lindström S, Brennan P, Bickeböller H, Houlston RS, Landi MT, Caporaso N, Risch A, Amin Al Olama A, Berndt SI, Giovannucci EL, Grönberg H, Kote-Jarai Z, Ma J, Muir K, Stampfer MJ, Stevens VL, Wiklund F, Willett WC, Goode EL, Permuth JB, Risch HA, Reid BM, Bezieau S, Brenner H, Chan AT, Chang-Claude J, Hudson TJ, Kocarnik JK, Newcomb PA, Schoen RE, Slattery ML, White E, Adank MA, Ahsan H, Aittomäki K, Baglietto L, Blomquist C, Canzian F, Czene K, Dos-Santos-Silva I, Eliassen AH, Figueroa JD, Flesch-Janys D, Fletcher O, Garcia-Closas M, Gaudet MM, Johnson N, Hall P, Hazra A, Hein R, Hofman A, Hopper JL, Irwanto A, Johansson M, Kaaks R, Kibriya MG, Lichtner P, Liu J, Lund E, Makalic E, Meindl A, Müller-Myhsok B, Muranen TA, Nevanlinna H, Peeters PH, Peto J, Prentice RL, Rahman N, Sanchez MJ, Schmidt DF, Schmutzler RK, Southey MC, Tamimi R, Travis RC, Turnbull C, Uitterlinden AG, Wang Z, Whittemore AS, Yang XR, Zheng W, Buchanan DD, Casey G, Conti DV, Edlund CK, Gallinger S, Haile RW, Jenkins M, Le Marchand L, Li L, Lindor NM, Schmit SL, Thibodeau SN, Woods MO, Rafnar T, Gudmundsson J, Stacey SN, Stefansson K, Sulem P, Chen YA, Tyrer JP, Christiani DC, Wei Y, Shen H, Hu Z, Shu XO, Shiraishi K, Takahashi A, Bossé Y, Obeidat M, Nickle D, Timens W, Freedman ML, Li Q, Seminara D, Chanock SJ, Gong J, Peters U, Gruber SB, Amos CI, Sellers TA, Easton DF, Hunter DJ, Haiman CA, Henderson BE, and Hung RJ

Subjects
Female, Genome-Wide Association Study, Genotype, Humans, Male, Breast Neoplasms genetics, Colorectal Neoplasms genetics, Lung Neoplasms genetics, Ovarian Neoplasms genetics, Prostatic Neoplasms genetics
Abstract

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR., Competing Interests: of Potential Conflicts of Interest: Dr. David Nickle is a full time employee at Merck & Co. No potential conflicts of interest were disclosed by other authors., (©2016 American Association for Cancer Research.)

Published
2016
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2. Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.

Author

Lin WY, Camp NJ, Ghoussaini M, Beesley J, Michailidou K, Hopper JL, Apicella C, Southey MC, Stone J, Schmidt MK, Broeks A, Van't Veer LJ, Th Rutgers EJ, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Fasching PA, Haeberle L, Ekici AB, Beckmann MW, Peto J, Dos-Santos-Silva I, Fletcher O, Johnson N, Bolla MK, Wang Q, Dennis J, Sawyer EJ, Cheng T, Tomlinson I, Kerin MJ, Miller N, Marmé F, Surowy HM, Burwinkel B, Guénel P, Truong T, Menegaux F, Mulot C, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Benitez J, Zamora MP, Arias Perez JI, Menéndez P, González-Neira A, Pita G, Alonso MR, Alvarez N, Herrero D, Anton-Culver H, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Meindl A, Lichtner P, Schmutzler RK, Müller-Myhsok B, Brauch H, Brüning T, Ko YD, Tessier DC, Vincent D, Bacot F, Nevanlinna H, Aittomäki K, Blomqvist C, Khan S, Matsuo K, Ito H, Iwata H, Horio A, Bogdanova NV, Antonenkova NN, Dörk T, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Neven P, Wauters E, Wildiers H, Lambrechts D, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Radice P, Peterlongo P, Manoukian S, Bonanni B, Couch FJ, Wang X, Vachon C, Purrington K, Giles GG, Milne RL, Mclean C, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Simard J, Goldberg MS, Labrèche F, Dumont M, Teo SH, Yip CH, Hassan N, Vithana EN, Kristensen V, Zheng W, Deming-Halverson S, Shrubsole MJ, Long J, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Kauppila S, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Devilee P, Tollenaar RA, Seynaeve C, Van Asperen CJ, García-Closas M, Figueroa J, Lissowska J, Brinton L, Czene K, Darabi H, Eriksson M, Brand JS, Hooning MJ, Hollestelle A, Van Den Ouweland AM, Jager A, Li J, Liu J, Humphreys K, Shu XO, Lu W, Gao YT, Cai H, Cross SS, Reed MW, Blot W, Signorello LB, Cai Q, Pharoah PD, Perkins B, Shah M, Blows FM, Kang D, Yoo KY, Noh DY, Hartman M, Miao H, Chia KS, Putti TC, Hamann U, Luccarini C, Baynes C, Ahmed S, Maranian M, Healey CS, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Sangrajrang S, Gaborieau V, Brennan P, Mckay J, Slager S, Toland AE, Yannoukakos D, Shen CY, Hsiung CN, Wu PE, Ding SL, Ashworth A, Jones M, Orr N, Swerdlow AJ, Tsimiklis H, Makalic E, Schmidt DF, Bui QM, Chanock SJ, Hunter DJ, Hein R, Dahmen N, Beckmann L, Aaltonen K, Muranen TA, Heikkinen T, Irwanto A, Rahman N, Turnbull CA, Waisfisz Q, Meijers-Heijboer HE, Adank MA, Van Der Luijt RB, Hall P, Chenevix-Trench G, Dunning A, Easton DF, and Cox A

Subjects
Breast Neoplasms ethnology, CASP8 and FADD-Like Apoptosis Regulating Protein genetics, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, Humans, Polymorphism, Single Nucleotide, Breast Neoplasms genetics, Caspase 8 genetics, Chromosomes, Human, Pair 2 genetics, Proteins genetics, White People genetics
Abstract

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2015
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3. MicroRNA related polymorphisms and breast cancer risk.

Author

Khan S, Greco D, Michailidou K, Milne RL, Muranen TA, Heikkinen T, Aaltonen K, Dennis J, Bolla MK, Liu J, Hall P, Irwanto A, Humphreys K, Li J, Czene K, Chang-Claude J, Hein R, Rudolph A, Seibold P, Flesch-Janys D, Fletcher O, Peto J, dos Santos Silva I, Johnson N, Gibson L, Aitken Z, Hopper JL, Tsimiklis H, Bui M, Makalic E, Schmidt DF, Southey MC, Apicella C, Stone J, Waisfisz Q, Meijers-Heijboer H, Adank MA, van der Luijt RB, Meindl A, Schmutzler RK, Müller-Myhsok B, Lichtner P, Turnbull C, Rahman N, Chanock SJ, Hunter DJ, Cox A, Cross SS, Reed MW, Schmidt MK, Broeks A, Van't Veer LJ, Hogervorst FB, Fasching PA, Schrauder MG, Ekici AB, Beckmann MW, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Benitez J, Zamora PM, Perez JI, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Pharoah PD, Dunning AM, Shah M, Luben R, Brown J, Couch FJ, Wang X, Vachon C, Olson JE, Lambrechts D, Moisse M, Paridaens R, Christiaens MR, Guénel P, Truong T, Laurent-Puig P, Mulot C, Marme F, Burwinkel B, Schneeweiss A, Sohn C, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Andrulis IL, Knight JA, Tchatchou S, Mulligan AM, Dörk T, Bogdanova NV, Antonenkova NN, Anton-Culver H, Darabi H, Eriksson M, Garcia-Closas M, Figueroa J, Lissowska J, Brinton L, Devilee P, Tollenaar RA, Seynaeve C, van Asperen CJ, Kristensen VN, Slager S, Toland AE, Ambrosone CB, Yannoukakos D, Lindblom A, Margolin S, Radice P, Peterlongo P, Barile M, Mariani P, Hooning MJ, Martens JW, Collée JM, Jager A, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Giles GG, McLean C, Brauch H, Brüning T, Ko YD, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Swerdlow A, Ashworth A, Orr N, Jones M, Simard J, Goldberg MS, Labrèche F, Dumont M, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Kataja V, Kosma VM, Hartikainen JM, Mannermaa A, Hamann U, Chenevix-Trench G, Blomqvist C, Aittomäki K, Easton DF, and Nevanlinna H

Subjects
3' Untranslated Regions, Binding Sites, Case-Control Studies, Chromosome Mapping, Computational Biology, Female, Genome-Wide Association Study, Genotype, Humans, Receptors, Estrogen metabolism, Breast Neoplasms diagnosis, Breast Neoplasms genetics, MicroRNAs genetics, Polymorphism, Single Nucleotide
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 predisposition to in situ and invasive lobular carcinoma of the breast.

Author

Sawyer E, Roylance R, Petridis C, Brook MN, Nowinski S, Papouli E, Fletcher O, Pinder S, Hanby A, Kohut K, Gorman P, Caneppele M, Peto J, Dos Santos Silva I, Johnson N, Swann R, Dwek M, Perkins KA, Gillett C, Houlston R, Ross G, De Ieso P, Southey MC, Hopper JL, Provenzano E, Apicella C, Wesseling J, Cornelissen S, Keeman R, Fasching PA, Jud SM, Ekici AB, Beckmann MW, Kerin MJ, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Guénel P, Truong T, Laurent-Puig P, Kerbrat P, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Milne RL, Perez JI, Menéndez P, Benitez J, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Meindl A, Lichtner P, Schmutzler RK, Lochmann M, Brauch H, Fischer HP, Ko YD, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Bogdanova NV, Dörk T, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Chenevix-Trench G, Lambrechts D, Weltens C, Van Limbergen E, Hatse S, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Radice P, Peterlongo P, Bonanni B, Volorio S, Giles GG, Severi G, Baglietto L, McLean CA, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Simard J, Goldberg MS, Labrèche F, Dumont M, Kristensen V, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Kauppila S, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Devillee P, Tollenaar RA, Seynaeve CM, Kriege M, Figueroa J, Chanock SJ, Sherman ME, Hooning MJ, Hollestelle A, van den Ouweland AM, van Deurzen CH, Li J, Czene K, Humphreys K, Cox A, Cross SS, Reed MW, Shah M, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Swerdlow A, Ashworth A, Orr N, Schoemaker M, Couch FJ, Hallberg E, González-Neira A, Pita G, Alonso MR, Tessier DC, Vincent D, Bacot F, Bolla MK, Wang Q, Dennis J, Michailidou K, Dunning AM, Hall P, Easton D, Pharoah P, Schmidt MK, Tomlinson I, and Garcia-Closas M

Subjects
Case-Control Studies, Female, Genome-Wide Association Study, Genotype, Humans, Middle Aged, Polymorphism, Single Nucleotide genetics, Breast Neoplasms genetics, Carcinoma in Situ genetics, Carcinoma, Lobular genetics, Genetic Predisposition to Disease genetics
Abstract

Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.

Published
2014
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5. Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers.

Author

French JD, Ghoussaini M, Edwards SL, Meyer KB, Michailidou K, Ahmed S, Khan S, Maranian MJ, O'Reilly M, Hillman KM, Betts JA, Carroll T, Bailey PJ, Dicks E, Beesley J, Tyrer J, Maia AT, Beck A, Knoblauch NW, Chen C, Kraft P, Barnes D, González-Neira A, Alonso MR, Herrero D, Tessier DC, Vincent D, Bacot F, Luccarini C, Baynes C, Conroy D, Dennis J, Bolla MK, Wang Q, Hopper JL, Southey MC, Schmidt MK, Broeks A, Verhoef S, Cornelissen S, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Fasching PA, Loehberg CR, Ekici AB, Beckmann MW, Peto J, dos Santos Silva I, Johnson N, Aitken Z, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Guénel P, Truong T, Laurent-Puig P, Menegaux F, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Milne RL, Zamora MP, Arias Perez JI, Benitez J, Anton-Culver H, Brenner H, Müller H, Arndt V, Stegmaier C, Meindl A, Lichtner P, Schmutzler RK, Engel C, Brauch H, Hamann U, Justenhoven C, Aaltonen K, Heikkilä P, Aittomäki K, Blomqvist C, Matsuo K, Ito H, Iwata H, Sueta A, Bogdanova NV, Antonenkova NN, Dörk T, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Lambrechts D, Peeters S, Smeets A, Floris G, Chang-Claude J, Rudolph A, Nickels S, Flesch-Janys D, Radice P, Peterlongo P, Bonanni B, Sardella D, Couch FJ, Wang X, Pankratz VS, Lee A, Giles GG, Severi G, Baglietto L, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Simard J, Goldberg MS, Labrèche F, Dumont M, Teo SH, Yip CH, Ng CH, Vithana EN, Kristensen V, Zheng W, Deming-Halverson S, Shrubsole M, Long J, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Devilee P, Seynaeve C, García-Closas M, Figueroa J, Chanock SJ, Lissowska J, Czene K, Klevebring D, Schoof N, Hooning MJ, Martens JW, Collée JM, Tilanus-Linthorst M, Hall P, Li J, Liu J, Humphreys K, Shu XO, Lu W, Gao YT, Cai H, Cox A, Balasubramanian SP, Blot W, Signorello LB, Cai Q, Pharoah PD, Healey CS, Shah M, Pooley KA, Kang D, Yoo KY, Noh DY, Hartman M, Miao H, Sng JH, Sim X, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Sangrajrang S, Gaborieau V, McKay J, Toland AE, Ambrosone CB, Yannoukakos D, Godwin AK, Shen CY, Hsiung CN, Wu PE, Chen ST, Swerdlow A, Ashworth A, Orr N, Schoemaker MJ, Ponder BA, Nevanlinna H, Brown MA, Chenevix-Trench G, Easton DF, and Dunning AM

Subjects
Binding Sites, Case-Control Studies, Cell Line, Tumor, Chromatin chemistry, Chromatin genetics, Chromatin Immunoprecipitation, Cyclin D1 metabolism, Electrophoretic Mobility Shift Assay, Female, GATA3 Transcription Factor antagonists & inhibitors, GATA3 Transcription Factor genetics, GATA3 Transcription Factor metabolism, Gene Expression Regulation, Neoplastic, Humans, Luciferases metabolism, Promoter Regions, Genetic genetics, RNA, Messenger genetics, RNA, Small Interfering genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Silencer Elements, Transcriptional genetics, ets-Domain Protein Elk-4 antagonists & inhibitors, ets-Domain Protein Elk-4 genetics, ets-Domain Protein Elk-4 metabolism, Breast Neoplasms genetics, Chromosomes, Human, Pair 11 genetics, Cyclin D1 genetics, Enhancer Elements, Genetic genetics, Polymorphism, Single Nucleotide genetics
Abstract

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2013
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6. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.

Author

Bojesen SE, Pooley KA, Johnatty SE, Beesley J, Michailidou K, Tyrer JP, Edwards SL, Pickett HA, Shen HC, Smart CE, Hillman KM, Mai PL, Lawrenson K, Stutz MD, Lu Y, Karevan R, Woods N, Johnston RL, French JD, Chen X, Weischer M, Nielsen SF, Maranian MJ, Ghoussaini M, Ahmed S, Baynes C, Bolla MK, Wang Q, Dennis J, McGuffog L, Barrowdale D, Lee A, Healey S, Lush M, Tessier DC, Vincent D, Bacot F, Vergote I, Lambrechts S, Despierre E, Risch HA, González-Neira A, Rossing MA, Pita G, Doherty JA, Alvarez N, Larson MC, Fridley BL, Schoof N, Chang-Claude J, Cicek MS, Peto J, Kalli KR, Broeks A, Armasu SM, Schmidt MK, Braaf LM, Winterhoff B, Nevanlinna H, Konecny GE, Lambrechts D, Rogmann L, Guénel P, Teoman A, Milne RL, Garcia JJ, Cox A, Shridhar V, Burwinkel B, Marme F, Hein R, Sawyer EJ, Haiman CA, Wang-Gohrke S, Andrulis IL, Moysich KB, Hopper JL, Odunsi K, Lindblom A, Giles GG, Brenner H, Simard J, Lurie G, Fasching PA, Carney ME, Radice P, Wilkens LR, Swerdlow A, Goodman MT, Brauch H, Garcia-Closas M, Hillemanns P, Winqvist R, Dürst M, Devilee P, Runnebaum I, Jakubowska A, Lubinski J, Mannermaa A, Butzow R, Bogdanova NV, Dörk T, Pelttari LM, Zheng W, Leminen A, Anton-Culver H, Bunker CH, Kristensen V, Ness RB, Muir K, Edwards R, Meindl A, Heitz F, Matsuo K, du Bois A, Wu AH, Harter P, Teo SH, Schwaab I, Shu XO, Blot W, Hosono S, Kang D, Nakanishi T, Hartman M, Yatabe Y, Hamann U, Karlan BY, Sangrajrang S, Kjaer SK, Gaborieau V, Jensen A, Eccles D, Høgdall E, Shen CY, Brown J, Woo YL, Shah M, Azmi MA, Luben R, Omar SZ, Czene K, Vierkant RA, Nordestgaard BG, Flyger H, Vachon C, Olson JE, Wang X, Levine DA, Rudolph A, Weber RP, Flesch-Janys D, Iversen E, Nickels S, Schildkraut JM, Silva Idos S, Cramer DW, Gibson L, Terry KL, Fletcher O, Vitonis AF, van der Schoot CE, Poole EM, Hogervorst FB, Tworoger SS, Liu J, Bandera EV, Li J, Olson SH, Humphreys K, Orlow I, Blomqvist C, Rodriguez-Rodriguez L, Aittomäki K, Salvesen HB, Muranen TA, Wik E, Brouwers B, Krakstad C, Wauters E, Halle MK, Wildiers H, Kiemeney LA, Mulot C, Aben KK, Laurent-Puig P, Altena AM, Truong T, Massuger LF, Benitez J, Pejovic T, Perez JI, Hoatlin M, Zamora MP, Cook LS, Balasubramanian SP, Kelemen LE, Schneeweiss A, Le ND, Sohn C, Brooks-Wilson A, Tomlinson I, Kerin MJ, Miller N, Cybulski C, Henderson BE, Menkiszak J, Schumacher F, Wentzensen N, Le Marchand L, Yang HP, Mulligan AM, Glendon G, Engelholm SA, Knight JA, Høgdall CK, Apicella C, Gore M, Tsimiklis H, Song H, Southey MC, Jager A, den Ouweland AM, Brown R, Martens JW, Flanagan JM, Kriege M, Paul J, Margolin S, Siddiqui N, Severi G, Whittemore AS, Baglietto L, McGuire V, Stegmaier C, Sieh W, Müller H, Arndt V, Labrèche F, Gao YT, Goldberg MS, Yang G, Dumont M, McLaughlin JR, Hartmann A, Ekici AB, Beckmann MW, Phelan CM, Lux MP, Permuth-Wey J, Peissel B, Sellers TA, Ficarazzi F, Barile M, Ziogas A, Ashworth A, Gentry-Maharaj A, Jones M, Ramus SJ, Orr N, Menon U, Pearce CL, Brüning T, Pike MC, Ko YD, Lissowska J, Figueroa J, Kupryjanczyk J, Chanock SJ, Dansonka-Mieszkowska A, Jukkola-Vuorinen A, Rzepecka IK, Pylkäs K, Bidzinski M, Kauppila S, Hollestelle A, Seynaeve C, Tollenaar RA, Durda K, Jaworska K, Hartikainen JM, Kosma VM, Kataja V, Antonenkova NN, Long J, Shrubsole M, Deming-Halverson S, Lophatananon A, Siriwanarangsan P, Stewart-Brown S, Ditsch N, Lichtner P, Schmutzler RK, Ito H, Iwata H, Tajima K, Tseng CC, Stram DO, van den Berg D, Yip CH, Ikram MK, Teh YC, Cai H, Lu W, Signorello LB, Cai Q, Noh DY, Yoo KY, Miao H, Iau PT, Teo YY, McKay J, Shapiro C, Ademuyiwa F, Fountzilas G, Hsiung CN, Yu JC, Hou MF, Healey CS, Luccarini C, Peock S, Stoppa-Lyonnet D, Peterlongo P, Rebbeck TR, Piedmonte M, Singer CF, Friedman E, Thomassen M, Offit K, Hansen TV, Neuhausen SL, Szabo CI, Blanco I, Garber J, Narod SA, Weitzel JN, Montagna M, Olah E, Godwin AK, Yannoukakos D, Goldgar DE, Caldes T, Imyanitov EN, Tihomirova L, Arun BK, Campbell I, Mensenkamp AR, van Asperen CJ, van Roozendaal KE, Meijers-Heijboer H, Collée JM, Oosterwijk JC, Hooning MJ, Rookus MA, van der Luijt RB, Os TA, Evans DG, Frost D, Fineberg E, Barwell J, Walker L, Kennedy MJ, Platte R, Davidson R, Ellis SD, Cole T, Bressac-de Paillerets B, Buecher B, Damiola F, Faivre L, Frenay M, Sinilnikova OM, Caron O, Giraud S, Mazoyer S, Bonadona V, Caux-Moncoutier V, Toloczko-Grabarek A, Gronwald J, Byrski T, Spurdle AB, Bonanni B, Zaffaroni D, Giannini G, Bernard L, Dolcetti R, Manoukian S, Arnold N, Engel C, Deissler H, Rhiem K, Niederacher D, Plendl H, Sutter C, Wappenschmidt B, Borg A, Melin B, Rantala J, Soller M, Nathanson KL, Domchek SM, Rodriguez GC, Salani R, Kaulich DG, Tea MK, Paluch SS, Laitman Y, Skytte AB, Kruse TA, Jensen UB, Robson M, Gerdes AM, Ejlertsen B, Foretova L, Savage SA, Lester J, Soucy P, Kuchenbaecker KB, Olswold C, Cunningham JM, Slager S, Pankratz VS, Dicks E, Lakhani SR, Couch FJ, Hall P, Monteiro AN, Gayther SA, Pharoah PD, Reddel RR, Goode EL, Greene MH, Easton DF, Berchuck A, Antoniou AC, Chenevix-Trench G, and Dunning AM

Subjects
Alternative Splicing, Breast Neoplasms pathology, Case-Control Studies, Chromatin genetics, DNA Methylation, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Luciferases metabolism, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms pathology, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Biomarkers, Tumor genetics, Breast Neoplasms etiology, Genetic Loci genetics, Ovarian Neoplasms etiology, Polymorphism, Single Nucleotide genetics, Telomerase genetics, Telomere genetics
Abstract

TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.

Published
2013
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7. Genome-wide association studies identify four ER negative-specific breast cancer risk loci.

Author

Garcia-Closas M, Couch FJ, Lindstrom S, Michailidou K, Schmidt MK, Brook MN, Orr N, Rhie SK, Riboli E, Feigelson HS, Le Marchand L, Buring JE, Eccles D, Miron P, Fasching PA, Brauch H, Chang-Claude J, Carpenter J, Godwin AK, Nevanlinna H, Giles GG, Cox A, Hopper JL, Bolla MK, Wang Q, Dennis J, Dicks E, Howat WJ, Schoof N, Bojesen SE, Lambrechts D, Broeks A, Andrulis IL, Guénel P, Burwinkel B, Sawyer EJ, Hollestelle A, Fletcher O, Winqvist R, Brenner H, Mannermaa A, Hamann U, Meindl A, Lindblom A, Zheng W, Devillee P, Goldberg MS, Lubinski J, Kristensen V, Swerdlow A, Anton-Culver H, Dörk T, Muir K, Matsuo K, Wu AH, Radice P, Teo SH, Shu XO, Blot W, Kang D, Hartman M, Sangrajrang S, Shen CY, Southey MC, Park DJ, Hammet F, Stone J, Veer LJ, Rutgers EJ, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Peto J, Schrauder MG, Ekici AB, Beckmann MW, Dos Santos Silva I, Johnson N, Warren H, Tomlinson I, Kerin MJ, Miller N, Marme F, Schneeweiss A, Sohn C, Truong T, Laurent-Puig P, Kerbrat P, Nordestgaard BG, Nielsen SF, Flyger H, Milne RL, Perez JI, Menéndez P, Müller H, Arndt V, Stegmaier C, Lichtner P, Lochmann M, Justenhoven C, Ko YD, Muranen TA, Aittomäki K, Blomqvist C, Greco D, Heikkinen T, Ito H, Iwata H, Yatabe Y, Antonenkova NN, Margolin S, Kataja V, Kosma VM, Hartikainen JM, Balleine R, Tseng CC, Berg DV, Stram DO, Neven P, Dieudonné AS, Leunen K, Rudolph A, Nickels S, Flesch-Janys D, Peterlongo P, Peissel B, Bernard L, Olson JE, Wang X, Stevens K, Severi G, Baglietto L, McLean C, Coetzee GA, Feng Y, Henderson BE, Schumacher F, Bogdanova NV, Labrèche F, Dumont M, Yip CH, Taib NA, Cheng CY, Shrubsole M, Long J, Pylkäs K, Jukkola-Vuorinen A, Kauppila S, Knight JA, Glendon G, Mulligan AM, Tollenaar RA, Seynaeve CM, Kriege M, Hooning MJ, van den Ouweland AM, van Deurzen CH, Lu W, Gao YT, Cai H, Balasubramanian SP, Cross SS, Reed MW, Signorello L, Cai Q, Shah M, Miao H, Chan CW, Chia KS, Jakubowska A, Jaworska K, Durda K, Hsiung CN, Wu PE, Yu JC, Ashworth A, Jones M, Tessier DC, González-Neira A, Pita G, Alonso MR, Vincent D, Bacot F, Ambrosone CB, Bandera EV, John EM, Chen GK, Hu JJ, Rodriguez-Gil JL, Bernstein L, Press MF, Ziegler RG, Millikan RM, Deming-Halverson SL, Nyante S, Ingles SA, Waisfisz Q, Tsimiklis H, Makalic E, Schmidt D, Bui M, Gibson L, Müller-Myhsok B, Schmutzler RK, Hein R, Dahmen N, Beckmann L, Aaltonen K, Czene K, Irwanto A, Liu J, Turnbull C, Rahman N, Meijers-Heijboer H, Uitterlinden AG, Rivadeneira F, Olswold C, Slager S, Pilarski R, Ademuyiwa F, Konstantopoulou I, Martin NG, Montgomery GW, Slamon DJ, Rauh C, Lux MP, Jud SM, Bruning T, Weaver J, Sharma P, Pathak H, Tapper W, Gerty S, Durcan L, Trichopoulos D, Tumino R, Peeters PH, Kaaks R, Campa D, Canzian F, Weiderpass E, Johansson M, Khaw KT, Travis R, Clavel-Chapelon F, Kolonel LN, Chen C, Beck A, Hankinson SE, Berg CD, Hoover RN, Lissowska J, Figueroa JD, Chasman DI, Gaudet MM, Diver WR, Willett WC, Hunter DJ, Simard J, Benitez J, Dunning AM, Sherman ME, Chenevix-Trench G, Chanock SJ, Hall P, Pharoah PD, Vachon C, Easton DF, Haiman CA, and Kraft P

Subjects
Breast Neoplasms metabolism, Breast Neoplasms pathology, Case-Control Studies, Cooperative Behavior, Female, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Oligonucleotide Array Sequence Analysis, Receptors, Estrogen genetics, Risk Factors, Breast Neoplasms etiology, Genetic Loci genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide genetics, Receptors, Estrogen metabolism
Abstract

Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

Published
2013
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8. Large-scale genotyping identifies 41 new loci associated with breast cancer risk.

Author

Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne RL, Schmidt MK, Chang-Claude J, Bojesen SE, Bolla MK, Wang Q, Dicks E, Lee A, Turnbull C, Rahman N, Fletcher O, Peto J, Gibson L, Dos Santos Silva I, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Czene K, Irwanto A, Liu J, Waisfisz Q, Meijers-Heijboer H, Adank M, van der Luijt RB, Hein R, Dahmen N, Beckman L, Meindl A, Schmutzler RK, Müller-Myhsok B, Lichtner P, Hopper JL, Southey MC, Makalic E, Schmidt DF, Uitterlinden AG, Hofman A, Hunter DJ, Chanock SJ, Vincent D, Bacot F, Tessier DC, Canisius S, Wessels LF, Haiman CA, Shah M, Luben R, Brown J, Luccarini C, Schoof N, Humphreys K, Li J, Nordestgaard BG, Nielsen SF, Flyger H, Couch FJ, Wang X, Vachon C, Stevens KN, Lambrechts D, Moisse M, Paridaens R, Christiaens MR, Rudolph A, Nickels S, Flesch-Janys D, Johnson N, Aitken Z, Aaltonen K, Heikkinen T, Broeks A, Veer LJ, van der Schoot CE, Guénel P, Truong T, Laurent-Puig P, Menegaux F, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Zamora MP, Perez JI, Pita G, Alonso MR, Cox A, Brock IW, Cross SS, Reed MW, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Henderson BE, Schumacher F, Le Marchand L, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Lindblom A, Margolin S, Hooning MJ, Hollestelle A, van den Ouweland AM, Jager A, Bui QM, Stone J, Dite GS, Apicella C, Tsimiklis H, Giles GG, Severi G, Baglietto L, Fasching PA, Haeberle L, Ekici AB, Beckmann MW, Brenner H, Müller H, Arndt V, Stegmaier C, Swerdlow A, Ashworth A, Orr N, Jones M, Figueroa J, Lissowska J, Brinton L, Goldberg MS, Labrèche F, Dumont M, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Brauch H, Hamann U, Brüning T, Radice P, Peterlongo P, Manoukian S, Bonanni B, Devilee P, Tollenaar RA, Seynaeve C, van Asperen CJ, Jakubowska A, Lubinski J, Jaworska K, Durda K, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Bogdanova NV, Antonenkova NN, Dörk T, Kristensen VN, Anton-Culver H, Slager S, Toland AE, Edge S, Fostira F, Kang D, Yoo KY, Noh DY, Matsuo K, Ito H, Iwata H, Sueta A, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Shu XO, Lu W, Gao YT, Cai H, Teo SH, Yip CH, Phuah SY, Cornes BK, Hartman M, Miao H, Lim WY, Sng JH, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Shen CY, Hsiung CN, Wu PE, Ding SL, Sangrajrang S, Gaborieau V, Brennan P, McKay J, Blot WJ, Signorello LB, Cai Q, Zheng W, Deming-Halverson S, Shrubsole M, Long J, Simard J, Garcia-Closas M, Pharoah PD, Chenevix-Trench G, Dunning AM, Benitez J, and Easton DF

Subjects
Case-Control Studies, Cooperative Behavior, Female, Gene-Environment Interaction, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Risk Factors, Breast Neoplasms etiology, Genetic Loci genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide genetics
Abstract

Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.

Published
2013
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9. A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11.

Author

Siddiq A, Couch FJ, Chen GK, Lindström S, Eccles D, Millikan RC, Michailidou K, Stram DO, Beckmann L, Rhie SK, Ambrosone CB, Aittomäki K, Amiano P, Apicella C, Baglietto L, Bandera EV, Beckmann MW, Berg CD, Bernstein L, Blomqvist C, Brauch H, Brinton L, Bui QM, Buring JE, Buys SS, Campa D, Carpenter JE, Chasman DI, Chang-Claude J, Chen C, Clavel-Chapelon F, Cox A, Cross SS, Czene K, Deming SL, Diasio RB, Diver WR, Dunning AM, Durcan L, Ekici AB, Fasching PA, Feigelson HS, Fejerman L, Figueroa JD, Fletcher O, Flesch-Janys D, Gaudet MM, Gerty SM, Rodriguez-Gil JL, Giles GG, van Gils CH, Godwin AK, Graham N, Greco D, Hall P, Hankinson SE, Hartmann A, Hein R, Heinz J, Hoover RN, Hopper JL, Hu JJ, Huntsman S, Ingles SA, Irwanto A, Isaacs C, Jacobs KB, John EM, Justenhoven C, Kaaks R, Kolonel LN, Coetzee GA, Lathrop M, Le Marchand L, Lee AM, Lee IM, Lesnick T, Lichtner P, Liu J, Lund E, Makalic E, Martin NG, McLean CA, Meijers-Heijboer H, Meindl A, Miron P, Monroe KR, Montgomery GW, Müller-Myhsok B, Nickels S, Nyante SJ, Olswold C, Overvad K, Palli D, Park DJ, Palmer JR, Pathak H, Peto J, Pharoah P, Rahman N, Rivadeneira F, Schmidt DF, Schmutzler RK, Slager S, Southey MC, Stevens KN, Sinn HP, Press MF, Ross E, Riboli E, Ridker PM, Schumacher FR, Severi G, Dos Santos Silva I, Stone J, Sund M, Tapper WJ, Thun MJ, Travis RC, Turnbull C, Uitterlinden AG, Waisfisz Q, Wang X, Wang Z, Weaver J, Schulz-Wendtland R, Wilkens LR, Van Den Berg D, Zheng W, Ziegler RG, Ziv E, Nevanlinna H, Easton DF, Hunter DJ, Henderson BE, Chanock SJ, Garcia-Closas M, Kraft P, Haiman CA, and Vachon CM

Subjects
Female, Humans, Polymorphism, Single Nucleotide genetics, Receptors, Estrogen genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.

Published
2012
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10. Genome-wide association analysis identifies three new breast cancer susceptibility loci.

Author

Ghoussaini M, Fletcher O, Michailidou K, Turnbull C, Schmidt MK, Dicks E, Dennis J, Wang Q, Humphreys MK, Luccarini C, Baynes C, Conroy D, Maranian M, Ahmed S, Driver K, Johnson N, Orr N, dos Santos Silva I, Waisfisz Q, Meijers-Heijboer H, Uitterlinden AG, Rivadeneira F, Hall P, Czene K, Irwanto A, Liu J, Nevanlinna H, Aittomäki K, Blomqvist C, Meindl A, Schmutzler RK, Müller-Myhsok B, Lichtner P, Chang-Claude J, Hein R, Nickels S, Flesch-Janys D, Tsimiklis H, Makalic E, Schmidt D, Bui M, Hopper JL, Apicella C, Park DJ, Southey M, Hunter DJ, Chanock SJ, Broeks A, Verhoef S, Hogervorst FB, Fasching PA, Lux MP, Beckmann MW, Ekici AB, Sawyer E, Tomlinson I, Kerin M, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Guénel P, Truong T, Cordina-Duverger E, Menegaux F, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Milne RL, Alonso MR, González-Neira A, Benítez J, Anton-Culver H, Ziogas A, Bernstein L, Dur CC, Brenner H, Müller H, Arndt V, Stegmaier C, Justenhoven C, Brauch H, Brüning T, Wang-Gohrke S, Eilber U, Dörk T, Schürmann P, Bremer M, Hillemanns P, Bogdanova NV, Antonenkova NN, Rogov YI, Karstens JH, Bermisheva M, Prokofieva D, Khusnutdinova E, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Lambrechts D, Yesilyurt BT, Floris G, Leunen K, Manoukian S, Bonanni B, Fortuzzi S, Peterlongo P, Couch FJ, Wang X, Stevens K, Lee A, Giles GG, Baglietto L, Severi G, McLean C, Alnaes GG, Kristensen V, Børrensen-Dale AL, John EM, Miron A, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Kauppila S, Andrulis IL, Glendon G, Mulligan AM, Devilee P, van Asperen CJ, Tollenaar RA, Seynaeve C, Figueroa JD, Garcia-Closas M, Brinton L, Lissowska J, Hooning MJ, Hollestelle A, Oldenburg RA, van den Ouweland AM, Cox A, Reed MW, Shah M, Jakubowska A, Lubinski J, Jaworska K, Durda K, Jones M, Schoemaker M, Ashworth A, Swerdlow A, Beesley J, Chen X, Muir KR, Lophatananon A, Rattanamongkongul S, Chaiwerawattana A, Kang D, Yoo KY, Noh DY, Shen CY, Yu JC, Wu PE, Hsiung CN, Perkins A, Swann R, Velentzis L, Eccles DM, Tapper WJ, Gerty SM, Graham NJ, Ponder BA, Chenevix-Trench G, Pharoah PD, Lathrop M, Dunning AM, Rahman N, Peto J, and Easton DF

Subjects
Female, Genome-Wide Association Study, Humans, Logistic Models, Polymorphism, Single Nucleotide genetics, Principal Component Analysis, White People genetics, Breast Neoplasms genetics, Chromosomes, Human, Pair 12 genetics, Chromosomes, Human, Pair 21 genetics, Genetic Loci genetics, Genetic Predisposition to Disease genetics
Abstract

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

Published
2012
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11. Low-risk variants FGFR2, TNRC9 and LSP1 in German familial breast cancer patients.

Author

Hemminki K, Müller-Myhsok B, Lichtner P, Engel C, Chen B, Burwinkel B, Försti A, Sutter C, Wappenschmidt B, Hellebrand H, Illig T, Arnold N, Niederacher D, Dworniczak B, Deissler H, Kast K, Gadzicki D, Meitinger T, Wichmann HE, Kiechle M, Bartram CR, Schmutzler RK, and Meindl A

Subjects
Adult, Aged, Apoptosis Regulatory Proteins, Breast Neoplasms pathology, Case-Control Studies, Chromosomes, Human, Pair 6 genetics, Female, Genotype, Germany, Heterozygote, High Mobility Group Proteins, Humans, Middle Aged, Phenotype, Prognosis, Receptors, Estrogen metabolism, Trans-Activators, Breast Neoplasms genetics, Genetic Predisposition to Disease, Microfilament Proteins genetics, Polymorphism, Single Nucleotide genetics, Receptor, Fibroblast Growth Factor, Type 2 genetics, Receptors, Progesterone genetics
Abstract

To validate common low-risk variants predisposing for breast cancer (BC) in a large set of BRCA1/2 negative familial or genetically enriched cases from Germany, we genotyped 1,415 cases and 1,830 healthy women by MALDI-TOF in 105 candidate SNPs. Significantly higher ORs than previously reported for heterozygous unselected cases were found for the minor allele in FGFR2 (OR = 1.43, 95% CI 1.30-1.59, p-value = 1.24 x 10(-12)) and for TNRC9 (OR = 1.33, 95% CI 1.19-1.46, p-value = 1.54 x 10(-7)). Most intriguing, however, were the ORs for homozygous carriers from high-risk families for FGFR2 (OR = 2.05, 95% CI 1.68-2.51, LSP1 (OR = 0.49, 95% CI 0.28-0.86) and TNRC9 (OR = 1.62, 95% CI 1.27-2.07). Moreover, the additional validation of 99 CGEMS-SNPs identified putative novel susceptibility alleles within the LSP1 gene (OR = 0.73, 95% CI 0.61-0.87, p-value = 5.23 x 10(-4)). Finally, we provide evidence for the first time that a low-risk variant located at 6q22.33 (rs6569479) is associated with estrogen receptor negative BC in familial cases (OR = 1.33, 95% CI 1.06-1.66; p-value = 0.012). Our data confirm the impact of the previously identified susceptibility loci and provide preliminary evidence for novel susceptibility loci in familial BC cases and correlate them to specific histopathological subtypes defined by estrogen receptor status.

Published
2010
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12. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene.

Author

Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H, Ramser J, Honisch E, Kubisch C, Wichmann HE, Kast K, Deissler H, Engel C, Müller-Myhsok B, Neveling K, Kiechle M, Mathew CG, Schindler D, Schmutzler RK, and Hanenberg H

Subjects
Alleles, Case-Control Studies, DNA-Binding Proteins genetics, Fanconi Anemia genetics, Female, Germany, Humans, Models, Genetic, Mutation, Pedigree, Phenotype, Breast Neoplasms genetics, Genetic Predisposition to Disease, Germ-Line Mutation, Ovarian Neoplasms genetics
Abstract

Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia-like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the 'common disease, rare allele' hypothesis.

Published
2010
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