Dataset Information

Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2.

ABSTRACT: Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08-1.13, P = 4.1 x 10(-23)) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92-0.97, P = 1.4 x 10(-8)). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.

SUBMITTER: Ahmed S

PROVIDER: S-EPMC2748125 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2.

Ahmed Shahana S Thomas Gilles G Ghoussaini Maya M Healey Catherine S CS Humphreys Manjeet K MK Platte Radka R Morrison Jonathan J Maranian Melanie M Pooley Karen A KA Luben Robert R Eccles Diana D Evans D Gareth DG Fletcher Olivia O Johnson Nichola N dos Santos Silva Isabel I Peto Julian J Stratton Michael R MR Rahman Nazneen N Jacobs Kevin K Prentice Ross R Anderson Garnet L GL Rajkovic Aleksandar A Curb J David JD Ziegler Regina G RG Berg Christine D CD Buys Saundra S SS McCarty Catherine A CA Feigelson Heather Spencer HS Calle Eugenia E EE Thun Michael J MJ Diver W Ryan WR Bojesen Stig S Nordestgaard Børge G BG Flyger Henrik H Dörk Thilo T Schürmann Peter P Hillemanns Peter P Karstens Johann H JH Bogdanova Natalia V NV Antonenkova Natalia N NN Zalutsky Iosif V IV Bermisheva Marina M Fedorova Sardana S Khusnutdinova Elza E Kang Daehee D Yoo Keun-Young KY Noh Dong Young DY Ahn Sei-Hyun SH Devilee Peter P van Asperen Christi J CJ Tollenaar R A E M RA Seynaeve Caroline C Garcia-Closas Montserrat M Lissowska Jolanta J Brinton Louise L Peplonska Beata B Nevanlinna Heli H Heikkinen Tuomas T Aittomäki Kristiina K Blomqvist Carl C Hopper John L JL Southey Melissa C MC Smith Letitia L Spurdle Amanda B AB Schmidt Marjanka K MK Broeks Annegien A van Hien Richard R RR Cornelissen Sten S Milne Roger L RL Ribas Gloria G González-Neira Anna A Benitez Javier J Schmutzler Rita K RK Burwinkel Barbara B Bartram Claus R CR Meindl Alfons A Brauch Hiltrud H Justenhoven Christina C Hamann Ute U Chang-Claude Jenny J Hein Rebecca R Wang-Gohrke Shan S Lindblom Annika A Margolin Sara S Mannermaa Arto A Kosma Veli-Matti VM Kataja Vesa V Olson Janet E JE Wang Xianshu X Fredericksen Zachary Z Giles Graham G GG Severi Gianluca G Baglietto Laura L English Dallas R DR Hankinson Susan E SE Cox David G DG Kraft Peter P Vatten Lars J LJ Hveem Kristian K Kumle Merethe M Sigurdson Alice A Doody Michele M Bhatti Parveen P Alexander Bruce H BH Hooning Maartje J MJ van den Ouweland Ans M W AM Oldenburg Rogier A RA Schutte Mieke M Hall Per P Czene Kamila K Liu Jianjun J Li Yuqing Y Cox Angela A Elliott Graeme G Brock Ian I Reed Malcolm W R MW Shen Chen-Yang CY Yu Jyh-Cherng JC Hsu Giu-Cheng GC Chen Shou-Tung ST Anton-Culver Hoda H Ziogas Argyrios A Andrulis Irene L IL Knight Julia A JA Beesley Jonathan J Goode Ellen L EL Couch Fergus F Chenevix-Trench Georgia G Hoover Robert N RN Ponder Bruce A J BA Hunter David J DJ Pharoah Paul D P PD Dunning Alison M AM Chanock Stephen J SJ Easton Douglas F DF

Nature genetics 20090329 5

Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 c ...[more]

PMID: 19330027

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Project description:Genome-wide association studies have discovered multiple genetic loci associated with breast cancer risk. Investigating these loci would be helpful to evaluate previous findings and identify causal variants for breast cancer. We evaluated index SNPs in 17 of these loci in a study of 1,511 cases and 1,454 controls of European descent.We investigated the overall association with breast cancer and among subtypes defined as ER+ (estrogen receptor positive), ER- (estrogen receptor negative) and triple-negative breast cancer (TNBC). Combined effects of SNPs on breast cancer risk were assessed via a genetic risk score. We evaluated the contribution of both genetic variants and traditional risk factors to a breast cancer risk assessment model.Five of the 17 SNPs were significantly associated (P ? 0.05) with overall breast cancer in the same direction as previously reported: rs13387042 (2q35/TNP1), rs4973768 (3p24/SLC4A7), rs2046210 (6q25/ESR1), rs1219648 (10q26/FGFR2), and rs4784227 (16q12/TOX3). When stratified by breast cancer subtype, all five SNPs were associated (P < 0.05) with ER+ cancer, three with ER- cancer (rs13387042, rs1219648, and rs4784227), and one with TNBC (rs1219648). A GRS, based on those five significant SNPs, showed strong association with overall breast cancer with ORs (95 % CI) of 1.48 (1.22-1.79), 1.85 (1.52-2.25) and 2.26 (1.82-2.80), respectively, for each quartile, (P = 2.0 × 10(-15)). Traditional risk factors, including previous benign breast disease, breast cancer family history and parity, were significantly associated with breast cancer risk in the present study. These factors, together with the GRS, were used to build a breast cancer risk assessment model with a c statistic of 0.6321 from receiver operating characteristic analysis. The contribution of the GRS to the model was greater than prior benign breast disease, family history and parity with the c statistic change of 0.0374, 0.0324, 0.0103, 0.0012, respectively.Our study demonstrates that five SNPs were associated with overall breast cancer, with stronger association for ER+ than ER- cancer as previously reported, and suggests that a risk assessment model incorporating the GRS from five loci is useful in identifying women at high risk of breast cancer.

Dataset Information

Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2.

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Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2.

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