Article Text
Abstract
Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.
Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.
Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.
Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
- Cancer: breast
- Cancer: prostate
- Genetics
- Cancer: ovary
- cancer predisposition
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Footnotes
Contributors All authors provided DNA samples and/or data and have participated in the Breast Cancer Association Consortium through attendance at regular meetings and planning of the iCOGS experiment. Each author has made substantial contribution through designing and coordinating the studies listed in the supplemental material and therefore have made substantial contributions to the conception or design of this work. Many authors played multiple roles across these activities. Specifically, MCS conceived this study, worked to include the rare variants on the iCOGS and drafted the manuscript. RLM led the statistical analysis and drafted the paper. Members of the PALB2 interest group, MCS, DEG, RW, KP, FC, MT, WF, JD, KM, EJvR, TH, HN, JLH, TD, KC, JR-F, ZLT, PR, IC, PP, HT, FAO, JGD contributed to the inclusion of the PALB2 rare variants on iCOGS. DFE coordinated the BCAC project and contributed to statistical analysis along with DEG. SVT contributed to the selection of CHEK2 rare variants. GC-T contributed to the selection of rare variants in ATM. AD, CL and JD made significant contribution to the data quality related to the calling of the rare genetics variants on iCOGS. MKS, AB, FBH, SV, JC, CC, RJS, PAF, LH, ABE, MWB, JP, IDSS, OF, NJ, MKB, EJS, IT, MJK, NM, FM, BB, RY, PG, TT, FM, MS, SB, SFN, HF, JB, MPZ, JIAP, PM, HAC, SN, AZ, CCD, HB, VA, CS, HB, TB, YDK, TAM, KA, CB, NVB, NNA, AL, SM, AM, VK, V-MK, JMH, AS, EW, DS, BB, GF, JCC, AR, PS, DFJ, JEO, CV, VSP, CM, CAH, BEH, FS, LLM, VK, GGA, WZ, DJH, SL, SEH, PK, IA, JAK, GG, AMM, AJV, MG, SK, PD, RAEMT, CS, AH, MGC, JF, SJC, JL, KC, HD, ME, DME, SR, WJT, SMG, MJH, JWMM, JMC, MTL, PH, JL, JSB, KH, AC, MWRR, CL, CB, AD, UH, DT, HUU, TR, AJ, JL, KJ, KD, SS, AET, CBA, DY, AS, AA, NO, MJ, AGN, GP, MRA, NA, DH, DCT, DV, FB, JS, MD, PS, RE, KM, FW, HG, JS, MW, BGN, RCT, DN, JLD, FCH, KTK, JLS, WJB, ST, DJS, JLK, CM, ASK, CC, LCA, KB, JP, RK, JB, MRT, ZKJ, AAAO, SB, SPR, AH, AH, MR, DL, EVN, IV, SL, JAD, MAR, SN, UE, SWG, KO, LES, GF, GL, JLK, LRW, MTG, IR, PAH, LMP, RB, FM, RPE, RBN, KBM, ADB, FH, PH, SK, BYK, CW, JL, AJ, SKK, EH, BP, BB, LB, ELG, BLF, RAV, JMC, MCL, ZCF, KRK, DL, KHL, MATH, XW, DAL, FD, MB, AB, ESI, JRM, LA, DWC, KLT, ELP, MS, SST, EVB, IO, SHO, LB, HBS, AMVA, KKHA, LAK, LFAGM, TP, YB, ABW, LEK, LSC, NDL, BG, JG, JM, CKH, LL, LN, SAE, ED, JT, IC, IN, JP, NS, RG, ASW, JHR, VG, WS, HC, XOS, RTT, RS, JRM, SAN, CP, ANM, DF, HYL, JPW, TAS, TAC, YYT, ZC, AGM, SAG, SJR, UM, AHW, CLP, DVDB, MCP, ADM, JPH, JMS, JK, PP, HS, IW, GC-T, GGG, SVT, DFE, RLM provided DNA samples and/or phenotypical data. All authors read and approved the final manuscript.
Funding Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692, CRUK C8197/A10123), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (No. 1 U19 CA 148537—the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, the Ovarian Cancer Research Fund and Susan G Komen (WF).
Further information about the financial report received is outlined in the supplementary file online.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement This would vary for each study—each study is listed in the supplemental material.