Are the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers?

被引：28

作者：

Win, Aung Ko ^{[1
]}

Hopper, John L. ^{[1
]}

Buchanan, Daniel D. ^{[2
]}

Young, Joanne P. ^{[2
]}

Tenesa, Albert ^{[3
,4
]}

Dowty, James G. ^{[1
]}

Giles, Graham G. ^{[5
]}

Goldblatt, Jack ^{[6
,7
]}

Winship, Ingrid ^{[8
,9
]}

Boussioutas, Alex ^{[10
,11
,12
]}

Young, Graeme P. ^{[13
]}

Parry, Susan ^{[14
,15
]}

Baron, John A. ^{[16
]}

Duggan, David ^{[17
]}

Gallinger, Steven ^{[18
,19
]}

Newcomb, Polly A. ^{[20
]}

Haile, Robert W. ^{[21
]}

Le Marchand, Loic ^{[22
]}

Lindor, Noralane M. ^{[23
]}

Jenkins, Mark A. ^{[1
]}

机构：

[1] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Parkville, Vic 3052, Australia

[2] Queensland Inst Med Res, Canc & Populat Studies Grp, Bancroft Ctr, Herston, Qld 4006, Australia

[3] Univ Edinburgh, Roslin Inst, Edinburgh, Midlothian, Scotland

[4] Univ Edinburgh, Human Genet Unit, MRC, Inst Genet & Mol Med,Western Gen Hosp, Edinburgh EH8 9YL, Midlothian, Scotland

[5] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia

[6] Univ Western Australia, Genet Serv Western Australia, Perth, WA 6009, Australia

[7] Univ Western Australia, Sch Paediat & Child Hlth, Perth, WA 6009, Australia

[8] Univ Melbourne, Dept Med, Parkville, Vic 3052, Australia

[9] Royal Melbourne Hosp, Parkville, Vic 3050, Australia

[10] Univ Melbourne, Dept Med, Royal Melbourne Hosp, Parkville, Vic 3052, Australia

[11] Peter MacCallum Canc Ctr, East Melbourne, Vic, Australia

[12] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia

[13] Flinders Univ S Australia, Flinders Ctr Innovat Canc, Adelaide, SA 5001, Australia

[14] Auckland City Hosp, New Zealand Familial Gastrointestinal Canc Regist, Auckland, New Zealand

[15] Middlemore Hosp, Dept Gastroenterol, Auckland 6, New Zealand

[16] Univ N Carolina, Dept Med, Chapel Hill, NC USA

[17] Translat Genom Res Inst TGen, Genet Basis Human Dis Div, Phoenix, AZ USA

[18] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada

[19] Canc Care Ontario, Toronto, ON, Canada

[20] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA

[21] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA

[22] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA

[23] Mayo Clin Arizona, Dept Hlth Sci Res, Scottsdale, AZ USA

来源：

EUROPEAN JOURNAL OF CANCER | 2013年 / 49卷 / 07期

基金：

美国国家卫生研究院;

关键词：

Genetic variant; Colorectal cancer; Lynch syndrome; Mismatch repair; GENOME-WIDE ASSOCIATION; LYNCH-SYNDROME; COLON-CANCER; SUSCEPTIBILITY LOCI; GERMLINE MUTATIONS; FAMILY REGISTRY; EPIDEMIOLOGY; 11Q23.1; 8Q23.3; MLH1;

D O I：

10.1016/j.ejca.2013.01.029

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: Genome-wide association studies have identified at least 15 independent common genetic variants associated with colorectal cancer (CRC) risk. The aim of this study was to investigate whether 11 of these variants are associated with CRC risk for carriers of germline mutations in DNA mismatch repair (MMR) genes. Methods: A total of 927 MMR gene mutation carriers (360 MLH1, 442 MSH2, 85 MSH6 and 40 PMS2) from 315 families enrolled in the Colon Cancer Family Registry, were genotyped for the single nucleotide polymorphisms (SNPs): rs16892766 (8q23.3), rs6983267 (8q24.21), rs719725 (9p24), rs10795668 (10p14), rs3802842 (11q23.1), rs4444235 (14q22.2), rs4779584 (15q13.3), rs9929218 (16q22.1), rs4939827 (18q21.1), rs10411210 (19q13.1) and rs961253 (20p12.3). We used a weighted Cox regression to estimate CRC risk for homozygous and heterozygous carriers of the risk allele compared with homozygous non-carriers as well as for an additive per allele model (on the log scale). Results: Over a total of 40,978 person-years observation, 426 (46%) carriers were diagnosed with CRC at a mean age of 44.3 years. For all carriers combined, we found no evidence of an association between CRC risk and the total number of risk alleles (hazard ratio [HR] per risk allele = 0.97, 95% confidence interval [CI] = 0.88-1.07, p = 0.52). Conclusions: We found no evidence that the SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall, and therefore any evidence of proven clinical utility in Lynch syndrome. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：1578 / 1587

页数：10

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