DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility

被引：26

作者：

Pardini, Barbara ^{[1
,2
]}

Corrado, Alda ^{[3
]}

Paolicchi, Elisa ^{[3
]}

Cugliari, Giovanni ^{[1
,2
]}

Berndt, Sonja, I ^{[4
]}

Bezieau, Stephane ^{[5
]}

Bien, Stephanie A. ^{[6
,7
]}

Brenner, Hermann ^{[8
,9
,10
,11
]}

Caan, Bette J. ^{[12
]}

Campbell, Peter T. ^{[13
]}

Casey, Graham ^{[14
]}

Chan, Andrew T. ^{[15
]}

Chang-Claude, Jenny ^{[16
]}

Cotterchio, Michelle ^{[17
]}

Gala, Manish ^{[15
]}

Gallinger, Steven J. ^{[18
]}

Haile, Robert W. ^{[19
]}

Harrison, Tabitha A. ^{[6
]}

Hayes, Richard B. ^{[20
]}

Hoffmeister, Michael ^{[8
]}

Hopper, John L. ^{[21
]}

Hsu, Li ^{[6
]}

Huyghe, Jeroen ^{[6
]}

Jenkins, Mark A. ^{[21
]}

Le Marchand, Loic ^{[22
]}

Lin, Yi ^{[6
]}

Lindor, Noralane M. ^{[23
]}

Nan, Hongmei ^{[24
]}

Newcomb, Polly A. ^{[6
]}

Ogino, Shuji ^{[25
,26
,27
,28
,29
]}

Potter, John D. ^{[6
]}

Schoen, Robert E. ^{[30
]}

Slattery, Martha L. ^{[31
]}

White, Emily ^{[6
]}

Vodickova, Ludmila ^{[32
,33
,34
]}

Vymetalkova, Veronika ^{[32
,33
,34
]}

Vodicka, Pavel ^{[32
,33
,34
]}

Gemignani, Federica ^{[3
]}

Peters, Ulrike ^{[6
]}

Naccarati, Alessio ^{[1
,34
]}

Landi, Stefano ^{[3
]}

机构：

[1] IIGM, Via Nizza 52, I-10126 Turin, Italy

[2] Univ Turin, Dept Med Sci, Turin, Italy

[3] Univ Pisa, Dept Biol, Via Derna 1, I-56126 Pisa, Italy

[4] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA

[5] CHU Nantes, Serv Genet Med, Nantes, France

[6] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA

[7] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA

[8] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany

[9] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany

[10] Natl Ctr Tumor Dis NCT, Heidelberg, Germany

[11] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany

[12] Kaiser Permanente Med Care Program Northern Calif, Oakland, CA USA

[13] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA

[14] Univ Virginia, Publ Hlth Sci, Charlottesville, VA USA

[15] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA

[16] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[17] Canc Care Ontario, Prevent & Canc Control, Toronto, ON, Canada

[18] Mt Sinai Hosp, Dept Surg, Toronto, ON, Canada

[19] Stanford Univ, Sch Med, Stanford, CA 94305 USA

[20] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY USA

[21] Univ Melbourne, Melbourne Sch Populat Hlth, Melbourne, Vic, Australia

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

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

[24] Indiana Univ, Dept Epidemiol, Richard M Fairbanks Sch Publ Hlth, Indianapolis, IN 46204 USA

[25] Brigham & Womens Hosp, Dept Pathol, Program MPE Mol Pathol Epidemiol, 75 Francis St, Boston, MA 02115 USA

[26] Harvard Med Sch, Boston, MA 02115 USA

[27] Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA 02115 USA

[28] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[29] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[30] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA

[31] Univ Utah, Dept Internal Med, Hlth Sci Ctr, Salt Lake City, UT 84112 USA

[32] Charles Univ Prague, Fac Med 1, Inst Biol & Med Genet, Prague, Czech Republic

[33] Charles Univ Prague, Fac Med & Biomed Ctr Pilsen, Plzen, Czech Republic

[34] Czech Acad Sci, Inst Expt Med, Dept Mol Biol Canc, Prague, Czech Republic

来源：

INTERNATIONAL JOURNAL OF CANCER | 2020年 / 146卷 / 02期

关键词：

colon cancer; rectal cancer; DNA repair; single nucleotide polymorphisms; cancer susceptibility; genome-wide association studies; GENOME-WIDE ASSOCIATION; SPORADIC COLORECTAL-CANCER; MISMATCH REPAIR; RISK; POLYMORPHISMS; PROMOTER; EPIDEMIOLOGY; METHYLATION; VARIANTS; MULTIPLE;

D O I：

10.1002/ijc.32516

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 x 10(-6)) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 x 10(-6)). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 x 10(-6). Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

引用

页码：363 / 372

页数：10

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