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

Barbara Pardini; Alda Corrado; Elisa Paolicchi; Giovanni Cugliari; Sonja I. Berndt; Stephane Bezieau; Stephanie A. Bien; Hermann Brenner; Bette J. Caan; Peter T. Campbell; Graham Casey; Andrew T. Chan; Jenny Chang-Claude; Michelle Cotterchio; Manish Gala; Steven J. Gallinger; Robert W. Haile; Tabitha A. Harrison; Richard B. Hayes; Michael Hoffmeister; John L. Hopper; Li Hsu; Jeroen Huyghe; Mark A. Jenkins; Loic Le Marchand; Yi Lin; Noralane M. Lindor; Hongmei Nan; Polly A. Newcomb; Shuji Ogino; John D. Potter; Robert E. Schoen; Martha L. Slattery; Emily White; Ludmila Vodickova; Veronika Vymetalkova; Pavel Vodicka; Federica Gemignani; Ulrike Peters; Alessio Naccarati; Stefano Landi

doi:10.1002/ijc.32516

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

Barbara Pardini, Alda Corrado, Elisa Paolicchi, Giovanni Cugliari, Sonja I. Berndt, Stephane Bezieau, Stephanie A. Bien, Hermann Brenner, Bette J. Caan, Peter T. Campbell, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, Michelle Cotterchio, Manish Gala, Steven J. Gallinger, Robert W. Haile, Tabitha A. Harrison, Richard B. Hayes, Michael HoffmeisterJohn L. Hopper, Li Hsu, Jeroen Huyghe, Mark A. Jenkins, Loic Le Marchand, Yi Lin, Noralane M. Lindor, Hongmei Nan, Polly A. Newcomb, Shuji Ogino, John D. Potter, Robert E. Schoen, Martha L. Slattery, Emily White, Ludmila Vodickova, Veronika Vymetalkova, Pavel Vodicka, Federica Gemignani, Ulrike Peters, Alessio Naccarati, Stefano Landi

Research

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

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 × 10⁻⁶) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10⁻⁶). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 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.

Original language	English (US)
Pages (from-to)	363-372
Number of pages	10
Journal	International Journal of Cancer
Volume	146
Issue number	2
DOIs	https://doi.org/10.1002/ijc.32516
State	Published - Jan 15 2020

Keywords

DNA repair
cancer susceptibility
colon cancer
genome-wide association studies
rectal cancer
single nucleotide polymorphisms

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1002/ijc.32516

Cite this

Pardini, B., Corrado, A., Paolicchi, E., Cugliari, G., Berndt, S. I., Bezieau, S., Bien, S. A., Brenner, H., Caan, B. J., Campbell, P. T., Casey, G., Chan, A. T., Chang-Claude, J., Cotterchio, M., Gala, M., Gallinger, S. J., Haile, R. W., Harrison, T. A., Hayes, R. B., ... Landi, S. (2020). DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility. International Journal of Cancer, 146(2), 363-372. https://doi.org/10.1002/ijc.32516

Pardini, B, Corrado, A, Paolicchi, E, Cugliari, G, Berndt, SI, Bezieau, S, Bien, SA, Brenner, H, Caan, BJ, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Cotterchio, M, Gala, M, Gallinger, SJ, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hopper, JL, Hsu, L, Huyghe, J, Jenkins, MA, Le Marchand, L, Lin, Y, Lindor, NM, Nan, H, Newcomb, PA, Ogino, S, Potter, JD, Schoen, RE, Slattery, ML, White, E, Vodickova, L, Vymetalkova, V, Vodicka, P, Gemignani, F, Peters, U, Naccarati, A & Landi, S 2020, 'DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility', International Journal of Cancer, vol. 146, no. 2, pp. 363-372. https://doi.org/10.1002/ijc.32516

@article{f6a5b09aaf754b14b98c944d785713fd,

title = "DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility",

abstract = "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 × 10−6) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10−6). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 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.",

keywords = "DNA repair, cancer susceptibility, colon cancer, genome-wide association studies, rectal cancer, single nucleotide polymorphisms",

author = "Barbara Pardini and Alda Corrado and Elisa Paolicchi and Giovanni Cugliari and Berndt, {Sonja I.} and Stephane Bezieau and Bien, {Stephanie A.} and Hermann Brenner and Caan, {Bette J.} and Campbell, {Peter T.} and Graham Casey and Chan, {Andrew T.} and Jenny Chang-Claude and Michelle Cotterchio and Manish Gala and Gallinger, {Steven J.} and Haile, {Robert W.} and Harrison, {Tabitha A.} and Hayes, {Richard B.} and Michael Hoffmeister and Hopper, {John L.} and Li Hsu and Jeroen Huyghe and Jenkins, {Mark A.} and {Le Marchand}, Loic and Yi Lin and Lindor, {Noralane M.} and Hongmei Nan and Newcomb, {Polly A.} and Shuji Ogino and Potter, {John D.} and Schoen, {Robert E.} and Slattery, {Martha L.} and Emily White and Ludmila Vodickova and Veronika Vymetalkova and Pavel Vodicka and Federica Gemignani and Ulrike Peters and Alessio Naccarati and Stefano Landi",

note = "Publisher Copyright: {\textcopyright} 2019 UICC",

year = "2020",

month = jan,

day = "15",

doi = "10.1002/ijc.32516",

language = "English (US)",

volume = "146",

pages = "363--372",

journal = "International Journal of Cancer",

issn = "0020-7136",

publisher = "Wiley-Liss Inc.",

number = "2",

}

TY - JOUR

T1 - DNA repair and cancer in colon and rectum

T2 - Novel players in genetic susceptibility

AU - Pardini, Barbara

AU - Corrado, Alda

AU - Paolicchi, Elisa

AU - Cugliari, Giovanni

AU - Berndt, Sonja I.

AU - Bezieau, Stephane

AU - Bien, Stephanie A.

AU - Brenner, Hermann

AU - Caan, Bette J.

AU - Campbell, Peter T.

AU - Casey, Graham

AU - Chan, Andrew T.

AU - Chang-Claude, Jenny

AU - Cotterchio, Michelle

AU - Gala, Manish

AU - Gallinger, Steven J.

AU - Haile, Robert W.

AU - Harrison, Tabitha A.

AU - Hayes, Richard B.

AU - Hoffmeister, Michael

AU - Hopper, John L.

AU - Hsu, Li

AU - Huyghe, Jeroen

AU - Jenkins, Mark A.

AU - Le Marchand, Loic

AU - Lin, Yi

AU - Lindor, Noralane M.

AU - Nan, Hongmei

AU - Newcomb, Polly A.

AU - Ogino, Shuji

AU - Potter, John D.

AU - Schoen, Robert E.

AU - Slattery, Martha L.

AU - White, Emily

AU - Vodickova, Ludmila

AU - Vymetalkova, Veronika

AU - Vodicka, Pavel

AU - Gemignani, Federica

AU - Peters, Ulrike

AU - Naccarati, Alessio

AU - Landi, Stefano

PY - 2020/1/15

Y1 - 2020/1/15

N2 - 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 × 10−6) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10−6). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 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.

AB - 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 × 10−6) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10−6). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 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.

KW - DNA repair

KW - cancer susceptibility

KW - colon cancer

KW - genome-wide association studies

KW - rectal cancer

KW - single nucleotide polymorphisms

UR - http://www.scopus.com/inward/record.url?scp=85068514355&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068514355&partnerID=8YFLogxK

U2 - 10.1002/ijc.32516

DO - 10.1002/ijc.32516

M3 - Article

C2 - 31209889

AN - SCOPUS:85068514355

SN - 0020-7136

VL - 146

SP - 363

EP - 372

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 2

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this