. 2020 Jan 15;146(2):363-372.

doi: 10.1002/ijc.32516. Epub 2019 Jul 4.

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

Barbara Pardini^{1

2}, Alda Corrado³, Elisa Paolicchi³, Giovanni Cugliari^{1

2}, Sonja I Berndt⁴, Stephane Bezieau⁵, Stephanie A Bien^{6

7}, Hermann Brenner^{8

9

10}, Bette J Caan¹¹, Peter T Campbell¹², Graham Casey¹³, Andrew T Chan¹⁴, Jenny Chang-Claude¹⁵, Michelle Cotterchio¹⁶, Manish Gala¹⁴, Steven J Gallinger¹⁷, Robert W Haile¹⁸, Tabitha A Harrison⁶, Richard B Hayes¹⁹, Michael Hoffmeister⁸, John L Hopper²⁰, Li Hsu⁶, Jeroen Huyghe⁶, Mark A Jenkins²⁰, Loic Le Marchand²¹, Yi Lin⁶, Noralane M Lindor²², Hongmei Nan²³, Polly A Newcomb⁶, Shuji Ogino^{24

25

26

27}, John D Potter⁶, Robert E Schoen²⁸, Martha L Slattery²⁹, Emily White⁶, Ludmila Vodickova^{30

31

32}, Veronika Vymetalkova^{30

31

32}, Pavel Vodicka^{30

31

32}, Federica Gemignani³, Ulrike Peters⁶, Alessio Naccarati^{1

32}, Stefano Landi³

Affiliations

¹ Italian Institute for Genomic Medicine (IIGM), Turin, Italy.
² Department of Medical Sciences, University of Turin, Turin, Italy.
³ Department of Biology, University of Pisa, Pisa, Italy.
⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD.
⁵ Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU), Nantes, France.
⁶ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
⁷ School of Public Health, University of Washington, Seattle, WA.
⁸ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁹ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹⁰ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹¹ Kaiser Permanente Medical Care Program of Northern California, Oakland, CA.
¹² Epidemiology Research Program, American Cancer Society, Atlanta, GA.
¹³ Public Health Sciences, University of Virginia, Charlottesville, VA.
¹⁴ Division of Gastroenterology, Massachusetts General Hospital, Boston, MA.
¹⁵ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁶ Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada.
¹⁷ Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada.
¹⁸ Stanford University School of Medicine, Stanford, CA.
¹⁹ Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY.
²⁰ Melbourne School of Population Health, The University of Melbourne, Melbourne, VIC, Australia.
²¹ Epidemiology Program, Research Cancer Center of Hawaii, University of Hawaii, Honolulu, HI.
²² Department of Health Sciences Research, Mayo Clinic Arizona, Scottsdale, AZ.
²³ Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN.
²⁴ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA.
²⁵ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA.
²⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.
²⁷ Broad Institute of MIT and Harvard, Cambridge, MA.
²⁸ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA.
²⁹ Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT.
³⁰ Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
³¹ Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic.
³² Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Prague, Czech Republic.

PMID: 31209889
PMCID: PMC7301215
DOI: 10.1002/ijc.32516

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

Barbara Pardini et al. Int J Cancer. 2020.

. 2020 Jan 15;146(2):363-372.

doi: 10.1002/ijc.32516. Epub 2019 Jul 4.

Authors

Affiliations

¹ Italian Institute for Genomic Medicine (IIGM), Turin, Italy.
² Department of Medical Sciences, University of Turin, Turin, Italy.
³ Department of Biology, University of Pisa, Pisa, Italy.
⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD.
⁵ Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU), Nantes, France.
⁶ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
⁷ School of Public Health, University of Washington, Seattle, WA.
⁸ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁹ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹⁰ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹¹ Kaiser Permanente Medical Care Program of Northern California, Oakland, CA.
¹² Epidemiology Research Program, American Cancer Society, Atlanta, GA.
¹³ Public Health Sciences, University of Virginia, Charlottesville, VA.
¹⁴ Division of Gastroenterology, Massachusetts General Hospital, Boston, MA.
¹⁵ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁶ Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada.
¹⁷ Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada.
¹⁸ Stanford University School of Medicine, Stanford, CA.
¹⁹ Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY.
²⁰ Melbourne School of Population Health, The University of Melbourne, Melbourne, VIC, Australia.
²¹ Epidemiology Program, Research Cancer Center of Hawaii, University of Hawaii, Honolulu, HI.
²² Department of Health Sciences Research, Mayo Clinic Arizona, Scottsdale, AZ.
²³ Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN.
²⁴ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA.
²⁵ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA.
²⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.
²⁷ Broad Institute of MIT and Harvard, Cambridge, MA.
²⁸ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA.
²⁹ Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT.
³⁰ Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
³¹ Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic.
³² Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Prague, Czech Republic.

PMID: 31209889
PMCID: PMC7301215
DOI: 10.1002/ijc.32516

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.

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Conflict of interest statement

The authors declare no conflict of interests

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References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials