DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility
Corresponding Author
Barbara Pardini
Italian Institute for Genomic Medicine (IIGM), Turin, Italy
Department of Medical Sciences, University of Turin, Turin, Italy
B.P., A.C., U.P., A.N., and S.L. contributed equally to this workCorrespondence to: Alda Corrado, Department of Biology, University of Pisa, Via Derna 1, 56126 Pisa, Italy, Tel.: +390502211524, Fax: +390502211527, E-mail: [email protected]; or Barbara Pardini, Italian Institute for Genomic Medicine (IIGM), Via Nizza 52, 10126 Turin, Italy, Tel.: +390116709542, Fax: +390112365601, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Alda Corrado
Department of Biology, University of Pisa, Pisa, Italy
B.P., A.C., U.P., A.N., and S.L. contributed equally to this workCorrespondence to: Alda Corrado, Department of Biology, University of Pisa, Via Derna 1, 56126 Pisa, Italy, Tel.: +390502211524, Fax: +390502211527, E-mail: [email protected]; or Barbara Pardini, Italian Institute for Genomic Medicine (IIGM), Via Nizza 52, 10126 Turin, Italy, Tel.: +390116709542, Fax: +390112365601, E-mail: [email protected]Search for more papers by this authorElisa Paolicchi
Department of Biology, University of Pisa, Pisa, Italy
Search for more papers by this authorGiovanni Cugliari
Italian Institute for Genomic Medicine (IIGM), Turin, Italy
Department of Medical Sciences, University of Turin, Turin, Italy
Search for more papers by this authorSonja I. Berndt
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD
Search for more papers by this authorStephane Bezieau
Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU), Nantes, France
Search for more papers by this authorStephanie A. Bien
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
School of Public Health, University of Washington, Seattle, WA
Search for more papers by this authorHermann Brenner
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorBette J. Caan
Kaiser Permanente Medical Care Program of Northern California, Oakland, CA
Search for more papers by this authorPeter T. Campbell
Epidemiology Research Program, American Cancer Society, Atlanta, GA
Search for more papers by this authorGraham Casey
Public Health Sciences, University of Virginia, Charlottesville, VA
Search for more papers by this authorAndrew T. Chan
Division of Gastroenterology, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorJenny Chang-Claude
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorMichelle Cotterchio
Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada
Search for more papers by this authorManish Gala
Division of Gastroenterology, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorSteven J. Gallinger
Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada
Search for more papers by this authorRobert W. Haile
Stanford University School of Medicine, Stanford, CA
Search for more papers by this authorTabitha A. Harrison
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorRichard B. Hayes
Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY
Search for more papers by this authorMichael Hoffmeister
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorJohn L. Hopper
Melbourne School of Population Health, The University of Melbourne, Melbourne, VIC, Australia
Search for more papers by this authorLi Hsu
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorJeroen Huyghe
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorMark A. Jenkins
Melbourne School of Population Health, The University of Melbourne, Melbourne, VIC, Australia
Search for more papers by this authorLoic Le Marchand
Epidemiology Program, Research Cancer Center of Hawaii, University of Hawaii, Honolulu, HI
Search for more papers by this authorYi Lin
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorNoralane M. Lindor
Department of Health Sciences Research, Mayo Clinic Arizona, Scottsdale, AZ
Search for more papers by this authorHongmei Nan
Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN
Search for more papers by this authorPolly A. Newcomb
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorShuji Ogino
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
Broad Institute of MIT and Harvard, Cambridge, MA
Search for more papers by this authorJohn D. Potter
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorRobert E. Schoen
Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA
Search for more papers by this authorMartha L. Slattery
Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT
Search for more papers by this authorEmily White
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorLudmila Vodickova
Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Prague, Czech Republic
Search for more papers by this authorVeronika Vymetalkova
Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Prague, Czech Republic
Search for more papers by this authorPavel Vodicka
Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Prague, Czech Republic
Search for more papers by this authorFederica Gemignani
Department of Biology, University of Pisa, Pisa, Italy
Search for more papers by this authorUlrike Peters
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
B.P., A.C., U.P., A.N., and S.L. contributed equally to this workSearch for more papers by this authorAlessio Naccarati
Italian Institute for Genomic Medicine (IIGM), Turin, Italy
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Prague, Czech Republic
B.P., A.C., U.P., A.N., and S.L. contributed equally to this workSearch for more papers by this authorStefano Landi
Department of Biology, University of Pisa, Pisa, Italy
B.P., A.C., U.P., A.N., and S.L. contributed equally to this workSearch for more papers by this authorCorresponding Author
Barbara Pardini
Italian Institute for Genomic Medicine (IIGM), Turin, Italy
Department of Medical Sciences, University of Turin, Turin, Italy
B.P., A.C., U.P., A.N., and S.L. contributed equally to this workCorrespondence to: Alda Corrado, Department of Biology, University of Pisa, Via Derna 1, 56126 Pisa, Italy, Tel.: +390502211524, Fax: +390502211527, E-mail: [email protected]; or Barbara Pardini, Italian Institute for Genomic Medicine (IIGM), Via Nizza 52, 10126 Turin, Italy, Tel.: +390116709542, Fax: +390112365601, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Alda Corrado
Department of Biology, University of Pisa, Pisa, Italy
B.P., A.C., U.P., A.N., and S.L. contributed equally to this workCorrespondence to: Alda Corrado, Department of Biology, University of Pisa, Via Derna 1, 56126 Pisa, Italy, Tel.: +390502211524, Fax: +390502211527, E-mail: [email protected]; or Barbara Pardini, Italian Institute for Genomic Medicine (IIGM), Via Nizza 52, 10126 Turin, Italy, Tel.: +390116709542, Fax: +390112365601, E-mail: [email protected]Search for more papers by this authorElisa Paolicchi
Department of Biology, University of Pisa, Pisa, Italy
Search for more papers by this authorGiovanni Cugliari
Italian Institute for Genomic Medicine (IIGM), Turin, Italy
Department of Medical Sciences, University of Turin, Turin, Italy
Search for more papers by this authorSonja I. Berndt
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD
Search for more papers by this authorStephane Bezieau
Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU), Nantes, France
Search for more papers by this authorStephanie A. Bien
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
School of Public Health, University of Washington, Seattle, WA
Search for more papers by this authorHermann Brenner
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorBette J. Caan
Kaiser Permanente Medical Care Program of Northern California, Oakland, CA
Search for more papers by this authorPeter T. Campbell
Epidemiology Research Program, American Cancer Society, Atlanta, GA
Search for more papers by this authorGraham Casey
Public Health Sciences, University of Virginia, Charlottesville, VA
Search for more papers by this authorAndrew T. Chan
Division of Gastroenterology, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorJenny Chang-Claude
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorMichelle Cotterchio
Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada
Search for more papers by this authorManish Gala
Division of Gastroenterology, Massachusetts General Hospital, Boston, MA
Search for more papers by this authorSteven J. Gallinger
Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada
Search for more papers by this authorRobert W. Haile
Stanford University School of Medicine, Stanford, CA
Search for more papers by this authorTabitha A. Harrison
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorRichard B. Hayes
Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY
Search for more papers by this authorMichael Hoffmeister
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorJohn L. Hopper
Melbourne School of Population Health, The University of Melbourne, Melbourne, VIC, Australia
Search for more papers by this authorLi Hsu
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorJeroen Huyghe
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorMark A. Jenkins
Melbourne School of Population Health, The University of Melbourne, Melbourne, VIC, Australia
Search for more papers by this authorLoic Le Marchand
Epidemiology Program, Research Cancer Center of Hawaii, University of Hawaii, Honolulu, HI
Search for more papers by this authorYi Lin
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorNoralane M. Lindor
Department of Health Sciences Research, Mayo Clinic Arizona, Scottsdale, AZ
Search for more papers by this authorHongmei Nan
Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN
Search for more papers by this authorPolly A. Newcomb
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorShuji Ogino
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
Broad Institute of MIT and Harvard, Cambridge, MA
Search for more papers by this authorJohn D. Potter
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorRobert E. Schoen
Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA
Search for more papers by this authorMartha L. Slattery
Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT
Search for more papers by this authorEmily White
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Search for more papers by this authorLudmila Vodickova
Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Prague, Czech Republic
Search for more papers by this authorVeronika Vymetalkova
Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Prague, Czech Republic
Search for more papers by this authorPavel Vodicka
Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Prague, Czech Republic
Search for more papers by this authorFederica Gemignani
Department of Biology, University of Pisa, Pisa, Italy
Search for more papers by this authorUlrike Peters
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
B.P., A.C., U.P., A.N., and S.L. contributed equally to this workSearch for more papers by this authorAlessio Naccarati
Italian Institute for Genomic Medicine (IIGM), Turin, Italy
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Prague, Czech Republic
B.P., A.C., U.P., A.N., and S.L. contributed equally to this workSearch for more papers by this authorStefano Landi
Department of Biology, University of Pisa, Pisa, Italy
B.P., A.C., U.P., A.N., and S.L. contributed equally to this workSearch for more papers by this authorAbstract
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.
Abstract
What's new?
DNA repair defects allow mutations to pile up, which can lead to cancer. These authors searched for single nucleotide polymorphisms (SNPs) in DNA repair pathways associated with sporadic colorectal cancer. So far, genome-wide association studies (GWAS) have not detected many such SNPs, likely due to the small effect of each variant individually. Here, the authors combined data from two large colorectal cancer consortia, evaluating 15,419 SNPs in 185 DNA repair genes. They uncovered 2 SNPs in genes in the mismatch repair and homologous recombination pathways associated with increased colon cancer risk. Further investigation of these variants could lead to better personalized treatments.
Open Research
Data availability
All custom Infinium OncoArray-500K array and Illumina HumanOmniExpressExome-8v1–2 array data used in the study have been deposited at dbGaP under accession number phs001415.v1.p1 and phs001315.v1.p1, respectively. Genotype data for the studies have been deposited at dbGaP under accession number phs001078.v1.p1.
Supporting Information
| Filename | Description |
|---|---|
| ijc32516-sup-0001-TableS1.xlsxExcel 2007 spreadsheet , 3.6 MB | Table S1 List of the SNPs investigated and retrieved in GECCO |
| ijc32516-sup-0002-TableS2.xlsxExcel 2007 spreadsheet , 5.5 MB | Table S2 List of the SNPs investigated and retrieved in GECCO stratified for cancer site |
| ijc32516-sup-0001-supinfo.docxWord 2007 document , 76.2 KB | Appendix S1: Supporting information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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