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Cancer Epidemiol Biomarkers Prev. 2016 Jan;25(1):193-200. doi: 10.1158/1055-9965.EPI-15-0649. Epub 2015 Dec 4.

A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer.

Author information

1
Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina. Cancer Prevention, Detection, and Control Research Program, Duke Cancer Institute, Durham, North Carolina. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
2
Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina. Cancer Prevention, Detection, and Control Research Program, Duke Cancer Institute, Durham, North Carolina.
3
Department of Statistical Science, Duke University, Durham, North Carolina.
4
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
5
Geisel School of Medicine, Dartmouth College, Lebanon, North Hemisphere.
6
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts.
7
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.
8
Institute for Human Genetics, University of California, San Francisco, San Francisco, California. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
9
Department of Oncology, University of Cambridge, Cambridge, United Kingdom. Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
10
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California. Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
11
Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts.
12
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
13
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom. Royal Marsden NHS Foundation Trust, London and Sutton, United Kingdom.
14
Institute of Population Health, University of Manchester, Manchester, United Kingdom. Warwick Medical School, University of Warwick, Coventry, United Kingdom.
15
Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina. Cancer Prevention, Detection, and Control Research Program, Duke Cancer Institute, Durham, North Carolina. Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia. jms2yf@virginia.edu.

Abstract

BACKGROUND:

DNA damage is an established mediator of carcinogenesis, although genome-wide association studies (GWAS) have identified few significant loci. This cross-cancer site, pooled analysis was performed to increase the power to detect common variants of DNA repair genes associated with cancer susceptibility.

METHODS:

We conducted a cross-cancer analysis of 60,297 single nucleotide polymorphisms, at 229 DNA repair gene regions, using data from the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. Our analysis included data from 32 GWAS and 48,734 controls and 51,537 cases across five cancer sites (breast, colon, lung, ovary, and prostate). Because of the unavailability of individual data, data were analyzed at the aggregate level. Meta-analysis was performed using the Association analysis for SubSETs (ASSET) software. To test for genetic associations that might escape individual variant testing due to small effect sizes, pathway analysis of eight DNA repair pathways was performed using hierarchical modeling.

RESULTS:

We identified three susceptibility DNA repair genes, RAD51B (P < 5.09 × 10(-6)), MSH5 (P < 5.09 × 10(-6)), and BRCA2 (P = 5.70 × 10(-6)). Hierarchical modeling identified several pleiotropic associations with cancer risk in the base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination pathways.

CONCLUSIONS:

Only three susceptibility loci were identified, which had all been previously reported. In contrast, hierarchical modeling identified several pleiotropic cancer risk associations in key DNA repair pathways.

IMPACT:

Results suggest that many common variants in DNA repair genes are likely associated with cancer susceptibility through small effect sizes that do not meet stringent significance testing criteria.

PMID:
26637267
PMCID:
PMC4713268
DOI:
10.1158/1055-9965.EPI-15-0649
[Indexed for MEDLINE]
Free PMC Article

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