title: A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Scarbrough
authors.affiliation: 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.
authors.forename: Rachel Palmieri
authors.initials: RP
authors.lastname: Weber
authors.affiliation: Department of Statistical Science, Duke University, Durham, North Carolina.
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Iversen
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Yonathan
authors.initials: Y
authors.lastname: Brhane
authors.affiliation: Geisel School of Medicine, Dartmouth College, Lebanon, North Hemisphere.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Rayjean J
authors.initials: RJ
authors.lastname: Hung
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Sellers
authors.affiliation: 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.
authors.forename: John S
authors.initials: JS
authors.lastname: Witte
authors.affiliation: Department of Oncology, University of Cambridge, Cambridge, United Kingdom. Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Pharoah
authors.affiliation: 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.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.affiliation: 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.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.affiliation: Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.affiliation: Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.affiliation: Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Amit D
authors.initials: AD
authors.lastname: Joshi
authors.affiliation: 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.
authors.forename: Kevin
authors.initials: K
authors.lastname: McDonnell
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Doug F
authors.initials: DF
authors.lastname: Easton
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom. Royal Marsden NHS Foundation Trust, London and Sutton, United Kingdom.
authors.forename: Ros
authors.initials: R
authors.lastname: Eeles
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom. Royal Marsden NHS Foundation Trust, London and Sutton, United Kingdom.
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Kote-Jarai
authors.affiliation: Institute of Population Health, University of Manchester, Manchester, United Kingdom. Warwick Medical School, University of Warwick, Coventry, United Kingdom.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Muir
authors.affiliation: Geisel School of Medicine, Dartmouth College, Lebanon, North Hemisphere.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Doherty
authors.affiliation: 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.
authors.forename: Joellen M
authors.initials: JM
authors.lastname: Schildkraut
mesh_terms: D024682:BRCA2 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C118481:MSH5 protein, human; C413002:RAD51B protein, human