title: Association of cancer susceptibility variants with risk of multiple primary cancers: The population architecture using genomics and epidemiology study.
abstract: BACKGROUND
  Multiple primary cancers account for approximately 16% of all incident cancers in the United States. Although genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC).
  
  
  METHODS
  As part of the National Human Genome Research Institute (NHGRI) Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort (MEC) and Women's Health Initiative (WHI). Incident MPC (IMPC) cases (n = 1,385) were defined as participants diagnosed with more than one incident cancer after cohort entry. Participants diagnosed with only one incident cancer after cohort entry with follow-up equal to or longer than IMPC cases served as controls (single-index cancer controls; n = 9,626). Fixed-effects meta-analyses of unconditional logistic regression analyses were used to evaluate the associations between 188 cancer risk variants and IMPC risk. To account for multiple comparisons, we used the false-positive report probability (FPRP) to determine statistical significance.
  
  
  RESULTS
  A nicotine dependence-associated and lung cancer variant, CHRNA3 rs578776 [OR, 1.16; 95% confidence interval (CI), 1.05-1.26; P = 0.004], and two breast cancer variants, EMBP1 rs11249433 and TOX3 rs3803662 (OR, 1.16; 95% CI, 1.04-1.28; P = 0.005 and OR, 1.13; 95% CI, 1.03-1.23; P = 0.006), were significantly associated with risk of IMPC. The associations for rs578776 and rs11249433 remained (P < 0.05) after removing subjects who had lung or breast cancers, respectively (P ≤ 0.046). These associations did not show significant heterogeneity by smoking status (Pheterogeneity ≥ 0.53).
  
  
  CONCLUSIONS
  Our study has identified rs578776 and rs11249433 as risk variants for IMPC.
  
  
  CONCLUSIONS
  These findings may help to identify genetic regions associated with IMPC risk.
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California. sungship@usc.edu.
authors.forename: S Lani
authors.initials: SL
authors.lastname: Park
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Caberto
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Yi
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authors.lastname: Lin
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Goodloe
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Logan
authors.initials: L
authors.lastname: Dumitrescu
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Shelly-Ann
authors.initials: SA
authors.lastname: Love
authors.affiliation: Department of Statistics and Biostatistics, Rutgers University, Piscataway, New Jersey.
authors.forename: Tara C
authors.initials: TC
authors.lastname: Matise
authors.affiliation: Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Lucia A
authors.initials: LA
authors.lastname: Hindorff
authors.affiliation: Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jay H
authors.initials: JH
authors.lastname: Fowke
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Fredrick R
authors.initials: FR
authors.lastname: Schumacher
authors.affiliation: School of Medicine, Wayne State University, Detroit, Michigan. Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Beebe-Dimmer
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Chu
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Preventative Medicine, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Lifang
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authors.lastname: Hou
authors.affiliation: Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Fridtjof
authors.initials: F
authors.lastname: Thomas
authors.affiliation: USC Information Sciences Institute, University of Southern California, Marina del Rey, California.
authors.forename: Ewa
authors.initials: E
authors.lastname: Deelman
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina. Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, California.
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Gerardo
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authors.lastname: Heiss
authors.affiliation: Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
authors.forename: Lynne R
authors.initials: LR
authors.lastname: Wilkens
authors.affiliation: Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio.
authors.forename: William S
authors.initials: WS
authors.lastname: Bush
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Charles
authors.initials: C
authors.lastname: Kooperberg
authors.affiliation: Cancer Prevention Institute of California, Fremont, California.
authors.forename: Iona
authors.initials: I
authors.lastname: Cheng
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
authors.forename: Loïc
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mesh_terms: D000368:Aged; D004198:Disease Susceptibility; D016021:Epidemiologic Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics; D005838:Genotype; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000209:etiology*; D020641:Polymorphism, Single Nucleotide