title: Pleiotropy of cancer susceptibility variants on the risk of non-Hodgkin lymphoma: the PAGE consortium.
abstract: BACKGROUND
  Risk of non-Hodgkin lymphoma (NHL) is higher among individuals with a family history or a prior diagnosis of other cancers. Genome-wide association studies (GWAS) have suggested that some genetic susceptibility variants are associated with multiple complex traits (pleiotropy).
  
  
  OBJECTIVE
  We investigated whether common risk variants identified in cancer GWAS may also increase the risk of developing NHL as the first primary cancer.
  
  
  METHODS
  As part of the Population Architecture using Genomics and Epidemiology (PAGE) consortium, 113 cancer risk variants were analyzed in 1,441 NHL cases and 24,183 controls from three studies (BioVU, Multiethnic Cohort Study, Women's Health Initiative) for their association with the risk of overall NHL and common subtypes [diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL)] using an additive genetic model adjusted for age, sex and ethnicity. Study-specific results for each variant were meta-analyzed across studies.
  
  
  RESULTS
  The analysis of NHL subtype-specific GWAS SNPs and overall NHL suggested a shared genetic susceptibility between FL and DLBCL, particularly involving variants in the major histocompatibility complex region (rs6457327 in 6p21.33: FL OR=1.29, p=0.013; DLBCL OR=1.23, p=0.013; NHL OR=1.22, p=5.9 × E-05). In the pleiotropy analysis, six risk variants for other cancers were associated with NHL risk, including variants for lung (rs401681 in TERT: OR per C allele=0.89, p=3.7 × E-03; rs4975616 in TERT: OR per A allele=0.90, p=0.01; rs3131379 in MSH5: OR per T allele=1.16, p=0.03), prostate (rs7679673 in TET2: OR per C allele=0.89, p=5.7 × E-03; rs10993994 in MSMB: OR per T allele=1.09, p=0.04), and breast (rs3817198 in LSP1: OR per C allele=1.12, p=0.01) cancers, but none of these associations remained significant after multiple test correction.
  
  
  CONCLUSIONS
  This study does not support strong pleiotropic effects of non-NHL cancer risk variants in NHL etiology; however, larger studies are warranted.
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America.
authors.forename: Unhee
authors.initials: U
authors.lastname: Lim
authors.affiliation: Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kocarnik
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: William S
authors.initials: WS
authors.lastname: Bush
authors.affiliation: Department of Genetics, Rutgers University, Piscataway, New Jersey, United States of America.
authors.forename: Tara C
authors.initials: TC
authors.lastname: Matise
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America.
authors.forename: Christian
authors.initials: C
authors.lastname: Caberto
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Sungshim Lani
authors.initials: SL
authors.lastname: Park
authors.affiliation: Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Carlson
authors.affiliation: Department of Genetics, Rutgers University, Piscataway, New Jersey, United States of America.
authors.forename: Ewa
authors.initials: E
authors.lastname: Deelman
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Duggan
authors.affiliation: Center for Child Health, Behavior and Development, Seattle Children's Research Institute, Seattle, Washington, United States of America.
authors.forename: Megan
authors.initials: M
authors.lastname: Fesinmeyer
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.affiliation: Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Lucia A
authors.initials: LA
authors.lastname: Hindorff
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America.
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.affiliation: Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America.
authors.forename: Maarit
authors.initials: M
authors.lastname: Tiirikainen
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America.
authors.forename: Lynne R
authors.initials: LR
authors.lastname: Wilkens
authors.affiliation: Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Chunyuan
authors.initials: C
authors.lastname: Wu
authors.affiliation: Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Charles
authors.initials: C
authors.lastname: Kooperberg
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America.
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
mesh_terms: D016022:Case-Control Studies; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012306:Risk