title: A Germline Variant on Chromosome 4q31.1 Associates with Susceptibility to Developing Colon Cancer Metastasis.
abstract: We tested for germline variants showing association to colon cancer metastasis using a genome-wide association study that compared Ashkenazi Jewish individuals with stage IV metastatic colon cancers versus those with stage I or II non-metastatic colon cancers. In a two-stage study design, we demonstrated significant association to developing metastatic disease for rs60745952, that in Ashkenazi discovery and validation cohorts, respectively, showed an odds ratio (OR) = 2.3 (P = 2.73E-06) and OR = 1.89 (P = 8.05E-04) (exceeding validation threshold of 0.0044). Significant association to metastatic colon cancer was further confirmed by a meta-analysis of rs60745952 in these datasets plus an additional Ashkenazi validation cohort (OR = 1.92; 95% CI: 1.28-2.87), and by a permutation test that demonstrated a significantly longer haplotype surrounding rs60745952 in the stage IV samples. rs60745952, located in an intergenic region on chromosome 4q31.1, and not previously associated with cancer, is, thus, a germline genetic marker for susceptibility to developing colon cancer metastases among Ashkenazi Jews.
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.|Department of Genetics, Case Western Reserve University, Cleveland, Ohio, United States of America.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Nora L
authors.initials: NL
authors.lastname: Nock
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.|USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Schmit
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Zsofia K
authors.initials: ZK
authors.lastname: Stadler
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Vijai
authors.initials: V
authors.lastname: Joseph
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Willis
authors.affiliation: Department of Genetics, Case Western Reserve University, Cleveland, Ohio, United States of America.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Scacheri
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Martina
authors.initials: M
authors.lastname: Veigl
authors.affiliation: Department of Genetics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Adams
authors.affiliation: Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Leon
authors.initials: L
authors.lastname: Raskin
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: John F
authors.initials: JF
authors.lastname: Sullivan
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Kelly
authors.initials: K
authors.lastname: Stratton
authors.affiliation: Department of Pathology, Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, 10065, United States of America.
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona, United States of America.
authors.forename: Nathan
authors.initials: N
authors.lastname: Ellis
authors.affiliation: Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel.|Clalit Health Services, National Cancer Control Center, Haifa, Israel.|Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Hedy S
authors.initials: HS
authors.lastname: Rennert
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Manschreck
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.|Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Elston
authors.affiliation: Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel.|Clalit Health Services, National Cancer Control Center, Haifa, Israel.|Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Gadi
authors.initials: G
authors.lastname: Rennert
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.|USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
mesh_terms: D000368:Aged; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D007585:Jews; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide