title: Functional and clinical significance of variants localized to 8q24 in colon cancer.
abstract: Multiple genome-wide association studies have identified several susceptibility variants for colon cancer at 8q24. However, the functional roles of these variants have yet to be elucidated. Here, we evaluated the potential role of these markers in tumor progression and examined association with commonly observed structural abnormalities in this region, c-MYC amplification and chromosome fragility at FRA8C and FRA8D. We first replicated the previously reported association by testing 1,178 cases and 1,009 clinic-based controls with eight markers localized to three specific regions at 8q24. We observed significant associations with colon cancer risk with markers rs13254738 (ordinal odds ratio, 0.82; 95% confidence interval, 0.072-0.94; P(trend) = 0.0037) and rs6983267 (ordinal odds ratio, 1.17; 95% confidence interval, 1.03-1.32, P(trend) = 0.013). Survival analysis was done using a separate set of 460 cases to evaluate the clinical significance of these markers. Overall, univariate analysis did not detect survival differences for any of the markers. We also tested a subset of the 460 cases (n = 380) for structural abnormalities at or near the c-MYC locus using fluorescence in situ hybridization analysis. Furthermore, we evaluated a small number of cases homozygous for the rs6983267 alleles to test for differences in fragile site induction. None of the 8q markers correlated with amplification at the c-MYC locus as detected by fluorescence in situ hybridization, and no clear pattern of breakage was observed at the FRA8C and FRA8D sites. In this study, we confirm the association for several single nucleotide polymorphisms at 8q24 in colon cancer but have not detected any structural role relating to c-MYC amplification or chromosomal fragility. Finally, these risk alleles do not seem to be associated with survival.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street Southwest, 920 Hilton Building, Rochester, MN 55905, USA.
authors.forename: Mine S
authors.initials: MS
authors.lastname: Cicek
authors.forename: Susan L
authors.initials: SL
authors.lastname: Slager
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Achenbach
authors.forename: Amy J
authors.initials: AJ
authors.lastname: French
authors.forename: Hilary E
authors.initials: HE
authors.lastname: Blair
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Fink
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Foster
authors.forename: Brian F
authors.initials: BF
authors.lastname: Kabat
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Halling
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Boardman
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.forename: Steven R
authors.initials: SR
authors.lastname: Alberts
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Limburg
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002898:Chromosomes, Human, Pair 8; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D053843:DNA Mismatch Repair; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D015996:Survival Rate; D055815:Young Adult
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