title: An association between the PTGS2 rs5275 polymorphism and colorectal cancer risk in families with inherited non-syndromic predisposition.
abstract: Recently our group completed a genome-wide linkage study investigating Australian and Spanish families with inherited risk of colorectal cancer (CRC). A minor linkage peak from that study located on chromosome 1 correlates with the location of a known CRC risk-modifying gene, prostaglandin synthase (PTGS2). PTGS2 encodes the inducible prostaglandin synthase enzyme cyclooxygenase-2 (COX-2). Prostaglandins are implicated in the initiation of carcinogenesis and progression of tumours. Sequencing of PTGS2 in a small subset of affected individuals identified a high frequency of the minor C allele of single nucleotide polymorphism rs5275. We then genotyped the rs5275 polymorphism in 183 affected and 223 unaffected individuals from our CRC predisposed families. Tests for association in the presence of linkage were made using family-based association tests. The C allele was found to be significantly associated (P<0.01) with diagnosis of hereditary non-syndromic CRC (P=0.0094, dominant model) and an earlier age of diagnosis (P=0.0089, heterozygous-advantage model). Interestingly, by stratifying the age of diagnosis data, we observed a speculative gender-discordant effect. Relative to other groups, female CC carriers were diagnosed less when young, but by 60 years of age were the most at risk group. Conversely, CT carriers of both genders showed a consistently earlier diagnosis relative to TT carriers. Our results suggest potential differential age-and gender-dependent efficacies of chemopreventative COX-2 inhibitors in the context of non-syndromic colorectal cancer.
authors.affiliation: 1] CSIRO, Preventative Health National Research Flagship, North Ryde, NSW, Australia [2] Animal, Food and Health Sciences, CSIRO, North Ryde, NSW, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Ross
authors.forename: Linda
authors.initials: L
authors.lastname: Lockett
authors.forename: Diana
authors.initials: D
authors.lastname: Brookes
authors.forename: Bruce
authors.initials: B
authors.lastname: Tabor
authors.forename: Konsta
authors.initials: K
authors.lastname: Duesing
authors.forename: Michael
authors.initials: M
authors.lastname: Buckley
authors.forename: Trevor
authors.initials: T
authors.lastname: Lockett
authors.forename: Peter
authors.initials: P
authors.lastname: Molloy
authors.forename: Finlay
authors.initials: F
authors.lastname: Macrae
authors.forename: Graeme
authors.initials: G
authors.lastname: Young
authors.forename: Ignacio
authors.initials: I
authors.lastname: Blanco
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capella
authors.forename: Garry N
authors.initials: GN
authors.lastname: Hannan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015179:Colorectal Neoplasms / Q000235:genetics*; D051546:Cyclooxygenase 2 / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D012306:Risk; D055815:Young Adult
chemical_list: D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human