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p16INK4a polymorphism: Associations with tumour progression in patients with sporadic colorectal cancer

McCloud, Jonathan M.; Sivakumar, Rangasamy; Greenhough, Alex; Elder, Jackie; Jones, Peter W.; Deakin, Mark; Elder, James B.; Fryer, Anthony A.; Hoban, Paul R.

Authors

Jonathan M. McCloud

Rangasamy Sivakumar

Jackie Elder

Peter W. Jones

Mark Deakin

James B. Elder

Anthony A. Fryer

Paul R. Hoban



Abstract

Deregulated tumour expression of p16INK4a has previously been described in association with clinical progression in sporadic colorectal cancer patients (CRC). Furthermore, p16INK4a promoter hypermethylation leading to gene silencing has been shown to occur in advanced colorectal tumours and has been associated with patient survival. p16INK4a is polymorphic, with variant alleles being associated with tumour progression in melanoma. In this study we have examined p16INK4a polymorphism as a marker of tumour progression in sporadic CRC. Polymorphic sites G/A(442), C/G(500), and C/T(540), were studied, these alleles obeyed Hardy Weinberg equilibrium in a control group, but not in the CRC cases. G/A(442) and CG(500) alleles were in linkage disequilibrium in both cases and controls. In controls the C/T(540) alleles demonstrated no linkage with either other site, whilst an association was demonstrated between C/G(500) and C/T(540) alleles in the cases (p=0.011). Furthermore, the distribution of C/T(540) genotypes was different between the groups (p=0.002). Within the CRC cases, patients with the GG(442) genotype were more commonly associated with decreased tumour differentiation (p=0.018), advancing Dukes' stage (p=0.006) and T-stage (p=0.007) than patients with the GA(442) and AA(442) genotypes. Patients with the CC(500) genotype were more commonly associated with decreased tumour differentiation (p=0.012), advancing Dukes' stage (p=0.015), and N-stage (p=0.031). No associations between patient C/T(540) genotype and clinical prognostic parameters were found. An analysis of patient tumour expression with p16INK4a genotype revealed patients with the CC(500) genotype were more commonly associated with reduced tumour p16 expression (p=0.046). In summary our data indicate that p16INK4a polymorphism is associated with tumour progression in patients with sporadic CRC.

Journal Article Type Article
Acceptance Date Oct 1, 2004
Online Publication Date Nov 1, 2004
Publication Date Nov 1, 2004
Journal International Journal of Oncology
Print ISSN 1019-6439
Publisher Spandidos Publications
Peer Reviewed Peer Reviewed
Volume 25
Issue 5
Pages 1447-1452
DOI https://doi.org/10.3892/ijo.25.5.1447
Public URL https://uwe-repository.worktribe.com/output/1057004
Publisher URL https://doi.org/10.3892/ijo.25.5.1447