Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 26, No 15S (May 20 Supplement), 2008: 11079
© 2008 American Society of Clinical Oncology

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Abstract

Effect of SNP haplotypes associated with colorectal cancer risk on outcome

London Research Intitute, Cancer Research UK, London, United Kingdom; Ludwig Institute for Cancer Research, Melbourne, Australia; University of Oxford, Oxford, United Kingdom; Aarhus University Hospital, Aarhus, Denmark; University of Helsinki, Helsinki, Finland

11079

Background: Familial colorectal cancer (CRC) is associated with an early age of onset, which in turn has anecdotally been associated with worse prognosis. We previously reported six SNPs (rs6983267 on 8q, rs4779584 and rs10318 on 15q, rs4939827, rs12953717 and rs4464148 on 18q) which increase the risk of CRC. In addition, we are currently evaluating a further six SNPs for their association with CRC risk. Here we present the impact of these susceptibility alleles on CRC prognosis. Methods: 931 patients enrolled in the Victor trial were typed on the Illumina Hap300 platform (rs6983267, rs4779584, rs10318, rs4939827, rs4464148) [Illumina Inc., San Diego] or using allele- specific PCR (rs12953717). All patients had stage 2 or 3 CRC treated with surgery and chemo- or radiotherapy as appropriate and randomised to rofecoxib or placebo. Survival analysis was performed using allelic odds ratios (OR), and hazard ratios (HR) from Cox-regression for time-to- event data based on a minimum of three years follow-up. Depending on the allele frequency, we had greater 90% power to detect a 1.2 to 1.6 - fold difference in survival associated with the high-risk genotype. SNPs which initially passed the significance threshold of p<0.05 will be evaluated further in additional samples sets (599 Danish non-trial patients, 1045 Finish non-trial patients). Results: After the first phase of testing, rs6983267 and a further unpublished SNP (rsX) was associated with prognosis at the 5% significance level. The HR for phase I for rs6983267 was 1.43 (95%CI 1.04–1.97, p=0.03) and for rsX 1.33 (95%CI 1.04–1.67, p=0.022). We will present data of the further genotyping in Phase 2, and the identity of rsX if found to be associated either with susceptibility or outcome. Conclusion: Germline predisposition to CRC may be associated with outcome. If proven to be true in phase 2, this will require validation in prospective clinical trials, but could represent a first step towards building a true and clinically useful molecular profile of CRC.

No significant financial relationships to disclose.

Abstract presentation from the 2008 ASCO Annual Meeting