4051 Background: Recent genome-wide association studies had identified colorectal cancer susceptibility loci on chromosomes 8q24 (rs6983267), 15q13(rs4779584), 18q21(rs4939827, rs12953717 and rs4464148), 10p14(rs10795668) and 8q23.3(rs16892766). Although the function role of these germline variants are unclear, given the importance of these variants and colorectal cancer risk, we have carried out the first pilot study to explore the association of these variants and clinical outcome. We used pooled data from two CRC-cohorts (locally advanced and metastatic CRC), and investigated the hypothesis that these germline variants may be associated with clinical outcome in adjuvant and metastatic colorectal cancer patients. Methods: Whole blood was collected from 515 patients with locally advanced (n=197) and metastatic CRC (n=318). After extraction of genomic-DNA, germline variants were genotyped as previously described (Haiman et al, Nat Genet, 2007). The genotype success rate was 98%. Blinded repeat samples (5%) were included for quality control purposes; genotype concordance was ≥ 99%. Results: Our results suggest that rs10795668 at 10p14 and rs719725 are significantly associated with time to tumor recurrence in adjuvant colorectal cancer patients, patients with rs10795668 AA genotype had significantly increased risk of time to tumor recurrence compared with those harboring G allele (TG+GG) patients(p=0.05, log-rank test). In metastatic cancer patients, we found rs4939827 at 18q21.1 were significantly associated with overall survival in female patients and rs10795668 at 10p14 were significantly associated with OS in male patients, respectively (p<0.05). Conclusions: Our preliminary results suggest cancer risk alleles may also associated with clinical outcome in adjuvant and metastatic colorectal cancer. Moreover, this correlation is sex-specific in metastatic colorectal cancer. Further comprehensive trials warranted to confirm our pilot findings. [Table: see text]
Molecular and clinical characteristics of MSH6 germline variants detected in colorectal cancer patients
