GALNT14 SNP as a potential predictor of response to combination chemotherapy using 5-FU, mitoxantrone and cisplatin in advanced HCC

Abstract

Aim: Despite the availability of targeted anticancer agents, combination chemotherapy remains an option for patients with far advanced hepatocellular carcinoma. We aimed to identify germline SNP markers in order to predict the objective response of combination chemotherapy using 5-fluorouracil, mitoxantrone and cisplatin (FMP). Materials & methods: This study was conducted in two steps. First, a genome-wide retrospective screen was performed in a cohort of 16 patients. A candidate SNP marker was identified as being associated with the objective responses to the first course of FMP. Second, a validation of this candidate SNP was performed prospectively in an independent cohort of 41 patients. The survival curves were also compared in patient subgroups stratified by the SNP marker. Results: The genome-wide screening revealed several candidate markers, including seven adjacent SNPs residing in a 5-kb linkage disequilibrium block and in an intronic region of GALNT14 on chromosome 2. Among them, the SNP rs9679162 manifested the strongest association when genotypic tests and kernel-based association tests were performed. Significant association was found again between rs9679162 and the therapeutic responses in the validation cohort (p = 0.006326). A follow-up survival analysis demonstrated that patients with a homozygous rs9679162 genotype had better progression-free survival in both the retrospective and prospective cohorts (p = 0.00041 and 0.01485, respectively) than the other genotypes did. However, the overall survival curve is only different in the retrospective cohort (p = 0.00622) and not in the prospective cohort. Conclusion: The rs9679162 GALNT14 genotype is potentially associated with the objective response of the first course of FMP chemotherapy in patients with far advanced hepatocellular carcinoma. Original submitted 26 January 2011; Revision submitted 3 March 2011