The genetic susceptibility and prognostic role of TERT-CLPTM1L and genes in DNA damage pathways in NPC

Abstract

Introduction The genetic etiology of nasopharyngeal carcinoma (NPC) remains unclear. We hypothesized that heritable NPC risk was attributable to the cumulative effects of multiple common low-risk variants. A multigenic pathway-based approach was used to systematically score the cumulative effects with SNPs in genes in DNA repair pathways for NPC risk. Although the radiotherapy is very effective in curing NPC patients with early- stage tumors, local failure and distant metastasis remain major challenges for treatment and it is necessary to identify prognostic biomarkers that predict poor clinical outcomes of advanced-stage NPC patients. Aims We aimed to identify genetic susceptibility genes involved in NPC development and prognostic biomarkers for NPC patients. Methods A case-control association study was performed with Mass ARRAY genotyping of about 300 SNPs covering 161 genes/loci in 2,349 Hong Kong individuals including 1,177 NPC patients and 1,172 Red Cross individuals. Both single SNP and pathway based analysis were performed for NPC risk. Patients were also stratified according to their familial status for meaningful association analysis. For identification of the prognostic biomarkers of NPC, the clinical pathological information of 1,177 NPC was collected for univariate and multivariate statistical analysis for survival. Results and discussions Single SNP association identified three SNPs (rs401681, rs6774494, and rs3757318) corresponding to TERT/ CLPTM1L, MDS1-EVI1, and CCDC170 conferring modest protective effects individually for NPC risk by the logistic regression analysis. Stratification of NPC cases according to familial status identified rs2380165 in BLM with an association with family history-positive (FH+) NPC patients. Multiple SNP pathway-based analysis observed cumulative effects for increasing numbers of unfavorable genotypes in TERT- CLPTM1L and double-strand break repair (DSBR) conferred elevated risk in FH+ and sporadic NPC patients. Our preliminary data suggested a SNP in p53 with prognostic value for survival of NPC patients. The prognostic role of p53 in NPC should be further validated in a larger cohort.