Multigene pathway-based analyses identify nasopharyngeal carcinoma risk associations for cumulative adverse effects of TERT-CLPTM1L and DNA double-strand breaks repair

Abstract

The genetic etiology of nasopharyngeal carcinoma (NPC) and mechanisms for inherited susceptibility remain unclear. To examine genetic risk factors for NPC, we hypothesized that heritable risk is attributable to cumulative effects of multiple common low-risk variants. With the premise that individual SNPs only confer subtle effects for cancer risk, a multigenic pathway-based approach was used to systematically examine associations between NPC genetic susceptibility with SNPs in genes in DNA repair pathways and from previously identified cancer genome-wide association study analyses. This case-control study covers 161 genes/loci and focuses on pathway-based analyses in 2,349 Hong Kong individuals, allowing stratification according to NPC familial status for meaningful association analysis. Three SNPs (rs401681, rs6774494 and rs3757318) corresponding to TERT/CLPTM1L (OR 95% CI = 0.77, 0.68-0.88), MDS1-EVI1 (OR 95% CI=0.79 0.69-0.89) and CCDC170 (OR 95% CI = 0.76, 0.66-0.86) conferred modest protective effects individually for NPC risk by the logistic regression analysis after multiple testing adjustment (pBonferroni < 0.05). Stratification of NPC according to familial status identified rs2380165 in BLM (OR 95% CI = 1.49, 1.20-1.86, pBonferroni < 0.05) association with family history-positive NPC (FH+ NPC) patients. Multiple SNPs pathway-based analysis revealed that the combined gene dosage 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 (ORs per allele, 95% CIs = 1.37, 1.22-1.55, pBonferroni = 5.00 × 10-6; 1.17, 1.09-1.26, pBonferroni = 4.58 × 10-4, respectively, in TERT/NHEJ pathways). Our data suggested cumulative increased NPC risk associations with TERT-CLPTM1L and DSBR pathways contribute to genetic susceptibility to NPC and have potential translational relevance for patient stratification and therapeutics. What's New? The etiology of nasopharyngeal carcinoma (NPC) is complex. In this study, the authors used a pathway-based approach to examine SNPs in DNA-repair and other cancer-linked genes in NPC. They found that particular SNPs in the TERT-CLPTM1L region and in double-strand break repair (DSBR) genes had a cumulative effect on the risk of developing NPC - in other words, the more harmful SNPs a patient inherits, the higher the risk that NPC will occur. These SNPs may thus provide useful risk and prognostic indicators for NPC, as well as biomarkers for therapeutics targeting DNA repair. © 2014 UICC.