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

摘要: The genetic etiology of nasopharyngeal carcinoma (NPC) and mechanisms for inherited susceptibility remain unclear. To examine risk factors NPC, we hypothesized that heritable is attributable to cumulative effects multiple common low-risk variants. With the premise individual SNPs only confer subtle cancer risk, a multigenic pathway-based approach was used systematically associations between NPC with in genes DNA repair pathways from previously identified genome-wide association study analyses. This case–control covers 161 genes/loci focuses on analyses 2,349 Hong Kong individuals, allowing stratification according familial status meaningful analysis. Three (rs401681, rs6774494 rs3757318) corresponding TERT/CLPTM1L (OR 95% CI = 0.77, 0.68–0.88), MDS1-EVI1 CI=0.79 0.69–0.89) CCDC170 CI = 0.76, 0.66–0.86) conferred modest protective individually by logistic regression analysis after testing adjustment (pBonferroni < 0.05). Stratification rs2380165 BLM CI = 1.49, 1.20–1.86, pBonferroni < 0.05) family history-positive (FH+ NPC) patients. Multiple revealed combined gene dosage increasing numbers unfavorable genotypes TERT-CLPTM1L double-strand break (DSBR) elevated FH+ sporadic patients (ORs per allele, CIs = 1.37, 1.22–1.55, pBonferroni = 5.00 × 10−6; 1.17, 1.09–1.26, pBonferroni = 4.58 10−4, respectively, TERT/NHEJ pathways). Our data suggested increased DSBR contribute have potential translational relevance patient therapeutics.