Case-control association studies of DNA damage repair genes associated with genetic susceptibility of nasopharyngeal carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) has a distinctive racial and geographical distribution and is especially prevalent in Southern Chinese. Its genetic etiology and the mechanisms responsible for inherited genetic susceptibility are complex and unclear. We hypothesized that heritable risk for NPC is attributable to cumulative effects of multiple common low-risk variants, especially those of the DNA damage repair (DDR) genes. To score the harmful effects of multiple common variants together conferring 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 other cancer-linked loci. This case - control association study covers 161 genes/loci with a focus on DDR pathway-based analyses in 2,349 Hong Kong individuals. Three SNPs (rs401681, rs6774494, rs3757318) corresponding to TERT/CLPTM1L, MDS1-EVI1, and CCDC170 conferred modest protective effects individually for NPC risk by the logistic regression analysis after multiple testing adjustment. Stratification of NPC according to familial status identified rs2380165 in BLM association with family history-positive (FH+) NPC patients. FH+ NPC patients carrying higher numbers of unfavorable genotypes in different DDR pathways, including homologous recombination (HR), Fanconi Anemia (FA)-HR, FA-BLM, non-homologous end-joining (NHEJ), double-strand break repair (DSBR) - (HR+NHEJ), exhibited elevated NPC risk, while similar pathway-based analysis was not observed in sporadic NPC patients. The combined effects of TERT-CLPTM1L and DSB repairs for NPC risk were examined, since shortened telomeres are recognized as DSBs and DNA repair and recombination machineries are crucial for maintaining normal telomere function. Both FH+ and sporadic patients exhibited progressively significantly elevated NPC risk; a similar but less pronounced risk elevation was observed in sporadic NPC patients with regards to the cumulative effects in the DSBR pathways and TERT-CLPTM1L. The data suggested increasing NPC risk associated with TERT-CLPTM1L and DSBR signaling pathways correlate with NPC genetic susceptibility. This suggested a potential translational relevance for patient stratification and therapeutics.