Identification of genetic factors for nasopharyngeal carcinoma and esophagus squamous cell carcinoma by large-scale targeted region sequencing

Abstract

The genetic susceptibilities of nasopharyngeal carcinoma (NPC) and esophagus squamous carcinomas (ESCC) have been studied in Hong Kong and Henan populations, respectively, using targeted region sequencing. In NPC, we targeted sequencing the whole major histocompatibility complex (MHC) region in NPC cases and controls from Hong Kong. After variants calling on these samples, the association analysis identified several new genetic factors that modify NPC risk. At the human leukocyte antigen (HLA) allele level, we have confirmed the association of HLA-A*02:07, HLA-A*11:01, HLA-B*46:01, HLA-C*01:02 and NPC risk in the Hong Kong population. In addition, several new rare HLA alleles: HLA-B*51:02, HLA-B*07:05, HLA-B*39:01, HLA-C*15:05, HLA-B*27:04 with protective effect for NPC were identified in this study. At the variant level, we profiled all SNPs in the MHC region; then the logistic regression association test, adjusted for sex and age, was performed on these SNPs. In addition, the conditional analysis on the significant SNPs identified 6 independent signals. More than 2000 SNPs were identified to be significantly associated with NPC risk at a genome-wide significance. Other than the two well-known signals located in HLA-A and HLA-B/C loci, two new loci located in genes ATAT1 and PRRT1 regions are now reported. In ESCC, by utilizing whole-exome sequencing (WES) in a cohort of 192 familial ESCC family history-positive (FH+) cases as the discovery phase, BRCA2 was identified as one of the top candidate cancer predisposition genes (CPGs). The Fanconi anemia pathway was found to be significantly enriched in the genes with rare loss-of-function (LoF) variants in the discovery phase. Subsequently, we further validated the importance of BRCA2 and other genes in DNA damage repair pathways in an independent larger cohort of 2500 individuals from the Henan high-risk area consisting of ESCC cases and healthy controls. The contribution of rare deleterious variants in BRCA2 and PALB2 were further validated with a second cohort of ESCC cases and controls from Hong Kong, which is a moderate risk region. In summary, using targeted sequencing, the base-resolution fine-mapping for the genomic regions of interest, new genetic factors were identified that contribute to genetic susceptibility for NPC and ESCC.