BRCA2 loss‐of‐function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese

Abstract

Esophageal squamous cell carcinoma (ESCC) occurs with highest frequency in China with over 90% mortality, highlighting the need for early detection and improved treatment strategies. We aimed to identify ESCC cancer predisposition gene(s). Our study included 4,517 individuals. The discovery phase using whole‐exome sequencing (WES) included 186 familial ESCC patients from high‐risk China. Targeted gene sequencing validation of 598 genes included 3,289 Henan and 1,228 moderate‐risk Hong Kong Chinese. A WES approach identified BRCA2 loss‐of‐function (LOF) mutations in 3.23% (6/186) familial ESCC patients compared to 0.21% (9/4300) in the ExAC East Asians (odds ratio [OR] = 15.89, p = 2.48 × 10−10). BRCA2 LOF mutation frequency in the combined Henan cohort has significantly higher prevalence (OR = 10.55, p = 0.0035). Results were independently validated in an ESCC Hong Kong cohort (OR = 10.64, p = 0.022). One Hong Kong pedigree was identified to carry a BRCA2 LOF mutation. BRCA2 inactivation in ESCC was via germline LOF mutations and wild‐type somatic allelic loss via loss of heterozygosity. Gene‐based association analysis, including LOF mutations and rare deleterious missense variants defined with combined annotation dependent depletion score ≥30, confirmed the genetic predisposition role of BRCA2 (OR = 9.50, p = 3.44 × 10−5), and provided new evidence for potential association of ESCC risk with DNA repair genes (POLQ and MSH2), inflammation (TTC39B) and angiogenesis (KDR). Our findings are the first to provide compelling evidence of the role of BRCA2 in ESCC genetic susceptibility in Chinese, suggesting defective homologous recombination is an underlying cause in ESCC pathogenesis, which is amenable to therapeutic options based on synthetic lethality approaches such as targeting BRCA2 with PARP1 inhibitors in ESCC.

Nasopharyngeal carcinoma MHC region deep sequencing identifies HLA and novel non-HLA TRIM31 and TRIM39 loci

“…The libraries for MHC-target sequencing were prepared and sequenced in the Illumina HiSeq platform according to manufacturer instructions 5 . Briefly, the pre-capture sequencing libraries were prepared with 100-200 ng genomic DNA after fragmentation to 300-400 bp by Covaris according to the KAPA HyperPrep Kits 58 and hybridized to the SeqCap EZ Choice Enrichment Kit (Roche). Each capture included 24 indexed libraries of blood DNAs.…”

Circular RNA hsa_circ_0000654 promotes esophageal squamous cell carcinoma progression by regulating the miR‐149‐5p/IL‐6/STAT3 pathway

“…Esophageal cancer is the eighth most‐common cancer in the world and the sixth leading cause of cancer death . Esophageal squamous cell carcinoma (ESCC) is the major histological subtype, especially in certain countries, such as China .…”

“…Esophageal cancer is the eighth most-common cancer in the world and the sixth leading cause of cancer death. 1,2 Esophageal squamous cell carcinoma (ESCC) is the major histological subtype, especially in certain countries, such as China. 3 Despite the rapid development of medical technology and continuous improvements in early diagnostic techniques, advanced ESCC cases still account for~50% of cases and exhibit a 5-year survival rate of only 15-25%.…”

A novel seven-gene signature as Prognostic Biomarker in Hepatocellular Carcinoma

“…Our study initially confirmed the negative effect of CBFA2T2, PAQR4 or C21orf58 on HCC prognosis for the first time. Conversely, tetratricopeptide repeat (TPR) domain protein 39B (TTC39B, C9orf52) (T39), a high density lipoprotein (HDL) gene discovered in human genome wide association studies (GWAS) [44,45], is associated with atherosclerosis and steatohepatitis as well as inflammation [46]. HSPB3 is an unfavorable molecular biomarker in colorectal adenocarcinoma [47].…”