Germline Genetic Associations for Hepatobiliary Cancers

Abstract

Hepatobiliary cancers (HBCs) include hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma, which originate from the liver, bile ducts, and gallbladder, respectively. They are responsible for a substantial burden of cancer-related deaths worldwide. Despite knowledge of risk factors and advancements in therapeutics and surgical interventions, the prognosis for most patients with HBC remains bleak. There is evidence from familial aggregation and case-control studies to suggest a familial risk component in HBC susceptibility. Recent progress in genomics research has led to the identification of germline variants including single nucleotide polymorphisms (SNPs) and pathogenic or likely pathogenic (P/LP) variants in cancer-associated genes associated with HBC risk. These findings emerged from genome-wide association studies and next-generation sequencing techniques such as whole-exome sequencing. Patients with other cancer types, including breast, colon, ovarian, prostate, and pancreatic cancer, are recommended by guidelines to undergo germline genetic testing, but similar recommendations are lagging in HBC. This prompts the question of whether multi-gene panel testing should be integrated into clinical guidelines for HBC management. Here, we review the hereditary genetics of HBC, explore studies investigating SNPs and P/LP variants in HBC patients, discuss the clinical implications and potential for personalized treatments and impact on patient's family members, and conclude that additional studies are needed to examine how genetic testing can be applied clinically.

Keywords: BRCA2; Cholangiocarcinoma; Genetic Testing; Hepatocellular Carcinoma; Personalized Medicine.

Figure 1

Prevalence of pathogenic and likely pathogenic germline variants across rare variant studies in HBCs. This chart summarizes the yield of genetic testing across studies that have included patients with (A) HCC (B) CCA, IHC, and EHC and (C) GBC and BTC. Biliary tract cancer studies group CCA and GBC patients into one cancer population. Lynch syndrome genes included MLH1, MSH2, MSH6, PMS2, or EPCAM. Other polyposis genes include BMPR1A, RPS20, SMAD4, or STK11. FANC family genes include FAN1, FANCA, FANCC, FANCD2, FANCG, FANCI, FANCL, or FANCM. Other groups included individuals who had ATR, ATRIP, AXIN1, BAP1, BARD1, BLM, BUB1B, BUB3, CDC73, DMBT1, EGFR, ERCC2, ERCC5, ERCC6, ECO1, FAM175A, FH c.1431_1433dup, GALNT12, HOXB13, LIG3, MCPH1, MDC1, MLH3, MITF, MRE11A, MMP8 MSH3 (monoallelic), NF1, NHEJ1, NTHL1, PIK3CG, PMS1, POT1, PRSS1, and POLQ. ^P Indicates studies that use a prospective cohort of patients. ^R Indicates studies that use a retrospective cohort of patients.