Low Frequency of Cancer-Predisposition Gene Mutations in Liver Transplant Candidates with Hepatocellular Carcinoma

Simple Summary Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related deaths worldwide. HCC mostly results from liver cirrhosis and its genetic predisposition is believed to be rare. A liver transplantation is considered a curative therapy for HCC; however, de novo tumor development is a feared complication in immunosuppressed transplant recipients. Having analyzed the prevalence of pathogenic/likely pathogenic germline variants in cancer-predisposition genes in 334 HCC patients considered for liver transplantation, we found only 7/334 (2.1%) carriers of pathogenic variants in established cancer-predisposition genes (PMS2, 4xNBN, FH or RET). Interestingly, two MRN complex genes (NBN and RAD50) were significantly more frequent among patients over controls. Therefore, we conclude that the genetic predisposition to HCC is rare and HCC does not meet the criteria for routine germline genetic testing; however, germline testing could be considered in liver transplant recipients as the variant carriers may benefit from tailored follow-up or targeted therapy. Hepatocellular carcinoma (HCC) mainly stems from liver cirrhosis and its genetic predisposition is believed to be rare. However, two recent studies describe pathogenic/likely pathogenic germline variants (PV) in cancer-predisposition genes (CPG). As the risk of de novo tumors might be increased in PV carriers, especially in immunosuppressed patients after a liver transplantation, we analyzed the prevalence of germline CPG variants in HCC patients considered for liver transplantation. Using the panel NGS targeting 226 CPGs, we analyzed germline DNA from 334 Czech HCC patients and 1662 population-matched controls. We identified 48 PVs in 35 genes in 47/334 patients (14.1%). However, only 7/334 (2.1%) patients carried a PV in an established CPG (PMS2, 4xNBN, FH or RET). Only the PV carriers in two MRN complex genes (NBN and RAD50) were significantly more frequent among patients over controls. We found no differences in clinicopathological characteristics between carriers and non-carriers. Our study indicated that the genetic component of HCC is rare. The HCC diagnosis itself does not meet criteria for routine germline CPG genetic testing. However, a low proportion of PV carriers may benefit from a tailored follow-up or targeted therapy and germline testing could be considered in liver transplant recipients.

Automated summary

Hepatocellular carcinoma (HCC) mainly results from liver cirrhosis and its genetic predisposition is believed to be rare. In 334 HCC patients considered for liver transplantation, we found only 7 carriers of pathogenic variants in established cancer-predisposition genes. However, two MRN complex genes (NBN and RAD50) were significantly more frequent among patients. Therefore, HCC's genetic predisposition is rare, but germline testing could be considered in liver transplant recipients for tailored follow-up or targeted therapy.