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, 4×NBN, 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.

Centre for Experimental Medicine Institute for Clinical and Experimental Medicine 14021 Prague Czech Republic

Department of Biochemistry Faculty of Natural Science Charles University 12800 Prague Czech Republic

Department of Hepatogastroenterology Institute for Clinical and Experimental Medicine 14021 Prague Czech Republic

Department of Internal Medicine 1st Faculty of Medicine Charles University and Military University Hospital 16902 Prague Czech Republic

Department of Oncology 1st Faculty of Medicine Charles University and General University Hospital Prague 12808 Prague Czech Republic

Department of Paediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague 12808 Prague Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University and General University Hospital Prague 12800 Prague Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague 12808 Prague Czech Republic

Institute of Pathological Physiology 1st Faculty of Medicine Charles University and General University Hospital Prague 12853 Prague Czech Republic

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A retrospective single-center pilot study of the genetic background of the transplanted kidney

A comprehensive analysis of germline predisposition to early-onset ovarian cancer

Importance of Germline and Somatic Alterations in Human MRE11, RAD50, and NBN Genes Coding for MRN Complex