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

Abstract

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.

Germline Genetic Associations for Hepatobiliary Cancers

“…A study in the Czech Republic consisted of 334 patients with HCC and 1662 controls from the general population who had their DNA sequenced with an in-house panel 226 cancer-related genes. 104 Within the patient cohort, a total of 47 patients carried P/LP variants representing a prevalence of 14.1%. However, a noteworthy finding was that only 7 of the 334 patients (2.1%) harbored a P/LP variant in established cancer-associated genes, specifically PMS2 , NBN , FH , or RET .…”

Population‐specific validation and comparison of the performance of 77‐ and 313‐variant polygenic risk scores for breast cancer risk prediction

“…The NGS libraries were prepared with KAPA HyperPlus/EvoPlus Library Preparation Kits (Roche) according to the manufacturer with minor modifications described previously. 19,21,36 The target regions were captured with pooled CZECANCA and PRSMAN panels in a 2:1 ratio. Sequencing was performed with NextSeq 500 instruments (Illumina, San Diego, California).…”

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

“…A recent meta-analysis of studies in prostate cancer patients confirmed an association between the NBN germline alterations and increased prostate cancer risk (with OR = 6.4 and OR = 7.5 for the total and Caucasian populations, respectively) [ 93 ]. Episodic reports have associated germline NBN variants with the risk of cervical [ 94 ] and hepatocellular carcinoma [ 95 ], medulloblastoma [ 96 ], or hematopoietic malignancies [ 94 , 97 ]. Interestingly, recent analysis of 34,046 US patients by Belhadj et al confirmed the lack of association with BC, but suggests a potential role of NBN germline pathogenic variants in the development of other cancer types [ 98 ].…”

“…Even more than for NBN , the clinical significance of heterozygous germline alterations in the MRE11 and RAD50 genes remains elusive. Analyses of the RAD50 gene have shown that its germline variants are associated with colorectal [ 99 ], pancreatic [ 100 ], hepatocellular [ 95 ] or breast cancer risk [ 101 , 102 , 103 ]. The recurrent, loss-of-function, germline, Finnish founder variant c.687delT (p.Leu229Ter) has been associated with increased breast cancer risk (OR = 4.3; 95% CI 1.5–12.5) in the Finnish population [ 101 ].…”