TP53 germline and somatic mutations in a patient with fibrolamellar hepatocellular carcinoma

Abstract

Li-Fraumeni syndrome is a rare hereditary cancer predisposition syndrome associated with germline pathogenic variants in TP53 gene. The phenotype may vary from classical to variant forms, known as Li-Fraumeni-like phenotypes. We searched for pathogenic variants in TP53 in a 14 year-old female diagnosed with fibrolamellar hepatocellular carcinoma, a rare subtype of hepatocellular carcinoma. The proband is a heterozygote carrier of the TP53 c.467G>A (p.Arg156His) in exon 5, and her mother is an asymptomatic carrier. Analysis of tumor DNA disclosed an additional somatic mutation in TP53, c.461G>A; p.Gly154Asp. The TP53 germline and somatic pathogenic variants may have acted as possible driver mutations, resulting in genomic instability and tumor development. The fibrolamellar subtype of hepatocellular carcinoma may be part of the broad spectrum of tumors associated with Li-Fraumeni phenotype.

Diagnostic Algorithm of Hepatocellular Carcinoma: Classics and Innovations in Radiology and Pathology

“…Association with germline pathogenic variants of TP53 gene has been reported suggesting that some cases of fibrolamellar HCC might represent Li-Fraumeni syndrome. Interestingly, in the case described by Andrade et al, a germline mutation of TP53 was identified not only in proband affected by fibrolamellar HCC but also in her asymptomatic mother [54].…”

Hepatocellular Carcinoma: Past and Present Challenges and Progress in Molecular Classification and Precision Oncology

“…Such a model was supported by a whole exome sequencing study of 34 tumors from 6 multifocal HCC patients, which mapped commonly mutated genes onto phylogenetic trees [32]. While oncogene-sis is predominately through the accumulation of somatic mutations, conditions such as Li-Fraumeni syndrome, a germline TP53 mutation, can also predispose individuals to HCC development under rare circumstances [33,34]. In pathway (A), a morphologically normal liver is exposed chronically to pro-cirrhotic viruses or toxins.…”

Systems Challenges of Hepatic Carcinomas: A Review

“…In extension to mutations, TP53 expression is altered by various other factors such as chromosomal abnormalities and viral infections either directly or indirectly. 42 Structural changes in chromosomes resulting in loss or gain of alleles have been detected in few chromosomes in more than 30% of HCCs. While tumor suppressor genes like p53, Rb and other CDKN2A fall in these regularly deleted chromosomal regions 43-45 epigenetic silencing of cancer related genes by unusual DNA methylation pattern also have been reported in HCC while p16 and.…”