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Distinction of intrahepatic metastasis from multicentric carcinogenesis in multifocal hepatocellular carcinoma using molecular alterations.

ABSTRACT: Patients with hepatocellular carcinoma (HCC) frequently have multiple anatomically distinct tumors. In these patients, multifocal HCC could represent intrahepatic metastases (IMs) of a single cancer or multicentric carcinogenesis (MC) with multiple independent neoplasms. To determine the frequency and clinical implications of these 2 possibilities, we performed histological and molecular analysis of 70 anatomically distinct HCCs from 24 patients. We assayed mutations in the TERT promoter region by Sanger sequencing and used next-generation sequencing to analyze the entire coding regions of 7 well-characterized HCC driver genes-based on shared or discordant mutations in these genes, we classified the HCCs in each patient as IM, MC, or indeterminate. Mutations in the TERT promoter were the most common alteration in our cohort, present in 71% of tumors analyzed. Mutations in the remaining genes occurred in less than 20% of analyzed tumors. We were able to determine the relatedness in 58% of the patients analyzed: MC occurred in 41% of patients, with 33% with exclusively MC and 8% with both MC and IM. IM occurred exclusively in 17% of patients, whereas the remainder were indeterminate. This study highlights the utility of molecular analyses to determine relatedness in multifocal HCC; however, targeted sequencing can only resolve this distinction in approximately 60% of patients with multifocal HCC.

SUBMITTER: Chianchiano P

PROVIDER: S-EPMC6435273 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Distinction of intrahepatic metastasis from multicentric carcinogenesis in multifocal hepatocellular carcinoma using molecular alterations.

Chianchiano Peter P Pezhouh Maryam Kherad MK Kim Amy A Luchini Claudio C Cameron Andrew A Weiss Matthew J MJ He Jin J Voltaggio Lysandra L Oshima Kiyoko K Anders Robert A RA Wood Laura D LD

Human pathology 20171124

Patients with hepatocellular carcinoma (HCC) frequently have multiple anatomically distinct tumors. In these patients, multifocal HCC could represent intrahepatic metastases (IMs) of a single cancer or multicentric carcinogenesis (MC) with multiple independent neoplasms. To determine the frequency and clinical implications of these 2 possibilities, we performed histological and molecular analysis of 70 anatomically distinct HCCs from 24 patients. We assayed mutations in the TERT promoter region ...[more]

PMID: 29180252

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Project description:Frequent recurrence is a major issue in liver cancer and histological heterogeneity frequently occurs in this cancer type. However, it has remained elusive whether such cancers are multicentric or monoclonal. To elucidate the clonal evolution of hepatocellular carcinoma (HCC) recurrence and combined hepatocellular-cholangiocarcinoma (cHCC-CCA) development, the somatic mutation frequency and signatures in a patient with triple occurrence of liver cancer every three years were examined, with samples designated as #1HCC, #2HCC and #3cHCC-CCA, respectively. A total of four tumor regions, including HCC (#3HCC) and intrahepatic CCA (#3iCCA) components of #3cHCC-CCA, and three nontumor regions (#1N, #2N and #3N) were precisely dissected from formalin-fixed paraffin-embedded tissues of each surgical specimen. DNA was extracted and subjected to tumor-specific somatic mutation determination. Of note, five nonsynonymous single-nucleotide variants (SNVs), namely those of KMT2D, TP53, DNMT3A, PKHD1 and TLR4, were identified in #3cHCC-CCA. All five SNVs were detected in both #3HCC and #3iCCA and #2HCC but not in #1HCC. The telomerase reverse transcriptase (TERT) promoter mutation C228T, but not C250T, was observed in all tumors. Digital PCR of C228T also indicated the presence of the TERT promoter mutation C228T in nontumorous liver tissues (#1N, #2N and #3N) at a frequency of 0.11-0.83% compared with normal liver and blood samples. These results suggest the following phylogenetic evolution of three metachronous liver cancers: #1HCC was not related to #2HCC, #3HCC and #3iCCA; both #3HCC and #3iCCA arose from #2HCC. From the above, three novel findings were deduced: i) Both multicentric occurrence and intrahepatic metastasis may be involved in liver cancer in a three-year interval; ii) transdifferentiation from HCC to iCCA is a possible pathogenic mechanism of cHCC-CCA; and iii) a nontumorous, noncirrhotic liver may contain a preneoplastic region with a cancer driver mutation in the TERT promoter.

Dataset Information

Distinction of intrahepatic metastasis from multicentric carcinogenesis in multifocal hepatocellular carcinoma using molecular alterations.

Publications

Distinction of intrahepatic metastasis from multicentric carcinogenesis in multifocal hepatocellular carcinoma using molecular alterations.

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