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Article Open Access

Direct molecular evidence for both multicentric and monoclonal carcinogenesis followed by transdifferentiation from hepatocellular carcinoma to cholangiocarcinoma in a case of metachronous liver cancer

  • Authors:
    • Sumie Ohni
    • Hiromi Yamaguchi
    • Yukari Hirotani
    • Yoko Nakanishi
    • Yutaka Midorikawa
    • Masahiko Sugitani
    • Hiromu Naruse
    • Tomohiro Nakayama
    • Makoto Makishima
    • Mariko Esumi
  • View Affiliations / Copyright

    Affiliations: Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173‑8610, Japan, Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo 173‑8610, Japan, Department of Surgery, Nihon University School of Medicine, Tokyo 173‑8610, Japan
    Copyright: © Ohni et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 22
    |
    Published online on: November 17, 2021
       https://doi.org/10.3892/ol.2021.13140
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Abstract

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.
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Copy and paste a formatted citation
Spandidos Publications style
Ohni S, Yamaguchi H, Hirotani Y, Nakanishi Y, Midorikawa Y, Sugitani M, Naruse H, Nakayama T, Makishima M, Esumi M, Esumi M, et al: Direct molecular evidence for both multicentric and monoclonal carcinogenesis followed by transdifferentiation from hepatocellular carcinoma to cholangiocarcinoma in a case of metachronous liver cancer. Oncol Lett 23: 22, 2022.
APA
Ohni, S., Yamaguchi, H., Hirotani, Y., Nakanishi, Y., Midorikawa, Y., Sugitani, M. ... Esumi, M. (2022). Direct molecular evidence for both multicentric and monoclonal carcinogenesis followed by transdifferentiation from hepatocellular carcinoma to cholangiocarcinoma in a case of metachronous liver cancer. Oncology Letters, 23, 22. https://doi.org/10.3892/ol.2021.13140
MLA
Ohni, S., Yamaguchi, H., Hirotani, Y., Nakanishi, Y., Midorikawa, Y., Sugitani, M., Naruse, H., Nakayama, T., Makishima, M., Esumi, M."Direct molecular evidence for both multicentric and monoclonal carcinogenesis followed by transdifferentiation from hepatocellular carcinoma to cholangiocarcinoma in a case of metachronous liver cancer". Oncology Letters 23.1 (2022): 22.
Chicago
Ohni, S., Yamaguchi, H., Hirotani, Y., Nakanishi, Y., Midorikawa, Y., Sugitani, M., Naruse, H., Nakayama, T., Makishima, M., Esumi, M."Direct molecular evidence for both multicentric and monoclonal carcinogenesis followed by transdifferentiation from hepatocellular carcinoma to cholangiocarcinoma in a case of metachronous liver cancer". Oncology Letters 23, no. 1 (2022): 22. https://doi.org/10.3892/ol.2021.13140
Copy and paste a formatted citation
x
Spandidos Publications style
Ohni S, Yamaguchi H, Hirotani Y, Nakanishi Y, Midorikawa Y, Sugitani M, Naruse H, Nakayama T, Makishima M, Esumi M, Esumi M, et al: Direct molecular evidence for both multicentric and monoclonal carcinogenesis followed by transdifferentiation from hepatocellular carcinoma to cholangiocarcinoma in a case of metachronous liver cancer. Oncol Lett 23: 22, 2022.
APA
Ohni, S., Yamaguchi, H., Hirotani, Y., Nakanishi, Y., Midorikawa, Y., Sugitani, M. ... Esumi, M. (2022). Direct molecular evidence for both multicentric and monoclonal carcinogenesis followed by transdifferentiation from hepatocellular carcinoma to cholangiocarcinoma in a case of metachronous liver cancer. Oncology Letters, 23, 22. https://doi.org/10.3892/ol.2021.13140
MLA
Ohni, S., Yamaguchi, H., Hirotani, Y., Nakanishi, Y., Midorikawa, Y., Sugitani, M., Naruse, H., Nakayama, T., Makishima, M., Esumi, M."Direct molecular evidence for both multicentric and monoclonal carcinogenesis followed by transdifferentiation from hepatocellular carcinoma to cholangiocarcinoma in a case of metachronous liver cancer". Oncology Letters 23.1 (2022): 22.
Chicago
Ohni, S., Yamaguchi, H., Hirotani, Y., Nakanishi, Y., Midorikawa, Y., Sugitani, M., Naruse, H., Nakayama, T., Makishima, M., Esumi, M."Direct molecular evidence for both multicentric and monoclonal carcinogenesis followed by transdifferentiation from hepatocellular carcinoma to cholangiocarcinoma in a case of metachronous liver cancer". Oncology Letters 23, no. 1 (2022): 22. https://doi.org/10.3892/ol.2021.13140
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