Comprehensive genetic analysis of cholangiolocellular carcinoma with a coexistent hepatocellular carcinoma-like area and metachronous hepatocellular carcinoma

Fukiko Kawai-Kitahata, Yasuhiro Asahina, Shun Kaneko, Jun Tsuchiya, Ayako Sato, Masato Miyoshi, Tomoyuki Tsunoda, Emi Inoue-Shinomiya, Miyako Murakawa, Sayuri Nitta, Yasuhiro Itsui, Mina Nakagawa, Seishin Azuma, Sei Kakinuma, Minoru Tanabe, Emiko Sugawara, Akira Takemoto, Hidenori Ojima, Michiie Sakamoto, Masaru MuraokaShinichi Takano, Shinya Maekawa, Nobuyuki Enomoto, Mamoru Watanabe

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


Aim: The genetic profile of cholangiolocellular carcinoma (CLC) and its origin in relation to hepatocellular carcinoma (HCC) remain unclear. To elucidate the genetic profile of CLC, a comprehensive analysis of genetic mutations was carried out in a case of CLC with an HCC-like focal area and metachronous HCC. Method: Liver tissue was obtained from CLC, a co-existent HCC-like area, and metachronously developed HCC by laser capture microdissection of formalin-fixed paraffin-embedded specimens obtained by hepatectomy. Gene mutational profiles were analyzed comprehensively by next-generation sequencing and digital PCR. Relationships among gene profiles, immunohistochemistry, and clinicopathological findings were investigated. Results: Mutations in EGFR, PTEN, RB1, TP53, and ERBB2 were found in CLC, whereas mutations in KIT, BRAF, PTEN, TP53, and SMAD4 were found in the coexistent HCC-like area. Only the mutation in PTEN has a common Catalogue of Somatic Mutations in Cancer ID in the CLC and coexistent HCC-like area, and is related to the kinase-RAS module. In contrast, no cancer-related mutations were found in the metachronous HCC. No TERT mutations were found in any of the regions by digital PCR. Immunohistochemical staining for p53 was negative in CLC, although ≤10% positive in the coexistent HCC-like area. Immunostaining of C-kit, HER2, PTEN, and SMAD4 were negative. Conclusion: The genomic features of CLC and the focal area of an HCC-like region differ, but are related to the kinase-RAS module. The development of carcinogenesis in the CLC and HCC-like areas in this case might differ, following a common PTEN mutation, although alteration of the kinase-RAS module is the most common molecular event in CLC.

Original languageEnglish
Pages (from-to)1466-1474
Number of pages9
JournalHepatology Research
Issue number12
Publication statusPublished - 2019 Dec 1


  • cholangiolocellular carcinoma
  • digital polymerase chain reaction
  • gene mutation
  • hepatocellular carcinoma
  • laser capture microdissection
  • next-generation sequencing

ASJC Scopus subject areas

  • Hepatology
  • Infectious Diseases


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