Genomic spectra of biliary tract cancer

Hiromi Nakamura, Yasuhito Arai, Yasushi Totoki, Tomoki Shirota, Asmaa Elzawahry, Mamoru Kato, Natsuko Hama, Fumie Hosoda, Tomoko Urushidate, Shoko Ohashi, Nobuyoshi Hiraoka, Hidenori Ojima, Kazuaki Shimada, Takuji Okusaka, Tomoo Kosuge, Shinichi Miyagawa, Tatsuhiro Shibata

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309 Citations (Scopus)

Abstract

The incidence of biliary tract cancer (BTC), including intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and gallbladder cancer, has increased globally; however, no effective targeted molecular therapies have been approved at the present time. Here we molecularly characterized 260 BTCs and uncovered spectra of genomic alterations that included new potential therapeutic targets. Gradient spectra of mutational signatures with a higher burden of the APOBEC-associated mutation signature were observed in gallbladder cancer and ECC. Thirty-two significantly altered genes, including ELF3, were identified, and nearly 40% of cases harbored targetable genetic alterations. Gene fusions involving FGFR2 and PRKACA or PRKACB preferentially occurred in ICC and ECC, respectively, and the subtype-associated prevalence of actionable growth factor-mediated signals was noteworthy. The subgroup with the poorest prognosis had significant enrichment of hypermutated tumors and a characteristic elevation in the expression of immune checkpoint molecules. Accordingly, immune-modulating therapies might also be potentially promising options for these patients.

Original languageEnglish
Pages (from-to)1003-1010
Number of pages8
JournalNature Genetics
Volume47
Issue number9
DOIs
Publication statusPublished - 2015 Aug 27

ASJC Scopus subject areas

  • Genetics

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    Nakamura, H., Arai, Y., Totoki, Y., Shirota, T., Elzawahry, A., Kato, M., Hama, N., Hosoda, F., Urushidate, T., Ohashi, S., Hiraoka, N., Ojima, H., Shimada, K., Okusaka, T., Kosuge, T., Miyagawa, S., & Shibata, T. (2015). Genomic spectra of biliary tract cancer. Nature Genetics, 47(9), 1003-1010. https://doi.org/10.1038/ng.3375