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Nat Genet. 2015 Sep;47(9):1003-10. doi: 10.1038/ng.3375. Epub 2015 Aug 10.

Genomic spectra of biliary tract cancer.

Author information

1
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
2
First Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan.
3
Department of Bioinformatics, National Cancer Center Research Institute, Tokyo, Japan.
4
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
5
Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
6
Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
7
Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan.
8
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.

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.

PMID:
26258846
DOI:
10.1038/ng.3375
[Indexed for MEDLINE]
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