Dataset Information

Molecular genomic landscapes of hepatobiliary cancer.

ABSTRACT: Hepatocellular carcinoma (HCC) and biliary tract cancer are more frequent in East Asia including Japan than in Europe or North America. A compilation of 1340 multi-ethnic HCC genomes, the largest cohort ever reported, identified a comprehensive landscape of HCC driver genes, comprised of three core drivers (TP53, TERT, and WNT signaling) and combinations of infrequent alterations in various cancer pathways. In contrast, five core driver genes (TP53, ARID1A, KRAS, SMAD4, and BAP1) with characteristic molecular alterations including fusion transcripts involving fibroblast growth factor receptor 2 and the protein kinase A pathway, and IDH1/2 mutation constituted the biliary tract cancer genomes. Consistent with their heterogeneous epidemiological backgrounds, mutational signatures and combinations of non-core driver genes within these cancer genomes were found to be complex. Integrative analyses of multi-omics data identified molecular classifications of these tumors that are associated with clinical outcome and enrichments of potential therapeutic targets, including immune checkpoint molecules. Translating comprehensive molecular-genomic analysis together with further basic research and international collaborations are highly anticipated for developing precise and better treatments, diagnosis, and prevention of these tumor types.

SUBMITTER: Shibata T

PROVIDER: S-EPMC5980207 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Molecular genomic landscapes of hepatobiliary cancer.

Shibata Tatsuhiro T Arai Yasuhito Y Totoki Yasushi Y

Cancer science 20180428 5

Hepatocellular carcinoma (HCC) and biliary tract cancer are more frequent in East Asia including Japan than in Europe or North America. A compilation of 1340 multi-ethnic HCC genomes, the largest cohort ever reported, identified a comprehensive landscape of HCC driver genes, comprised of three core drivers (TP53, TERT, and WNT signaling) and combinations of infrequent alterations in various cancer pathways. In contrast, five core driver genes (TP53, ARID1A, KRAS, SMAD4, and BAP1) with characteri ...[more]

PMID: 29573058

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Project description:BackgroundDespite the putatively targetable genomic landscape of high-grade gliomas, the long-term survival benefit of genomically-tailored targeted therapies remains discouraging.MethodsUsing glioblastoma (GBM) as a representative example of high-grade gliomas, we evaluated the clonal architecture and distribution of hotspot mutations in 388 GBMs from the Cancer Genome Atlas (TCGA). Mutations were matched with 54 targeted therapies, followed by a comprehensive evaluation of drug biochemical properties in reference to the drug's clinical efficacy in high-grade gliomas. We then assessed clinical outcomes of a cohort of patients with high-grade gliomas with targetable mutations reviewed at the Johns Hopkins Molecular Tumor Board (JH MTB; n = 50).ResultsAmong 1,156 sequence alterations evaluated, 28.6% represented hotspots. While the frequency of hotspot mutations in GBM was comparable to cancer types with actionable hotspot alterations, GBMs harbored a higher fraction of subclonal mutations that affected hotspots (7.0%), compared to breast cancer (4.9%), lung cancer (4.4%), and melanoma (1.4%). In investigating the biochemical features of targeted therapies paired with recurring alterations, we identified a trend toward higher lipid solubility and lower IC50 in GBM cell lines among drugs with clinical efficacy. The drugs' half-life, molecular weight, surface area and binding to efflux transporters were not associated with clinical efficacy. Among the JH MTB cohort of patients with IDH1 wild-type high-grade gliomas who received targeted therapies, trametinib monotherapy or in combination with dabrafenib conferred radiographic partial response in 75% of patients harboring BRAF or NF1 actionable mutations. Cabozantinib conferred radiographic partial response in two patients harboring a MET and a PDGFRA/KDR amplification. Patients with IDH1 wild-type gliomas that harbored actionable alterations who received genotype-matched targeted therapy had longer progression-free (PFS) and overall survival (OS; 7.37 and 14.72 respectively) than patients whose actionable alterations were not targeted (2.83 and 4.2 months respectively).ConclusionWhile multiple host, tumor and drug-related features may limit the delivery and efficacy of targeted therapies for patients with high-grade gliomas, genotype-matched targeted therapies confer favorable clinical outcomes. Further studies are needed to generate more data on the impact of biochemical features of targeted therapies on their clinical efficacy for high-grade gliomas.

Dataset Information

Molecular genomic landscapes of hepatobiliary cancer.

Publications

Molecular genomic landscapes of hepatobiliary cancer.

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