Abstract
BackgroundThe genetics of advanced biliary tract cancers (BTC), which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined.MethodsTo better characterize mutations in established known oncogenes and tumor suppressor genes we tested a mass spectrometric based platform to interrogate common cancer associated mutations across a panel of 77 formalin fixed paraffin embedded archived BTC cases.ResultsMutations among three genes, KRAS, NRAS and PIK3CA were confirmed in this cohort. Activating mutations in PIK3CA were identified exclusively in GBC (4/32, 12.5%). KRAS mutations were identified in 3 (13%) intra-hepatic cholangiocarcinomas and 1 (33%) perihillar cholangiocarcinoma but were not identified in gallbladder carcinomas and extra-hepatic cholangiocarcinoma.ConclusionsThe presence of activating mutations in PIK3CA specifically in GBC has clinical implications in both the diagnosis of this cancer type, as well as the potential utility of targeted therapies such as PI3 kinase inhibitors.
Highlights
The genetics of advanced biliary tract cancers (BTC), which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined
Identification of mutations in BTC Mutations in KRAS, NRAS, and PIK3CA were identified as outlined in Table 1 and 2
In summary the process leading to positive identification of mutations involved a two-step process was used as previously described [21], where candidate mutations identified using OncoMap technology were subsequently subject to a second round of homogenous Mass-Extend (hME) validation
Summary
The genetics of advanced biliary tract cancers (BTC), which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined. Regardless of the site of origin, these tumors display a remarkably similar histologic appearance, variable amount of gland formation, and an exuberant desmoplastic stromal reaction. These tumors share an anatomic origin in the biliary system; there are important differences in disease behavior, molecular profiles, and sensitivity to therapy. Mutations in the tumor suppressor genes CDKN2A, TP53 and SMAD4 have been identified [12,13,14,15,16] The relationship of these mutations to each other as well as the frequency of each mutation within subsets of BTC is not yet fully explored. Many established mutations identified in other cancer remain to be evaluated in BTC
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