Whole-exome tumor sequencing study in biliary cancer patients with a response to MEK inhibitors

Daniel Ahn, Hatice Gulcin Ozer, Baris Hancioglu, Gregory B. Lesinski, Cynthia Timmers, Tanios Bekaii-Saab

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

We previously conducted a phase-II study with selumetinib (AZD6244), a small molecule inhibitor of MEK1/2, in advanced biliary tract cancers (BTC), where the primary endpoint was response rate. Several patients experienced objective response. These findings were confirmed with MEK162 in a similar patient population. To assess for tumor-specific genetic variants that mediate sensitivity to MEK inhibition in BTC, we performed whole-exome sequencing in patients with an objective response to selumetinib. Normal and tumor DNA from FFPE tissue from two patients who experienced an objective response underwent whole-exome sequencing. Raw sequence reads were processed with GATK workflow and tumor specific variants were identified using MuTect and VarScan2. Ensemble Variant Effect Predictor was used to determine functional consequences of these variants. Copy number changes and potential gene fusion events were also screened. Findings were compared to assess for any commonality between the two tumor samples, and whether the identified variants were intrinsic to the MAPK pathway. 1169 and 628 tumor-specific variants were identified in the two samples. Further analysis demonstrated 60 and 53 functional and novel variants, respectively. Of the identified tumor-specific variants, fusion events or copy number changes, no commonality was seen. Several variants in genes associated with ERK signaling were present in each tumor sample. Although there were no common tumor-specific variants in the two patients who exhibited an objective response to selumetinib, several genes associated with ERK signaling were identified. Confirmatory studies investigating the role of the identified genes and other potential tumor independent factors need further investigation.

Original languageEnglish (US)
Pages (from-to)5306-5312
Number of pages7
JournalOncotarget
Volume7
Issue number5
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Keywords

  • Biliary cancer
  • MEK inhibition
  • Whole-exome sequencing

ASJC Scopus subject areas

  • Oncology

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