Author(s): Quinn L.; Palmer D.; Goldring C.; Jones R.; Fenwick S.; Malik H.

Source: European Journal of Surgical Oncology; Nov 2019; vol. 45 (no. 11); p. 2216

Publication Date: Nov 2019

Publication Type(s): Conference Abstract

Abstract:Background: Heterogeneity of actionable mutations remains poorly defined in peri-hilar cholangiocarcinoma with absence of effective targeted therapies. Whole exome sequencing accurately defines protein-coding regions of cancer cell genomes and can identify novel targetable mutations. We completed the first whole exome sequencing study of a Western resected peri-hilar cholangiocarcinoma cohort, to unravel mutational heterogeneity between patients and identify actionable targets. Method(s): Matched tumour and normal bile duct formalin-fixed-paraffin-embedded tissue sections from 40 peri-hilar cholangiocarcinoma resections underwent microdissection increasing tumour cellularity. DNA extraction completed according to Qiagen FFPE DNEasy protocol. DNA quantity and purity were confirmed with Qubit and Nanodrop (Thermofisher). Whole exome sequencing of DNA samples was completed on Illumina HiSeq 2000. Raw sequencing data from matched normal bile duct filtered out non-somatic mutations. Variant calling was cross-referenced to human genome and the Catalogue of Somatic Mutations in Cancer (Sanger Institute) using VarScan and STRELKA software. Result(s): 25 tumour samples yielded high quality DNA for sequencing with 80.65% mapped reads. Median number of total mutations was 1307 (interquartile range 1206 – 1653) with a median number of 334 moderate impact non-synonymous mutations (interquartile range 213 – 454). The median number of high impact mutations including frameshifts and premature stop codons was 53 (interquartile range 46 – 97). Conclusion(s): Peri-hilar cholangiocarcarcinoma demonstrates significant inter-tumoral heterogeneity of mutations in the first Western cohort whole exome sequencing study. Greater numbers of actionable mutations have been identified comparative to published Eastern studies. Significant mutations have completed downstream pathway analysis with considerable implications for targeted therapy development.

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Database: EMBASE