Whole exome sequencing of multi-regions reveals tumor heterogeneity in Opisthorchis viverrini-associated cholangiocarcinoma

Abstract

The study examines Opisthorchis viverrini (OV)-related cholangiocarcinoma (CCA), a serious malignancy common in Southeast Asia. Through multi-regional whole-exome sequencing of 52 tumor samples and 13 adjacent tissues from 13 patients, significant intratumoral heterogeneity (ITH) and inter-patient heterogeneity are shown. Chronic liver fluke infection induces a distinct mutational landscape, with 48–90% of mutations concentrated in each region of the tumor. The average mutation burden is 95 non-synonymous mutations per area, exceeding previous CCA investigations. Critical driver mutations in TP53, SMAD4, and other genes underscore their significance in pathogenesis. Mutational markers elucidate mechanisms including spontaneous deamination and impaired DNA repair. Unique mutation patterns distinguish OV-associated CCA from other variants. Chromosomal instability in patient K110 signifies aggressive tumor behavior and unfavorable prognosis. Targetable mutations such as ERBB2 underscore the possibility for personalized therapeutics. These findings underscore the necessity for personalized strategies for treatment that target both trunk and branch mutations in endemic areas.