The mutational landscape and actionable targets of gallbladder cancer: an ancestry-informed and comparative analysis of a Chilean population
The first genomic landscape of Chilean gallbladder cancer, in 56 tumours, found TP53, TSC2 and NOTCH1 the most mutated genes, actionable changes in ATM, BRCA1/2, EGFR and ERBB2, and a hint that Mapuche ancestry goes with TP53 mutation.
Overview
118 tumour samples were collected, of which 56 passed sequencing quality control on the Oncomine Comprehensive Assay v1. Somatic variants were annotated with ANNOVAR and the Cancer Genome Interpreter, ancestry was inferred with ADMIXTURE and principal components on ancestry-informative markers, and comparisons were made with Japanese, Singaporean and United States cohorts.
535 somatic mutations were detected in 43 genes, with TP53 (30%), TSC2 (29%) and NOTCH1 (27%) most frequently mutated. 121 clinically actionable variants were identified in ATM, BRCA1/2, EGFR, ERBB2 and other genes. Exploratory analysis suggested an association between higher Mapuche ancestry and TP53 mutations, and comparative analyses revealed distinct mutational patterns in the Chilean cohort relative to Asian and United States datasets.
- TP53 30%, TSC2 29%, NOTCH1 27% among 56 Chilean tumours.
- 121 actionable variants in ATM, BRCA1/2, EGFR, ERBB2 and other genes.
- Exploratory association between Mapuche ancestry and TP53 mutation.
Chile has the world's highest gallbladder cancer mortality and until this paper almost no tumour genomics; the lower TP53 rate and high TSC2 and NOTCH1 hint at a different mutational grammar, but the panel and sample size mean the figures need replication.
- Only 56 of 118 samples passed quality control; the 143-gene panel does not cover ELF3, SMAD4 or ARID1A comprehensively.
- Ancestry association was exploratory.
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