Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes
A 190-patient study found gallbladder cancer has a low mutation rate by exome standards, evidence of aflatoxin exposure in some tumours, and three gene-expression subtypes whose survival differences track the immune and stromal surroundings rather than the mutations.
Overview
The mutational landscape of gallbladder cancer was profiled by whole-exome sequencing in 92 and targeted sequencing in 98 patients (190 in total), with matched transcriptomes, DNA methylomes and somatic copy-number alterations in a subset of 45. TP53 was the most mutated gene and the overall mutation rate was low (median 0.82 mutations per megabase). APOBEC-mediated mutational signatures were more common in tumours with higher mutational burden, and aflatoxin-related signatures tended to be highly clonal.
A 95-gene signature stratified patients into three subtypes associated with overall survival after resection. The two poor-survival subtypes were associated with advanced stage, nodal and distant metastasis, immunosuppressive microenvironments (myeloid-derived suppressor cell accumulation, extensive desmoplasia, hypoxia) and T-cell dysfunction, whereas the good-survival subtype showed the opposite features.
- Median tumour mutational burden 0.82 mutations per megabase by exome; TP53 the most mutated gene.
- APOBEC signatures tracked higher mutation burden; aflatoxin signatures were highly clonal.
- Three transcriptomic subtypes; the two poor-survival subtypes showed myeloid suppressor cells, desmoplasia, hypoxia and T-cell dysfunction.
The exome-level TMB here (0.82 per megabase) is an order of magnitude below panel estimates, a warning against comparing TMB across assays; and the survival signal sits in the microenvironment, which is where immunotherapy biomarkers for this disease may have to be found.
- Subtypes were derived from 47 tumours and validated on 34 public cases.
- Aflatoxin attribution rests on mutational signature analysis.
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