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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.
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.
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.
Shares Mutational signature, Tumour mutational burden (TMB).
Shares Tumour-infiltrating lymphocytes (TILs), Gallbladder cancer.
Shares TMB-high (tumour mutational burden >= 10 mutations per megabase), Mutational signature, Tumour mutational burden (TMB).
Shares TMB-high (tumour mutational burden >= 10 mutations per megabase), Tumour mutational burden (TMB), TP53, Gallbladder cancer.
Shares Tumour-infiltrating lymphocytes (TILs), Gallbladder cancer.
Shares Mutational signature, Tumour mutational burden (TMB), TP53.
Shares TMB-high (tumour mutational burden >= 10 mutations per megabase), Mutational signature, Tumour mutational burden (TMB).
Shares TMB-high (tumour mutational burden >= 10 mutations per megabase), Tumour mutational burden (TMB).