# Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes

Source: https://onco.cc/key-papers/paper-nepal-gallbladder-microenvironment-subtypes-j-hepatol-2021/  
OnCo record `paper-nepal-gallbladder-microenvironment-subtypes-j-hepatol-2021` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Journal of Hepatology
- Year: 2021
- DOI: 10.1016/j.jhep.2020.11.033
- Authors: Nepal C, Zhu B, O'Rourke CJ, et al.
- Findings: 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.
- What it means: 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.
- Caveats: Subtypes were derived from 47 tumours and validated on 34 public cases.; Aflatoxin attribution rests on mutational signature analysis.

## Sources

- Nepal et al., J Hepatol 2021: integrative molecular characterisation of 190 gallbladder cancers: https://doi.org/10.1016/j.jhep.2020.11.033
- PubMed: https://pubmed.ncbi.nlm.nih.gov/33276026/

## Connected records

- cancers: [Gallbladder cancer](https://onco.cc/cancers/gallbladder/)
- targets: [TP53](https://onco.cc/targets/tp53/)
- terms: [Mutational signature](https://onco.cc/terms/mutational-signature/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/), [Tumour-infiltrating lymphocytes (TILs)](https://onco.cc/terms/tils/)
- biomarkers: [TMB-high (tumour mutational burden >= 10 mutations per megabase)](https://onco.cc/biomarkers/tmb-high/)

---
JSON: https://onco.cc/api/v1/entities/paper-nepal-gallbladder-microenvironment-subtypes-j-hepatol-2021.json