{"entity":{"id":"paper-nepal-gallbladder-microenvironment-subtypes-j-hepatol-2021","kind":"paper","name":"Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes","aka":[],"tldr":"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.\n\nA 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.","asOf":"2026-09-24","links":[{"label":"Nepal et al., J Hepatol 2021: integrative molecular characterisation of 190 gallbladder cancers","url":"https://doi.org/10.1016/j.jhep.2020.11.033"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33276026/"}],"tags":[],"related":[],"cancers":["gallbladder"],"sections":[],"technologies":[],"targets":["tp53"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["tmb","mutational-signature","tils"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Journal of Hepatology","year":2021,"doi":"10.1016/j.jhep.2020.11.033","pmid":"33276026","authors":"Nepal C, Zhu B, O'Rourke CJ, et al.","paperType":"translational","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."],"whatItMeans":"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."],"changedPractice":false,"participants":190},"route":"/key-papers/paper-nepal-gallbladder-microenvironment-subtypes-j-hepatol-2021/","neighbours":{"cancer":[{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","route":"/cancers/gallbladder/"}],"target":[{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"term":[{"id":"mutational-signature","kind":"term","name":"Mutational signature","route":"/terms/mutational-signature/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"},{"id":"tils","kind":"term","name":"Tumour-infiltrating lymphocytes (TILs)","route":"/terms/tils/"}],"biomarker":[{"id":"tmb-high","kind":"biomarker","name":"TMB-high (tumour mutational burden >= 10 mutations per megabase)","route":"/biomarkers/tmb-high/"}]}}