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

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dc.contributor.authorNepal, Chirag
dc.contributor.authorZhu, Bin
dc.contributor.authorO'Rourke, Colm J.
dc.contributor.authorBhatt, Deepak Kumar
dc.contributor.authorLee, Donghyuk
dc.contributor.authorSong, Lei
dc.contributor.authorWang, Difei
dc.contributor.authorVan Dyke, Alison L.
dc.contributor.authorChoo-Wosoba, Hyoyoung
dc.contributor.authorLiu, Zhiwei
dc.contributor.authorHildesheim, Allan
dc.contributor.authorGoldstein, Alisa M.
dc.contributor.authorDean, Michael
dc.contributor.authorLaFuente-Barquero, Juan
dc.contributor.authorLawrence, Scott
dc.contributor.authorMutreja, Karun
dc.contributor.authorOlanich, Mary E.
dc.contributor.authorBermejo, Justo Lorenzo
dc.contributor.authorFerreccio, Catterina
dc.contributor.authorRoa, Juan Carlos
dc.contributor.authorRashid, Asif
dc.contributor.authorHsing, Ann W.
dc.contributor.authorGao, Yu-Tang
dc.contributor.authorChanock, Stephen J.
dc.contributor.authorAraya, Juan Carlos
dc.contributor.authorAndersen, Jesper B.
dc.contributor.authorKoshiol, Jill
dc.date.accessioned2025-01-20T23:50:55Z
dc.date.available2025-01-20T23:50:55Z
dc.date.issued2021
dc.description.abstractBackground & Aims: Gallbladder cancer (GBC) is the most common type of biliary tract cancer, but the molecular mechanisms involved in gallbladder carcinogenesis remain poorly understood. In this study, we applied integrative genomics approaches to characterise GBC and explore molecular subtypes associated with patient survival. Methods: We profiled the mutational landscape of GBC tumours (whole-exome sequencing on 92, targeted sequencing on 98, in total 190 patients). In a subset (n = 45), we interrogated the matched transcriptomes, DNA methylomes, and somatic copy number alterations. We explored molecular subtypes identified through clustering tumours by genes whose expression was associated with survival in 47 tumours and validated subtypes on 34 publicly available GBC cases. Results: Exome analysis revealed TP53was themostmutated gene. The overallmutation ratewas low(median 0.82Mut/Mb). APOBECmediated mutational signatures were more common in tumours with higher mutational burden. Aflatoxin-related signatures tended to be highly clonal (present in >-50% of cancer cells). Transcriptome-wide survival association analysis revealed a 95gene signature that stratified all GBC patients into 3 subtypes that suggested an association with overall survival post-resection. The 2 poor-survival subtypes were associated with adverse clinicopathologic features (advanced stage, pN1, pM1), immunosuppressive micro-environments (myeloid-derived suppressor cell accumulation, extensive desmoplasia, hypoxia) and T cell dysfunction, whereas the good-survival subtype showed the opposite features. Conclusion: These data suggest that the tumour microenvironment and immune profiles could play an important role in gallbladder carcinogenesis and should be evaluated in future clinical studies, along with mutational profiles. Lay summary: Gallbladder cancer is highly fatal, and its causes are poorly understood. We evaluated gallbladder tumours to see if there were differences between tumours in genetic information such as DNA and RNA. We found evidence of aflatoxin exposure in these tumours, and immune cells surrounding the tumours were associated with survival. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
dc.fuente.origenWOS
dc.identifier.doi10.1016/j.jhep.2020.11.033
dc.identifier.eissn1600-0641
dc.identifier.issn0168-8278
dc.identifier.urihttps://doi.org/10.1016/j.jhep.2020.11.033
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/94748
dc.identifier.wosidWOS:000640696100016
dc.issue.numero5
dc.language.isoen
dc.pagina.final1144
dc.pagina.inicio1132
dc.revistaJournal of hepatology
dc.rightsacceso restringido
dc.subjectAflatoxin
dc.subjectGallbladder cancer
dc.subjectImmunogenomics
dc.subjectMicro-environment
dc.subjectMolecular subgroups
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleIntegrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes
dc.typeartículo
dc.volumen74
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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