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

Autor: Nepal C; Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Denmark., Zhu B; Division of Cancer Epidemiology and Genetics, NIH, Rockville, MD, USA., O'Rourke CJ; Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Denmark., Bhatt DK; Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Denmark., Lee D; Division of Cancer Epidemiology and Genetics, NIH, Rockville, MD, USA., Song L; Division of Cancer Epidemiology and Genetics, NIH, Rockville, MD, USA., Wang D; Division of Cancer Epidemiology and Genetics, NIH, Rockville, MD, USA., Van Dyke AL; Division of Cancer Epidemiology and Genetics, NIH, Rockville, MD, USA., Choo-Wosoba H; Division of Cancer Epidemiology and Genetics, NIH, Rockville, MD, USA., Liu Z; Division of Cancer Epidemiology and Genetics, NIH, Rockville, MD, USA., Hildesheim A; Division of Cancer Epidemiology and Genetics, NIH, Rockville, MD, USA., Goldstein AM; Division of Cancer Epidemiology and Genetics, NIH, Rockville, MD, USA., Dean M; Division of Cancer Epidemiology and Genetics, NIH, Rockville, MD, USA., LaFuente-Barquero J; Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Denmark., Lawrence S; Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Mutreja K; Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Olanich ME; Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Lorenzo Bermejo J; Statistical Genetics Research Group, Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany., Ferreccio C; Department of Public Health, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), FONDAP, Santiago, Chile., Roa JC; Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile., Rashid A; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Hsing AW; Stanford Cancer Institute and Stanford Prevention Research Center, Department of Medicine, Stanford School of Medicine, Stanford, CA, USA., Gao YT; Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China., Chanock SJ; Division of Cancer Epidemiology and Genetics, NIH, Rockville, MD, USA., Araya JC; Advanced Center for Chronic Diseases (ACCDiS), FONDAP, Santiago, Chile; Hospital Dr. Hernán Henríquez Aravena, Temuco, Chile; Department of Pathology, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile., Andersen JB; Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: jesper.andersen@bric.ku.dk., Koshiol J; Division of Cancer Epidemiology and Genetics, NIH, Rockville, MD, USA. Electronic address: koshiolj@mail.nih.gov.
Jazyk: angličtina
Zdroj: Journal of hepatology [J Hepatol] 2021 May; Vol. 74 (5), pp. 1132-1144. Date of Electronic Publication: 2020 Dec 01.
DOI: 10.1016/j.jhep.2020.11.033
Abstrakt: Background & 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 TP53 was the most mutated gene. The overall mutation rate was low (median 0.82 Mut/Mb). APOBEC-mediated 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 95-gene 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 micro-environment 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.
Competing Interests: Conflict of interest The authors have no relevant affiliation or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in this manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Please refer to the accompanying ICMJE disclosure forms for further details.
(Published by Elsevier B.V.)
Databáze: MEDLINE
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