Mutational signatures define immune and Wnt-associated subtypes of ampullary carcinoma.

Autor:	Zhuravleva E; Biotech Research and Innovation Center (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Lewinska M; Biotech Research and Innovation Center (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., O'Rourke CJ; Biotech Research and Innovation Center (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Pea A; University of Glasgow, Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, Glasgow, UK.; University of Verona, Verona, Italy., Rashid A; Department of Pathology, Division of Pathology/Lab Medicine, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA., Hsing AW; Stanford Cancer Institute and Stanford Prevention Research Center, Department of Medicine, Stanford School of Medicine, Stanford University, Palo Alto, California, USA., Taranta A; Biotech Research and Innovation Center (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Chang D; University of Glasgow, Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, Glasgow, UK., Gao YT; Department of Epidemiology, Shanghai Cancer Institute, Shanghai, Shanghai, China., Koshiol J; Division of Cancer Epidemiology and Genetics, NIH, Rockville, Maryland, USA., Oliveira RC; Centro Hospitalar de Coimbra, Universitário de Coimbra, Coimbra, Portugal., Andersen JB; Biotech Research and Innovation Center (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark jesper.andersen@bric.ku.dk.
Jazyk:	angličtina
Zdroj:	Gut [Gut] 2024 Dec 26. Date of Electronic Publication: 2024 Dec 26.
DOI:	10.1136/gutjnl-2024-333368
Abstrakt:	Background and Objective: Ampullary carcinoma (AMPAC) taxonomy is based on morphology and immunohistochemistry. This classification lacks prognostic reliability and unique genetic associations. We applied an approach of integrative genomics characterising patients with AMPAC exploring molecular subtypes that may guide personalised treatments. Design: We analysed the mutational landscapes of 170 patients with AMPAC. The discovery included 110 tumour/normal pairs and the validation comprised 60 patients. In a tumour subset, we interrogated the transcriptomes and DNA methylomes. Patients were stratified based on mutational signatures and associated with molecular and clinical features. To evaluate tumour and immune cellularity, 22 tumours were independently assessed histomorphologically and by digital pathology. Results: We defined three patient clusters by mutational signatures independent of histomorphology. Cluster 1 (C1) was defined by spontaneous deamination of DNA 5-methylcytosine and defective mismatch repair. C2 and C3 were related to the activity of transcription-coupled nucleotide excision repair but C3 was further defined by the polymerase eta mutational process. C1-2 showed enrichment of Wnt pathway alterations, aberrant DNA methylation profiles, immune cell exclusion and patients with poor prognosis. These features were associated with a hypermutator phenotype caused by C>T alterations at CpGs. C3 patients with improved overall survival were associated with activation of immune-related pathways, immune infiltration and elevated expression of immunoinhibitory checkpoint genes. Conclusion: Immunogenicity and Wnt pathway associations, emphasised by the mutational signatures, defined patients with prospective sensitivity to either immunotherapy or Wnt pathway inhibitors. This emphasises a novel mutational signature-based AMPAC classification with prognostic potential, suggesting prospective implications for subgroup-specific management of patients with AMPAC. Competing Interests: Competing interests: JBA declares consultancies for Flagship Pioneering, Seald, QED Therapeutics and AstraZeneca. JBA has received funding from the Incyte Corporation (EU-DK-ST-21122) but not related to this study. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)
Databáze:	MEDLINE
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