Clinical, Genomic, and Transcriptomic Data Profiling of Biliary Tract Cancer Reveals Subtype-Specific Immune Signatures.

Autor:	Mody K; Mayo Clinic, Jacksonville, FL., Jain P; Tempus Labs Inc, Chicago, IL., El-Refai SM; Tempus Labs Inc, Chicago, IL., Azad NS; Johns Hopkins University, Baltimore, MD., Zabransky DJ; Johns Hopkins University, Baltimore, MD., Baretti M; Johns Hopkins University, Baltimore, MD., Shroff RT; Division of Hematology and Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, AZ., Kelley RK; The University of California, San Francisco Medical Center, San Francisco, CA., El-Khouiery AB; USC Norris Comprehensive Cancer Center, Los Angeles, CA., Hockenberry AJ; Tempus Labs Inc, Chicago, IL., Lau D; Tempus Labs Inc, Chicago, IL., Lesinski GB; Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA., Yarchoan M; Johns Hopkins University, Baltimore, MD.
Jazyk:	angličtina
Zdroj:	JCO precision oncology [JCO Precis Oncol] 2022 Jun; Vol. 6, pp. e2100510.
DOI:	10.1200/PO.21.00510
Abstrakt:	Purpose: Biliary tract cancers (BTCs) are aggressive cancers that carry a poor prognosis. An enhanced understanding of the immune landscape of anatomically and molecularly defined subsets of BTC may improve patient selection for immunotherapy and inform immune-based combination treatment strategies. Methods: We analyzed deidentified clinical, genomic, and transcriptomic data from the Tempus database to determine the mutational frequency and mutational clustering across the three major BTC subtypes (intrahepatic cholangiocarcinoma [IHC], extrahepatic cholangiocarcinoma, and gallbladder cancer). We subsequently determined the relationship between specific molecular alterations and anatomical subsets and features of the BTC immune microenvironment. Results: We analyzed 454 samples of BTC, of which the most commonly detected alterations were TP53 (42.5%), CDKN2A (23.4%), ARID1A (19.6%), BAP1 (15.5%), KRAS (15%), CDKN2B (14.2%), PBRM1 (11.7%), IDH1 (11.7%), TERT (8.4%), KMT2C (10.4%) and LRP1B (8.4%), and FGFR2 fusions (8.7%). Potentially actionable molecular alterations were identified in 30.5% of BTCs including 39.1% of IHC. Integrative cluster analysis revealed four distinct molecular clusters, with cluster 4 predominately associated with FGFR2 rearrangements and BAP1 mutations in IHC. Immune-related biomarkers indicative of an inflamed tumor-immune microenvironment were elevated in gallbladder cancers and in cluster 1, which was enriched for TP53 , KRAS , and ATM mutations. Multiple common driver genes, including TP53 , FGFR2 , IDH1 , TERT , BRAF , and BAP1 , were individually associated with unique BTC immune microenvironments. Conclusion: BTC subtypes exhibit diverse DNA alterations, RNA inflammatory signatures, and immune biomarkers. The association between specific BTC anatomical subsets, molecular alterations, and immunophenotypes highlights new opportunities for therapeutic development. Competing Interests: Kabir ModyStock and Other Ownership Interests: CytoDyn, ONCOtherapeuticsConsulting or Advisory Role: Celgene, Genentech/Roche, Merrimack, Eisai, AstraZeneca, Vicus Therapeutics, Ipsen, Boston Scientific, BTG, BTG, Exelixis, Incyte (Inst), QED TherapeuticsResearch Funding: FibroGen (Inst), Senhwa Biosciences (Inst), ARIAD (Inst), TRACON Pharma (Inst), MedImmune (Inst), Agios (Inst), ArQule (Inst), Taiho Pharmaceutical (Inst), Gritstone Bio (Inst), Incyte (Inst), Merck (Inst), Vyriad (Inst), Turnstone Bio (Inst), AstraZeneca (Inst), Basilea (Inst) Prerna JainEmployment: Tempus, Concerto HealthAITravel, Accommodations, Expenses: Tempus Sherif M. El-RefaiEmployment: TempusStock and Other Ownership Interests: Tempus Nilofer S. AzadConsulting or Advisory Role: QED Therapeutics, Merck, Incyte, Helsinn Therapeutics/QED Therapeutics, AstraZeneca, Mirati TherapeuticsResearch Funding: Celgene (Inst), Genentech (Inst), Astex Pharmaceuticals (Inst), Agios (Inst), Merck (Inst), Bristol Myers Squibb (Inst), Syndax (Inst), Array BioPharma (Inst), Intensity Therapeutics (Inst), Bayer (Inst), EMD Serono, Debiopharm Group (Inst), Incyte (Inst), Loxo/Lilly (Inst), AtlasMedx (Inst) Daniel J. ZabranskyHonoraria: Remedy Health Group, LLCResearch Funding: Roche/GenentechPatents, Royalties, Other Intellectual Property: Under separate licensing agreements between Horizon Discovery, Ltd and The Johns Hopkins University, I am entitled to a share of royalties received by the university on sales of products Rachna T. ShroffConsulting or Advisory Role: Exelixis, Merck, QED Therapeutics, Incyte, AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Servier, Genentech, BasileaResearch Funding: Pieris Pharmaceuticals, Taiho Pharmaceutical, Merck, Exelixis, QED Therapeutics, Rafael Pharmaceuticals, Bristol Myers Squibb, Bayer, Immunovaccine, Seattle Genetics, Novocure, NuCana, Loxo/Lilly, Faeth Therapeutics R. Katie KelleyConsulting or Advisory Role: Agios (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst), Genentech/Roche, Merck (Inst), Gilead Sciences, Exact Sciences, Kinnate Biopharma, Exelixis/Ipsen (Inst)Research Funding: Lilly (Inst), Exelixis (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), MedImmune (Inst), Merck Sharp & Dohme (Inst), Agios (Inst), AstraZeneca (Inst), Adaptimmune (Inst), Taiho Pharmaceutical (Inst), Bayer (Inst), QED Therapeutics (Inst), EMD Serono (Inst), Partner Therapeutics (Inst), Genentech/Roche (Inst), Surface Oncology (Inst), Relay Therapeutics (Inst), Loxo/Lilly (Inst)Travel, Accommodations, Expenses: Ipsen Anthony B. El-KhouieryHonoraria: Bayer, Bristol Myers Squibb, Roche/Genentech, EMD Serono, Eisai, Merck, Agenus, Pieris Pharmaceuticals, Exelixis, CytomX Therapeutics, Gilead Sciences, AstraZeneca/MedImmune, ABL Bio, QED Therapeutics, Servier, Tallac TherapeuticsConsulting or Advisory Role: CytomX Therapeutics, Bristol Myers Squibb, Bayer, Eisai, Roche, EMD Serono, Merck, Exelixis, Pieris Pharmaceuticals, Agenus, Gilead Sciences, AstraZeneca/MedImmune, ABL Bio, QED Therapeutics, Servier, Tallac TherapeuticsResearch Funding: AstraZeneca, Astex Pharmaceuticals, Fulgent Genetics Adam J. HockenberryEmployment: TempusStock and Other Ownership Interests: Tempus Denise LauEmployment: TempusStock and Other Ownership Interests: TempusPatents, Royalties, Other Intellectual Property: Tempus Gregory B. LesinskiConsulting or Advisory Role: ProDaResearch Funding: Merck (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Boehringer Ingelheim (Inst), Vaccinex (Inst) Mark YarchoanConsulting or Advisory Role: Eisai, Exelixis, AstraZeneca, Genentech/Roche, Replimune, Hepion PharmaceuticalsResearch Funding: Bristol Myers Squibb (Inst), Merck (Inst), Exelixis (Inst), Incyte (Inst)Uncompensated Relationships: MerckNo other potential conflicts of interest were reported.
Databáze:	MEDLINE
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