1. Next-generation sequencing analysis of cholangiocarcinoma identifies distinct IDH1-mutated clusters.
- Author
-
Rimini M, Loi E, Fabregat-Franco C, Burgio V, Lonardi S, Niger M, Scartozzi M, Raposelli IG, Aprile G, Ratti F, Pedica F, Verdaguer H, Rizzato M, Nichetti F, Lai E, Cappetta A, Macarulla T, Fassan M, De Braud F, Pretta A, Simionato F, De Cobelli F, Aldrighetti L, Fornaro L, Cascinu S, Zavattari P, and Casadei-Gardini A
- Subjects
- Bile Ducts, Intrahepatic metabolism, Chromatin metabolism, High-Throughput Nucleotide Sequencing, Humans, Isocitrate Dehydrogenase genetics, Mutation, Phosphatidylinositol 3-Kinases metabolism, Bile Duct Neoplasms pathology, Cholangiocarcinoma pathology
- Abstract
Background: IDH1-mutated intrahepatic cholangiocarcinomas (IDH1m iCCAs) could be treated with anti-IDH1 drugs, although the high heterogeneity in this class of tumours could limit treatment efficacy., Methods: We selected 125 IDH1m iCCAs that were treated as resectable, locally advanced, or metastatic and were screened by the NGS-based FoundationOne gene panel. We conducted a mutation-based clustering of tumours and survival analysis., Results: Three main clusters were identified. The most altered pathways in cluster 1 were cell cycle and apoptosis, RTK/RAS, PI3K, and chromatin modification. Of note, CDKN2A/2B were mutated in 41/44 patients of this cluster. In cluster 2, the most affected pathways were as follows: Chromatin modification, DNA damage control, PI3K, and RTK/RAS. In this cluster, the most frequently mutated genes were ARID1A and PBRM1. The most altered pathways in cluster 3 were as follows: Cell cycle and apoptosis, DNA damage control, TP53, and chromatin modification. Importantly, TP53 was mutated only in cluster 3 patients. In the cohort of patients treated with surgery, cluster 2 showed statistically significant better disease-free survival (DFS) and overall survival (OS) compared with patients in cluster 3 and cluster 1 (p = 0.0014 and p = 0.0003, respectively). In the advanced setting, cluster 2 experienced a statistically significant better PFS (p = 0.0012), a tendency toward a better OS from first-line treatment, and a better OS from first-line progression compared with patients in cluster 1 and cluster 3 (p = 0.0017). We proposed an easy-to-use algorithm able to stratify patients in the three clusters on the basis of the genomic profile., Conclusion: We highlighted three different mutation-based clusters with prognostic significance in a cohort of IDH1m iCCAs., Competing Interests: Conflict of interest statement MN: Travel expenses from Celgene and AstraZeneca, speaker honorarium from Accademia della Medicina; honoraria from Sandoz, Medpoint SRL for editorial collaboration. Consultant honoraria from EMD Serono, Basilea Pharmaceutica, Incyte, MSD Italia and Servier. FdB: Honoraria from Roche, Pfizer, BMS, Merck, MSD, SERVIER, Sanofi, Amgen Astellas BioPharma, Incyte. Consulting or Advisory Role for Roche, Incyte, EMD Serono, BMS, Nerviano Medical Sciences, Sanofi, Novartis Italy, Menarini, research funding (institution): Novartis, Roche, Merck Serono, Pfizer, Servier, Philogen, Loxo, Tesaro, Nerviano Medical Sciences, Kymab. Research funding: BMS/Medarex, Merck KGaA, Ignyta, MedImmune, Exelis, Bayer health, Daiichi Sangyo Europe GmbH, Incyte, Basilea Pharmaceutical, Jassen Oncology. TM: (SOBI) Swedish Orpahn Biovitrum AB, Ability Pharmaceuticals SL, Aptitude Health, AstraZeneca, Basilea Pharma, Baxter, BioLineRX Ltd, Celgene, Eisai, Ellipses, Genzyme, Got It Consulting SL, Hirslanden/GITZ, Imedex, Incyte, Ipsen Bioscience, Inc, Janssen, Lilly. Marketing Farmacéutico & Investigación Clínica, S.L, MDS, Medscape, Novocure, Paraxel, PPD Development, Polaris, QED Therapeutics, Roche Farma, Sanofi-Aventis, Servier, Scilink Comunicación Científica SC, Surface Oncology, and Zymeworks., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF