Next-generation sequencing analysis of cholangiocarcinoma identifies distinct IDH1-mutated clusters.
Cholangiocarcinoma
Clustering analysis
Genomic profiling
IDH1 mutation
Next-generation sequencing
Journal
European journal of cancer (Oxford, England : 1990)
ISSN: 1879-0852
Titre abrégé: Eur J Cancer
Pays: England
ID NLM: 9005373
Informations de publication
Date de publication:
11 2022
11 2022
Historique:
received:
09
06
2022
revised:
20
08
2022
accepted:
24
08
2022
pubmed:
2
10
2022
medline:
19
10
2022
entrez:
1
10
2022
Statut:
ppublish
Résumé
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. 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. 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. We highlighted three different mutation-based clusters with prognostic significance in a cohort of IDH1m iCCAs.
Sections du résumé
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.
Identifiants
pubmed: 36182816
pii: S0959-8049(22)00519-6
doi: 10.1016/j.ejca.2022.08.026
pii:
doi:
Substances chimiques
Chromatin
0
Isocitrate Dehydrogenase
EC 1.1.1.41
IDH1 protein, human
EC 1.1.1.42.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
299-310Informations de copyright
Copyright © 2022 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
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.