Title :

Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma

Author(s) :

Meiller, Clément [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Montagne, François [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Hirsch, Theo [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Caruso, Stefano [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
De Wolf, Julien [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Bayard, Quentin [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Assié, Jean-Baptiste [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique [CEpiA]
Centre Hospitalier Intercommunal de Créteil [CHIC]
Meunier, Léa [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Blum, Yuna [Auteur]
(le programme) Cartes d'identité des tumeurs [CIT]
Quetel, Lisa [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Gibault, Laure [Auteur]
Hôpital Européen Georges Pompidou [APHP] [HEGP]
Université Paris Cité [UPCité]
Pintilie, Ecaterina [Auteur]
Université de Lille
Hôpital Albert Calmette
Badoual, Cécile [Auteur]
Hôpital Européen Georges Pompidou [APHP] [HEGP]
Université Paris Cité [UPCité]
Humez, Sarah [Auteur]
Université de Lille
Institut de Pathologie [CHU Lille]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Galateau-Sallé, Françoise [Auteur]
Copin, Marie-Christine [Auteur]
Université de Lille
Institut de Pathologie [CHU Lille]
Letouzé, Eric [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Scherpereel, Arnaud [Auteur]
Thérapies Assistées par Lasers et Immunothérapies pour l'Oncologie - U 1189 [OncoThAI]
Zucman-Rossi, Jessica [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Hôpital Européen Georges Pompidou [APHP] [HEGP]
Le Pimpec-Barthes, Françoise [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Hôpital Européen Georges Pompidou [APHP] [HEGP]
Jaurand, Marie-Claude [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Jean, Didier [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]

Journal title :

Genome Medicine

Pages :

113

Publisher :

BioMed Central

Publication date :

2021-12

ISSN :

1756-994X

English keyword(s) :

Clonality
NF2 subclonal mutation
Spatial molecular intra-tumor heterogeneity
Thoracic tumor
Tumor microenvironment

HAL domain(s) :

Sciences du Vivant [q-bio]/Cancer
Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire

English abstract : [en]

Background Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. ...
Show more >Background Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. Methods Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. Results Sequencing analysis identified heterogeneous variants notably in NF2 , a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients. Conclusions This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

Collections :

• Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277
• Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017
• Thérapies Lasers Assistées par l'Image pour l'Oncologie (ONCO-THAI) - U1189

Submission date :

2021-10-30T01:30:52Z