TY - JOUR
T1 - Genetic alterations of malignant pleural mesothelioma
T2 - association with tumor heterogeneity and overall survival
AU - Quetel, Lisa
AU - Meiller, Clément
AU - Assié, Jean Baptiste
AU - Blum, Yuna
AU - Imbeaud, Sandrine
AU - Montagne, François
AU - Tranchant, Robin
AU - de Wolf, Julien
AU - Caruso, Stefano
AU - Copin, Marie Christine
AU - Hofman, Véronique
AU - Gibault, Laure
AU - Badoual, Cécile
AU - Pintilie, Ecaterina
AU - Hofman, Paul
AU - Monnet, Isabelle
AU - Scherpereel, Arnaud
AU - Le Pimpec-Barthes, Françoise
AU - Zucman-Rossi, Jessica
AU - Jaurand, Marie Claude
AU - Jean, Didier
N1 - Publisher Copyright:
© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Development of precision medicine for malignant pleural mesothelioma (MPM) requires a deep knowledge of tumor heterogeneity. Histologic and molecular classifications and histo-molecular gradients have been proposed to describe heterogeneity, but a deeper understanding of gene mutations in the context of MPM heterogeneity is required and the associations between mutations and clinical data need to be refined. We characterized genetic alterations on one of the largest MPM series (266 tumor samples), well annotated with histologic, molecular and clinical data of patients. Targeted next-generation sequencing was performed focusing on the major MPM mutated genes and the TERT promoter. Molecular heterogeneity was characterized using predictors allowing classification of each tumor into the previously described molecular subtypes and the determination of the proportion of epithelioid-like and sarcomatoid-like components (E/S.scores). The mutation frequencies are consistent with literature data, but this study emphasized that TERT promoter, not considered by previous large sequencing studies, was the third locus most affected by mutations in MPM. Mutations in TERT promoter, NF2, and LATS2 were more frequent in nonepithelioid MPM and positively associated with the S.score. BAP1, NF2, TERT promoter, TP53, and SETD2 mutations were enriched in some molecular subtypes. NF2 mutation rate was higher in asbestos unexposed patient. TERT promoter, NF2, and TP53 mutations were associated with a poorer overall survival. Our findings lead to a better characterization of MPM heterogeneity by identifying new significant associations between mutational status and histologic and molecular heterogeneity. Strikingly, we highlight the strong association between new mutations and overall survival.
AB - Development of precision medicine for malignant pleural mesothelioma (MPM) requires a deep knowledge of tumor heterogeneity. Histologic and molecular classifications and histo-molecular gradients have been proposed to describe heterogeneity, but a deeper understanding of gene mutations in the context of MPM heterogeneity is required and the associations between mutations and clinical data need to be refined. We characterized genetic alterations on one of the largest MPM series (266 tumor samples), well annotated with histologic, molecular and clinical data of patients. Targeted next-generation sequencing was performed focusing on the major MPM mutated genes and the TERT promoter. Molecular heterogeneity was characterized using predictors allowing classification of each tumor into the previously described molecular subtypes and the determination of the proportion of epithelioid-like and sarcomatoid-like components (E/S.scores). The mutation frequencies are consistent with literature data, but this study emphasized that TERT promoter, not considered by previous large sequencing studies, was the third locus most affected by mutations in MPM. Mutations in TERT promoter, NF2, and LATS2 were more frequent in nonepithelioid MPM and positively associated with the S.score. BAP1, NF2, TERT promoter, TP53, and SETD2 mutations were enriched in some molecular subtypes. NF2 mutation rate was higher in asbestos unexposed patient. TERT promoter, NF2, and TP53 mutations were associated with a poorer overall survival. Our findings lead to a better characterization of MPM heterogeneity by identifying new significant associations between mutational status and histologic and molecular heterogeneity. Strikingly, we highlight the strong association between new mutations and overall survival.
KW - gene mutations
KW - prognosis
KW - thoracic cancer
KW - tumor heterogeneity
KW - tumor molecular classification
UR - http://www.scopus.com/inward/record.url?scp=85081271245&partnerID=8YFLogxK
U2 - 10.1002/1878-0261.12651
DO - 10.1002/1878-0261.12651
M3 - Article
C2 - 32083805
AN - SCOPUS:85081271245
SN - 1574-7891
VL - 14
SP - 1207
EP - 1223
JO - Molecular Oncology
JF - Molecular Oncology
IS - 6
ER -