Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival

Our plain-English summary of Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival, by L. Quetel, C. Meiller, J.B. Assié, et al (Molecular Oncology, 2020).

The study

• Authors: L. Quetel, C. Meiller, J.B. Assié, Y. Blum, S. Imbeaud, F. Montagne, R. Tranchant, J. de Wolf, S. Caruso, M.C. Copin, V. Hofman, L. Gibault, C. Badoual, E. Pintilie, P. Hofman, I. Monnet, A. Scherpereel, F. Le Pimpec-Barthes, J. Zucman-Rossi, M.C. Jaurand, D. Jean
• Journal: Molecular Oncology
• Published: 2020;14(6):1207-1223
• Cited by: 92 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

In plain English

This laboratory study examined tumor genetics in malignant pleural mesothelioma. The authors sequenced 21 genes and the TERT promoter in frozen tumors from 266 patients diagnosed from 2001 to 2017, held in French hospital biobanks. Exposure status was recorded as exposed for 186 patients and nonexposed for 45. Damaging mutations were found in 52.3% (139/266) of tumors, or 57.5% (153/266) when TERT promoter mutations were counted. The most often mutated were BAP1 (24.5%), NF2 (19.2%) and the TERT promoter (12.0%). TERT promoter, NF2 and LATS2 mutations were less frequent in epithelioid tumors than in biphasic and sarcomatoid tumors taken together, with desmoplastic tumors counted as sarcomatoid. NF2 mutations were more frequent in nonexposed patients (31%) than in exposed patients (17%), P = 0.036. Patients whose tumors had TERT promoter, TP53 or NF2 mutations had lower overall survival. In multivariate analysis, TP53 alone, and the three genes considered together, predicted prognosis. The authors wrote that this supports NF2 as a key driver of mesothelioma arising without asbestos, as mouse studies had suggested. They noted that large deletions went undetected, so some mutation counts were likely underestimated.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory genetic study of tumor samples using targeted next-generation sequencing, with comparison to histologic type, molecular subtype, clinical and epidemiologic data and overall survival
• Who was studied: Frozen malignant pleural mesothelioma tumor samples (biopsies or surgical resections) from 266 patients, drawn from biobanks of French hospitals in Lille, Nice, Paris and Créteil. Patients were diagnosed between 2001 and 2017. 203 were male and 63 female. 201 tumors were epithelioid.
• Exposure: Asbestos exposure status (exposed vs nonexposed) taken from pathology reports. 186 patients (81%) were exposed and 45 (19%) nonexposed. No fiber types or doses are given. The main variables studied were tumor gene mutations.
• Main results:
  • Damaging mutations were found in 52.3% (139/266) of tumors, and in 57.5% (153/266) when TERT promoter mutations were included.
  • The most frequently mutated were BAP1 (24.5%), NF2 (19.2%) and the TERT promoter (12.0%).
  • TERT promoter, NF2 and LATS2 mutations were significantly less frequent in epithelioid tumors (n = 201) than in biphasic (n = 30) and sarcomatoid tumors (n = 26) taken together. Figure 2 classed desmoplastic tumors with sarcomatoid. The two lymphohistiocytoid tumors were not among these groups.
  • NF2 mutations were significantly associated with asbestos exposure status (P = 0.036). They were more frequent in nonexposed patients (31%) than in exposed patients (17%).
  • LATS2 mutations were more frequent in nonexposed patients (7%) than in exposed patients (2%). No statistical test is reported for this comparison.
  • No significant association was found between mutation profile and age, gender or tobacco consumption.
  • Mutations were more frequent in patients with stage IV tumors than in those with stage I to III tumors: TERT promoter 20% vs 9%, and NF2 28% vs 13%.
  • Overall survival was lower in patients whose tumors had TERT promoter, TP53 or NF2 mutations than in patients without these mutations.
  • In multivariate analysis, mutation status in a single gene predicted prognosis only for TP53, not for the TERT promoter or NF2. Having at least one mutation in any of the three genes showed strong prognostic value.
  • In 12 pairs of samples taken from the same patient at different times, mutation status did not differ between the two samples.
• The authors' conclusion: The authors wrote that the high frequency of NF2 mutations in nonexposed patients supports NF2 as a key driver of asbestos-independent mesothelioma development, as earlier mouse models had suggested. They also wrote that the genetic alterations have strong prognostic value.
• Limitations the authors state:
  • Targeted sequencing could not accurately detect large exon deletions. The authors stated that CDKN2A, BAP1 and NF2 alteration frequencies are therefore most likely underestimated.
  • Some mutations may be inherited (germline) rather than acquired in the tumor, especially in BAP1.
  • The finding that mutation profiles stayed stable over time came from a small number of sample pairs and needs confirmation in larger series.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Overall Survival, Next-Generation Sequencing (NGS), Epithelioid, Sarcomatoid, BAP1.

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• Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma — S. Hiltbrunner, L. Mannarino, et al. (2021)
• Similar tumor suppressor gene alteration profiles in asbestos-induced murine and human mesothelioma — C. Lecomte, P. Andujar, et al. (2005)

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