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

Our plain-English summary of Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma, by C. Meiller, F. Montagne, T.Z. Hirsch, et al (Genome Medicine, 2021).

The study

• Authors: C. Meiller, F. Montagne, T.Z. Hirsch, S. Caruso, J. de Wolf, Q. Bayard, J.B. Assié, L. Meunier, Y. Blum, L. Quetel, L. Gibault, E. Pintilie, C. Badoual, S. Humez, F. Galateau-Sallé, M.C. Copin, E. Letouzé, A. Scherpereel, J. Zucman-Rossi, F. Le Pimpec-Barthes, M.C. Jaurand, D. Jean
• Journal: Genome Medicine
• Published: 2021;13(1):113
• Cited by: 63 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

© 2021. The Author(s).

In plain English

This laboratory study looked at how malignant pleural mesothelioma differs between parts of the chest within the same patient. The authors analysed paired tumor samples from 16 patients, diagnosed between 2014 and 2017, who had diagnostic biopsies or surgery at two French hospitals. The samples were taken before chemotherapy from two different sites in the chest. The authors also analysed five cell lines grown from these patients' tumors. Most patients were male (81%), and 62% had a past exposure to asbestos, which the study did not analyse further. Most of the protein-altering mutations detected were shared between the two sites. However, among eight patients with mutations in the NF2 gene, three showed differences between samples. In eight patients, the number of genes expressed differently between the paired samples ranged from 647 to 2119. In three patients, one sample had a 'hot' immune profile (many immune cells) and the other a 'cold' one. The authors concluded that this variation is complex and differs between patients, and that the results support taking samples from several sites. They named the small number of patients and samples as a limitation.

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 molecular study (multi-omics sequencing) of paired tumor samples taken from different sites in the chest of the same patients, plus tumor-derived cell lines
• Who was studied: 16 patients with malignant pleural mesothelioma who had diagnostic biopsies or surgical resections at two French hospitals (CHRU of Lille and Hôpital Européen Georges Pompidou of Paris), diagnosed 2014 to 2017. Patients had not received chemotherapy and were mostly male (81%), with a median age at diagnosis of 74 years. One tumor was biphasic and the rest epithelioid. Five cell lines were derived from these tumors.
• Exposure: Not an exposure study. 62% of patients had a past exposure to asbestos; no fiber types or doses were reported.
• Main results:
  • Most of the protein-altering somatic variants (mutations) were shared between the paired samples from a given patient
  • Among eight patients with NF2 mutations, three showed differences in NF2 mutation between their samples (intra-tumor heterogeneity)
  • In patient T333HP, a subclonal tumor population (cells present in only part of the tumor) was found in both biopsies, which the authors read as suggesting the tumor spread from more than one group of cells
  • No structural (chromosome-level) differences between sites with an evident contribution to cancer development were observed
  • In the eight patients with RNA sequencing, the number of genes expressed differently between paired samples ranged from 647 to 2119
  • Changes greater than 10% in the epithelioid-like and sarcomatoid-like scores (E/S.scores) between paired samples were seen in three patients
  • Of five patients with methylation profiling, two showed many differentially methylated sites between their paired samples (5476 and 19178)
  • In three patients, the immune profile was hot in one sample and cold in the other. Expression of immune checkpoints targeted by immunotherapy (PDL1, CTLA4, PD1) differed by more than twofold between paired samples in some patients.
• The authors' conclusion: The authors concluded that spatial heterogeneity within the tumor is complex in malignant pleural mesothelioma and varies among patients, and that their results support taking multiple samples for molecular-based precision medicine
• Limitations the authors state:
  • Small number of patients and of tumor samples per patient
  • Methylation analysis covered only 5 patients, only two of whom showed consistent changes, so only descriptive conclusions can be drawn
  • The series does not fully reflect the range of mesothelioma tissue types

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, Tumor Microenvironment, Tumor Suppressor Gene, Carcinogenesis.

Related studies

• Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival — L. Quetel, C. Meiller, et al. (2020)
• Yale Cancer Center Precision Medicine Tumor Board: molecular findings alter a diagnosis and treatment plan — J.A. Gibson, K.E. Finberg, et al. (2021)
• Special Issue on Mechanisms of Mesothelioma Heterogeneity: Highlights and Open Questions — E. Felley-Bosco (2018)
• Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity — L. Mangiante, N. Alcala, et al. (2023)
• Gender differences in molecular-guided therapy recommendations for metastatic malignant mesothelioma — H. Taghizadeh, S. Zöchbauer-Müller, et al. (2020)
• Poorly differentiated neoplasms of unknown primary site: diagnostic usefulness of a molecular cancer classifier assay — F.A. Greco, W.J. Lennington, et al. (2015)

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