Mutational Profiling of Driver Tumor Suppressor and Oncogenic Genes in Brazilian Malignant Pleural Mesotheliomas

Our plain-English summary of Mutational Profiling of Driver Tumor Suppressor and Oncogenic Genes in Brazilian Malignant Pleural Mesotheliomas, by N.C. Campanella, E.C. Silva, G. Dix, et al (Pathobiology, 2020).

The study

• Authors: N.C. Campanella, E.C. Silva, G. Dix, F. de Lima Vazquez, F. Escremim de Paula, G.N. Berardinelli, M. Balancin, R. Chammas, R.V. Mendoza Lopez, H.C.S. Silveira, V.L. Capelozzi, R.M. Reis
• Journal: Pathobiology
• Published: 2020;87(3):208-216
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma (MPM) is a highly lethal disease comprising a heterogeneous group of tumors with challenging to predict biological behavior. The diagnosis is complex, and the histologic classification includes 2 major subtypes of MPM: epithelioid (∼60% of cases) and sarcomatous (∼20%). Its identification depends upon pathological investigation supported by clinical and radiological evidence and more recently ancillary molecular testing. Treatment options are currently limited, with no known targeted therapies available.

Objectives: To elucidate the mutation profile of driver tumor suppressor and oncogenic genes in a cohort of Brazilian patients.

Methods: We sequenced 16 driver genes in a series of 43 Brazilian malignant mesothelioma (MM) patients from 3 distinct Brazilian centers. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue blocks, and the TERT promoter region was amplified by PCR followed by direct capillary sequencing. The Illumina TruSight Tumor 15 was used to evaluate 250 amplicons from 15 genes associated with solid tumors (AKT1, GNA11, NRAS, BRAF, GNAQ, PDGFRA, EGFR, KIT, PIK3CA, ERBB2, KRAS, RET, FOXL2, MET,and TP53). Library preparation with the TruSight Tumor 15 was performed before sequencing at the MiSeq platform. Data analysis was performed using Sophia DDM software.

Results: Out of 43 MPM patients, 38 (88.4%) were epithelioid subtype and 5 (11.6%) were sarcomatoid histotype. Asbestos exposure was present in 15 (39.5%) patients with epithelioid MPM and 3 (60%) patients with sarcomatoid MPM. We found a TERT promoter mutation in 11.6% of MM, and the c.-146C>T mutation was the most common event. The next-generation sequencing was successful in 33 cases. A total of 18 samples showed at least 1 pathogenic, with a median of 1.8 variants, ranging from 1 to 6. The most mutated genes were TP53 and ERBB2 with 7 variants each, followed by NRAS BRAF, PI3KCA, EGFR and PDGFRA with 2 variants each. KIT, AKT1, and FOXL2 genes exhibited 1 variant each. Interestingly, 2 variants observed in the PDGFRA gene are classic imatinib-sensitive therapy.

Conclusions: We concluded that Brazilian MPM harbor mutation in classic tumor suppressor and oncogenic genes, which might help in the guidance of personalized treatment of MPM.

© 2020 S. Karger AG, Basel.

In plain English

This laboratory study looked for gene changes (mutations) in stored tumor tissue from 43 Brazilian patients diagnosed with malignant pleural mesothelioma between 2008 and 2018 at three Brazilian centers. Of these, 38 had the epithelioid type and 5 the sarcomatoid type. Asbestos exposure was recorded for 15 (39.5%) epithelioid and 3 (60%) sarcomatoid patients. The article does not name fiber types. The TERT gene's promoter region was tested in all 43 samples, and mutations were found in 5 (11.6%). Testing of 15 other cancer-related genes worked in only 33 samples because of DNA quality problems. Of these, 18 (54.5%) had at least one variant. TP53 variants were found in 7 of 33 cases (21.2%) and ERBB2 variants in 6 of 33 (18.2%). Two PDGFRA variants had previously been described as targets of imatinib, a drug approved for gastrointestinal stromal tumor (GIST) patients. The authors stated they could not relate asbestos exposure history to the mutation findings. They concluded that clinically actionable alterations were found in 2 cases and suggested these patients could benefit from such therapy.

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: Retrospective laboratory study of genetic mutations in archived tumor samples (Sanger sequencing of the TERT promoter plus targeted next-generation sequencing of 15 genes)
• Who was studied: 43 patients diagnosed with malignant pleural mesothelioma between 2008 and 2018 at Barretos Cancer Hospital, the Cancer Institute of São Paulo (ICESP), and a large reference pathology laboratory in São Paulo, Brazil. 38 had epithelioid and 5 had sarcomatoid tumors, and all were pleural.
• Exposure: The study did not measure an exposure. Asbestos exposure was recorded as yes or no for 15 (39.5%) epithelioid and 3 (60%) sarcomatoid patients. No fiber types, products, jobs or doses are given, and the method of determining exposure is not described.
• Main results:
  • TERT promoter mutations were found in 5 of 43 tumors (11.6%): c.-146C>T in 3 cases and c.-124C>T in 2 cases. All TERT-mutated cases were epithelioid.
  • Targeted next-generation sequencing succeeded in only 33 samples because of DNA quality issues.
  • Of the 33 sequenced samples, 18 (54.5%) showed at least 1 variant. The number of variants per sample ranged from 1 to 6, with a median printed as 1.8.
  • TP53 had 7 different variants in 7 of 33 cases (21.2%). ERBB2 had 7 different variants in 6 of 33 cases (18.2%).
  • In total 27 different variants were identified. According to the Sophia DDM software reports, 21 were classed as potentially pathogenic and 6 as most likely pathogenic.
  • Two PDGFRA variants found in the mesothelioma samples had already been described as targets of imatinib, an FDA-approved targeted therapy for GIST patients.
• The authors' conclusion: The authors concluded that the most altered genes in this Brazilian series were TP53, ERBB2 and TERT. They found clinically actionable alterations in 2 cases, which they suggested means these patients could benefit from that type of treatment.
• Limitations the authors state:
  • The authors could not correlate patients' asbestos exposure history with the clinical, pathological and mutation findings.
  • The authors did not evaluate the BAP1, SETD2 and NF2 genes.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Epithelioid, Molecular Profiling, Malignant Mesothelioma, Paraffin Block, EGFR, Sarcomatoid, Asbestos Exposure.

Related studies

• Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling — G.J. Gordon, G.N. Rockwell, et al. (2005)
• Oncogenes and tumor-suppressor genes in mesothelioma--a synopsis — J.F. Lechner, J. Tesfaigzi, et al. (1997)
• Similar tumor suppressor gene alteration profiles in asbestos-induced murine and human mesothelioma — C. Lecomte, P. Andujar, et al. (2005)
• LATS2 is a tumor suppressor gene of malignant mesothelioma — H. Murakami, T. Mizuno, et al. (2011)
• Asbestos, chromosomal deletions, and tumor suppressor gene alterations in human malignant mesothelioma — S.S. Murthy, J.R. Testa (1999)
• Recurring loss involving chromosomes 1, 3, and 22 in malignant mesothelioma: possible sites of tumor suppressor genes — W.L. Flejter, F.P. Li, et al. (1989)

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