Genomic Landscape of Malignant Mesotheliomas

Our plain-English summary of Genomic Landscape of Malignant Mesotheliomas, by S. Kato, B.N. Tomson, T.P. Buys, et al (Molecular Cancer Therapeutics, 2016).

The study

• Authors: S. Kato, B.N. Tomson, T.P. Buys, S.K. Elkin, J.L. Carter, R. Kurzrock
• Journal: Molecular Cancer Therapeutics
• Published: 2016;15(10):2498-2507
• Cited by: 73 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Understanding the genomic landscape of malignant mesothelioma may identify novel molecular drivers of this ultra-rare disease, which can lead to an expanded roster of targeted therapies and clinical trial options for patients with mesothelioma. We examined the molecular profiles of 42 patients with malignant mesothelioma (including pleural, peritoneal, and pericardial) that were referred by clinicians to be tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory using next-generation sequencing (NGS; 182 or 236 genes). Among 42 patients, there were 116 alterations, with 92 being distinct. The number of genomic alterations per patient ranged from 1 to 5 (median = 3). No two patients had identical molecular portfolios. The most common aberrations were in BAP1 (BRCA1-associated protein 1; 47.6% [20/42]), NF2 (38.1% [16/42]), and CDKN2A/B (loss) (35.7% [15/42]). BAP1 alterations and CDKN2A/B loss were associated with pleural mesothelioma (OR 3.4, P = 0.059 [BAP1] [trend]; OR 5.8, P = 0.01 [CDKN2A/B]). All 42 patients had a molecular abnormality that was potentially actionable (median = three actionable alterations per patient; range, 1 to 5), and, in 40 patients (95.2%), a drug approved by the FDA was applicable. In conclusion, each individual with malignant mesothelioma harbored a unique set of genomic aberrations, suggesting that NGS-based profiling of patients will be needed if patients are to be optimally matched to cognate treatments. All 42 patients had at least one alteration that was, in theory, pharmacologically tractable. Mol Cancer Ther; 15(10); 2498-507. ©2016 AACR.

©2016 American Association for Cancer Research.

In plain English

This study examined tumor genetic changes in 42 people with malignant mesothelioma. Doctors sent the samples, from December 2011 to November 2013, to a laboratory testing 182 or 236 cancer-related genes. Of these, 23 had pleural, 11 peritoneal and 2 pericardial mesothelioma; 6 were of unknown type. Asbestos exposure histories were not reported for these 42 patients. The data lacked clinical details, so findings could not be linked to outcomes. The tumors carried 116 changes (1 to 5 per patient, median 3); no two patients had the same set. The most often altered genes were BAP1 (20 of 42), NF2 (16 of 42) and CDKN2A/B loss (15 of 42). CDKN2A/B loss was significantly associated with pleural mesothelioma (odds ratio 5.8, p = 0.01). BAP1 showed only a trend toward pleural disease (odds ratio 3.4, p = 0.059). Every patient had at least one theoretically drug-targetable change; 40 (95.2%) had one potentially targetable by a drug FDA-approved for other cancers. The authors concluded that genetic profiling will be needed to match patients to treatments. They cautioned that patient numbers were small.

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 analysis of de-identified tumor gene-sequencing data (next-generation sequencing) from a clinical laboratory database
• Who was studied: 42 patients with malignant mesothelioma whose samples were referred to Foundation Medicine (Cambridge, MA) from December 2011 through November 2013: 23 pleural, 11 peritoneal, 2 pericardial, 6 subtype unknown. Tumor types were as reported by the submitting physicians.
• Exposure: Not studied. Asbestos exposure histories are not reported for the 42 study patients, and the dataset had no clinical details. Asbestos is mentioned only in the introduction, as background from earlier research. The study examined genetic changes in tumors, testing 182 or 236 cancer-related genes.
• Main results:
  • Across the 42 patients, 116 genetic aberrations were found, 92 of them distinct. Patients had 1 to 5 aberrations each (median 3).
  • Most common aberrations among all 42 patients: BAP1 47.6% (20/42), NF2 38.1% (16/42), CDKN2A/B loss 35.7% (15/42), TP53 16.7% (7/42).
  • Among the 23 pleural mesothelioma patients: BAP1 60.9% (14/23), CDKN2A/B loss 52.2% (12/23), NF2 34.8% (8/23), TP53 17.4% (4/23).
  • Among the 11 peritoneal mesothelioma patients: NF2 36.4% (4/11), BAP1 27.3% (3/11).
  • Pleural mesothelioma was significantly associated with CDKN2A/B loss (OR 5.8, p = 0.01). There was only a trend toward association with BAP1 aberration (OR 3.4, p = 0.059), and no association with NF2 aberration (OR 0.73, p = 0.63).
  • Peritoneal mesothelioma was significantly less associated with CDKN2A/B loss (OR 0.12, p = 0.032).
  • All 42 patients had at least one theoretically actionable aberration. In 40 (95.2%) it was potentially targetable by an FDA-approved drug (approved for other cancers). In the other 2 (4.8%) it was potentially targetable only by an investigational drug in a clinical trial. These were theoretical matches; the study did not report giving these drugs.
  • No two of the 42 patients had an identical set of specific genetic aberrations.
• The authors' conclusion: The authors concluded that each patient's tumor had a unique set of genetic aberrations. In their view, this suggests that gene-sequencing-based profiling will be needed to match patients optimally to treatments. They also noted that all 42 patients had at least one alteration that was, in theory, drug-targetable.
• Limitations the authors state:
  • The dataset had no clinical information, so genetic findings could not be correlated with clinical outcomes.
  • Normal tissue was not tested, so inherited (germline) mutations could not be distinguished from those arising in the tumor.
  • Cancer diagnoses came from referring physicians. Histological subtypes (epithelioid, biphasic, sarcomatoid) could not be confirmed, and pathology slides could not be reviewed.
  • The number of patients was small, so the associations found should be viewed with caution and need verification in larger groups.
  • Among chromatin-modifying genes, only SETD2 was evaluated (SETDB1 was not).

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: Malignant Mesothelioma, Clinical Trial, Mesothelioma, Pericardial, Next-Generation Sequencing (NGS), BAP1, CDKN2A, Pleural Mesothelioma.

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