Recent insights emerging from malignant mesothelioma genome sequencing

Our plain-English summary of Recent insights emerging from malignant mesothelioma genome sequencing, by M. Carbone, G. Gaudino, H. Yang (Journal of Thoracic Oncology, 2015).

The study

• Authors: M. Carbone, G. Gaudino, H. Yang
• Journal: Journal of Thoracic Oncology
• Published: 2015;10(3):409-11
• Type of article: Editorial, Comment
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Summary of the article

This editorial discussed two studies that sequenced the genomes of malignant mesothelioma (MM). Lo Iacono et al. used targeted next-generation sequencing of a commercial cancer-gene library on 123 formalin-fixed, paraffin-embedded biopsies from 123 patients, with separate testing of BAP1 and NF2. Guo et al. performed whole exome sequencing on 22 frozen biopsies with matched blood samples, together with copy number analysis. All patients in the first study and 41% in the second had received chemotherapy, which the authors noted may have contributed to some mutations. Both studies found fewer mutations than in other cancers. Guo et al. found 490 mutated genes, 447 (97%) of them mutated in only one biopsy, with an average of 23 mutations per biopsy. The genes most often mutated in both studies were BAP1, NF2 and CDKN2A. Somatic BAP1 mutations were found in 41% and 58% of MMs, and NF2 mutations in about 50%. The authors also described their own integrated genomic approach, which found BAP1 mutation or inactivation in 14 of 22 (63.6%) biopsies. No single method captured all cases, but immunohistochemistry for nuclear BAP1 appeared to. The authors concluded that shared driver mutations were rare and that tumour heterogeneity complicates targeted therapy, but that BAP1 is a frequent and potentially useful therapeutic target.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

In plain English

This was an editorial, not an original study. The authors commented on two other teams' genetic sequencing studies of malignant mesothelioma. One was by Lo Iacono et al., who tested 123 preserved biopsies from 123 patients with a panel of cancer genes. The other was by Guo et al., who did exome sequencing of 22 frozen biopsies from 22 patients. The editorial does not discuss asbestos. In both studies the genes most often mutated were BAP1, NF2 and CDKN2A. BAP1 mutations appeared in 41% of tumors in Guo et al. and 58% in Lo Iacono et al., and NF2 mutations in about 50%. The authors noted that all of Lo Iacono et al.'s patients and 41% of Guo et al.'s had received chemotherapy, which may have contributed to some mutations. They also noted that neither study examined genetic differences within a single tumor. The authors concluded that inactivating mutations occur randomly and are rarely shared between tumors, except BAP1 and, less so, NF2, CDKN2A and possibly CUL1, and that BAP1 may be a treatment target. One author disclosed pending patent applications on BAP1.

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: Editorial commenting on two published genome sequencing studies of malignant mesothelioma (Lo Iacono et al. and Guo et al.)
• Who was studied: No new population. The editorial discussed Lo Iacono et al. (123 formalin-fixed, paraffin-embedded biopsies from 123 malignant mesothelioma patients) and Guo et al. (22 frozen biopsies from 22 patients, with matched blood samples)
• Main results:
  • In Lo Iacono et al., as reported here, variations in the cancer genes studied were found in 25 of 123 (20%) of the biopsies
  • In Guo et al., as reported here, 490 mutated genes were found, of which 447 (97%) were mutated in only one biopsy
  • Guo et al. found an average of 23 mutations per biopsy, with a range of 2 to 51
  • The genes most often mutated in both studies were BAP1, NF2 and CDKN2A
  • Somatic BAP1 mutations were found in 41% of mesotheliomas in Guo et al. and 58% in Lo Iacono et al.
  • In Lo Iacono et al., 52% of 116 mesothelioma biopsies stained for nuclear BAP1 and 48% did not. Nuclear BAP1 staining correlated with the presence or absence of DNA mutations (p = 0.001)
  • Both studies reported NF2 mutations at about 50% frequency. In Lo Iacono et al., 92% of specimens still showed NF2 protein expression
  • The authors wrote that the two studies identified recurrent alterations that may be "actionable," with BAP1 the most common
• The authors' conclusion: The authors concluded that, in these two studies, inactivating mutations occurred randomly and were rarely shared among mesothelioma biopsies. The exceptions were BAP1 and, to a lesser extent, NF2, CDKN2A and possibly CUL1.
• Limitations the authors state:
  • Biopsies in both reviewed studies came from patients previously treated with chemotherapy (100% in Lo Iacono et al., 41% in Guo et al.), which may have contributed to some of the mutations detected
  • The targeted sequencing method used by Lo Iacono et al. could not detect large genetic losses, gene amplifications, translocations or epigenetic changes
  • Neither reviewed study explored genetic differences within a single tumor
  • The authors stated that studies relying on only one molecular method, including these sequencing studies, will underestimate the share of mesotheliomas carrying BAP1 mutations

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Next-Generation Sequencing (NGS), BAP1, Chemotherapy, Biopsy, CDKN2A, Immunohistochemistry, Targeted Therapy.

Related studies

• Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma — G. Guo, J. Chmielecki, et al. (2015)
• Malignant cells from pleural fluids in malignant mesothelioma patients reveal novel mutations — S. Sneddon, I. Dick, et al. (2018)
• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)
• Molecular Analysis of a Patient With Neurofibromatosis 2 (NF2) and Peritoneal Malignant Mesothelioma — C. Glass, L.M. Sholl, et al. (2020)
• BAP1 immunohistochemistry and p16 FISH to separate benign from malignant mesothelial proliferations — B.S. Sheffield, H.C. Hwang, et al. (2015)
• Utility of BAP1 Immunohistochemistry and p16 (CDKN2A) FISH in the Diagnosis of Malignant Mesothelioma in Effusion Cytology Specimens — H.C. Hwang, B.S. Sheffield, et al. (2016)

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