Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma

Our plain-English summary of Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma, by G. Guo, J. Chmielecki, C. Goparaju, et al (Cancer Research, 2015).

The study

• Authors: G. Guo, J. Chmielecki, C. Goparaju, A. Heguy, I. Dolgalev, M. Carbone, S. Seepo, M. Meyerson, H.I. Pass
• Journal: Cancer Research
• Published: 2015;75(2):264-9
• Cited by: 261 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm associated with asbestos exposure. Although previous studies based on candidate gene approaches have identified important common somatic mutations in MPM, these studies have focused on small sets of genes and have provided a limited view of the genetic alterations underlying this disease. Here, we performed whole-exome sequencing on DNA from 22 MPMs and matched blood samples, and identified 517 somatic mutations across 490 mutated genes. Integrative analysis of mutations and somatic copy-number alterations revealed frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1. Our study presents the first unbiased view of the genomic basis of MPM.

©2014 American Association for Cancer Research.

In plain English

This laboratory study read the protein-coding DNA (the 'exome') of tumors from 22 people diagnosed with malignant pleural mesothelioma at the New York University General Thoracic Surgery Service. Each tumor was compared with the same person's blood. The article does not report the patients' asbestos exposure. The authors found 517 tumor-specific (somatic) mutations, a mean of 23 per tumor. The gene BAP1 was mutated in 8 of 22 tumors (36%), and one patient also had a germline BAP1 mutation, meaning it was present in the patient's normal DNA and not only in the tumor. NF2 had truncating mutations in three tumors (14%). CUL1, a gene in which mutations had not previously been reported in this cancer, was mutated in two tumors. A deletion in a chromosome region containing CDKN2A was found in 10 tumors (45%). Three other genes were each mutated in two tumors, but no mutations in them were found when 10 more tumors were checked. The authors concluded that BAP1, NF2 and CDKN2A were the three most frequently altered genes. They named the small number of tumors studied 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 genetic study: whole-exome sequencing of tumor DNA compared with matched blood DNA from the same patients, with a follow-up check of three genes in additional samples
• Who was studied: 22 malignant pleural mesothelioma tumors and matched blood samples from patients diagnosed at the New York University General Thoracic Surgery Service. By tissue type: 18 epithelial, 3 biphasic, 1 desmoplastic. A further 10 tumor-normal pairs and 9 mesothelioma cell lines were used to check three genes. Collection dates are not given.
• Exposure: Not reported. The article gives no information on the patients' asbestos or other exposures; it studied genetic changes in the tumors.
• Main results:
  • Across the 22 tumors, 517 somatic mutations were identified.
  • Tumors had a mean of 23 somatic mutations each (range 2 to 51), an average of 0.79 mutations per megabase.
  • BAP1 had protein-altering mutations in 8 of 22 tumors (36%), the most of any gene.
  • Counting both mutations and copy-number changes, nine tumors (41%) had alterations in BAP1.
  • One case (NYU754) also had a germline splice-site mutation in BAP1. Germline means it was present in the patient's normal DNA. The article does not say whether it was passed on from a parent.
  • NF2 was inactivated by truncating mutations in three cases (14%).
  • CUL1, a gene in which mutations had not previously been reported in pleural mesothelioma, was mutated in two tumors.
  • The most common focal deletion was at chromosome region 9p21, which contains CDKN2A and CDKN2B. It was found in 10 tumors (45%). No point mutations or small insertions or deletions were found in CDKN2A itself.
  • The cell cycle pathway was the most frequently altered pathway, in 12 of the tumors (55%).
  • Three genes newly found mutated in two tumors each (RDX, PIK3C2B and TAOK1) were checked in 10 additional tumors. No somatic mutations in them were found.
• The authors' conclusion: The authors concluded that BAP1, NF2 and CDKN2A, genes already known to be altered in pleural mesothelioma, were the three most frequently altered genes in their study. They described the study as the first unbiased view of somatic mutations in this cancer.
• Limitations the authors state:
  • Only a small number of tumors were analyzed. Larger groups are needed to describe the genetic landscape and to estimate more precisely how often these genes are mutated.
  • Further functional studies are needed to define the role of newly found mutated genes such as CUL1.
  • Three tumors had very few mutations. The authors could not tell whether this reflected low tumor content in the sample or a real feature of those tumors.

Topics

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

Medical terms in this study, explained in our Lexicon: BAP1, CDKN2A, Pleural Mesothelioma, Neoplasm, Asbestos Exposure, Somatic Mutation.

Related studies

• Recent insights emerging from malignant mesothelioma genome sequencing — M. Carbone, G. Gaudino, 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)
• Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas — H.C. Kang, H.K. Kim, et al. (2016)
• 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)
• The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma — A.D. Singhi, A.M. Krasinskas, et al. (2016)

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