A study of somatic BRCA variants and their putative effect on protein properties in malignant mesothelioma

Our plain-English summary of A study of somatic BRCA variants and their putative effect on protein properties in malignant mesothelioma, by K. Krishnamurthy, K.S. Oh, S. Alghamdi, et al (Pleura and Peritoneum, 2023).

The study

• Authors: K. Krishnamurthy, K.S. Oh, S. Alghamdi, V. Sriganeshan, R. Poppiti
• Journal: Pleura and Peritoneum
• Published: 2023;8(1):19-25
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objectives: The aim of this study is to analyze the prevalence of somatic mutations in BRCA1 and BRCA2 in malignant mesothelioma and their putative impact on protein properties.

Methods: Eighteen cases of malignant mesothelioma were retrieved from the archives and for next generation sequencing analysis of BRCA1 and BRCA2 genes. Variants were analyzed using Ensembl VEP17, Polyphen 2.0 software, SIFT software, MutpredV2, and SWISS-MODEL homology-modeling pipeline server.

Results: BRCA2 variants were found in significantly higher percentage (22%) of cases (p=0.02). Five missense variants were identified. These were p.A2351P, p.T2250A, p.A895V, pG1771D, and p.R2034C. The SIFT scores of all except one were ≥ 0.03. The Polyphen scores of these four alterations were ≤0.899. In case of p.A2315, the SIFT score was 0.01, while the Polyphen 2 score was 0.921. MutPred2 scores were ≤0.180 for all. Loss of intrinsic disorder was predicted (Pr=0.32, p=0.07) for p.R2034C, while gain of intrinsic disorder was predicted for p.A2351P (Pr=0.36, p=0.01) and p.G1771D (Pr=0.34, p=0.02).

Conclusions: BRCA2 somatic variants were identified in 22% cases of malignant mesotheliomas in this study. The variants localize more frequently to the disordered regions of the protein and are predicted to affect the level of disorder.

© 2023 the author(s), published by De Gruyter, Berlin/Boston.

In plain English

This laboratory study looked for changes in the BRCA1 and BRCA2 genes that arise in the tumour itself (somatic changes) in malignant mesothelioma. The authors used archived tumour tissue from 18 patients: 14 men and 4 women, average age 77.6 years. The tumour began in the pleura in 12 patients, the peritoneum in 5 and the pericardium in 1. The tissue was tested by next generation sequencing, and computer programs predicted how each variant might affect the protein. The article does not report the patients' asbestos exposure. A BRCA1 variant was found in one case (5.5%) and was classed as a variant of uncertain significance. BRCA2 variants were found in 4 cases (22%), significantly more often than BRCA1 (p=0.02). There were six BRCA2 variants, made up of five different missense substitutions. Most were predicted to be tolerated or benign. One was predicted to be damaging by two programs. Some were predicted to change the protein's intrinsic disorder. The authors found no statistically significant links with patient or tumour characteristics or with survival. The authors concluded that BRCA2 somatic variants were much more common than BRCA1 variants. They noted that the sample was 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: Laboratory genetic study of archived tumour tissue (next generation sequencing of BRCA1 and BRCA2), with computer-based prediction of the variants' effects on the protein
• Who was studied: 18 cases of malignant mesothelioma from the pathology archives (Mount Sinai Medical Center, Miami Beach, Florida). 14 men and 4 women, mean age 77.6 years. Primary site: pleura 12, peritoneum 5, pericardium 1. Histology: 14 epithelioid, 3 biphasic, 1 sarcomatoid.
• Exposure: No asbestos exposure was assessed or reported. The study examined somatic BRCA1 and BRCA2 gene variants in tumour tissue.
• Main results:
  • A BRCA1 variant (a novel missense variant, p.N1052S) was found in 1 of 18 cases (5.5%) and was classified as a variant of uncertain significance.
  • BRCA2 variants were found in 4 of 18 cases (22%), significantly more often than BRCA1 variants (p=0.02).
  • Six BRCA2 variants were identified, all missense: p.A2351P, p.T2250A, p.A895V, p.G1771D and p.R2034C. Only p.R2034C was seen in two cases.
  • Four BRCA2 substitutions had SIFT and Polyphen scores read as tolerated or benign. For one substitution (labelled p.A2315 in this sentence) the SIFT score was 0.01 and the Polyphen 2 score was 0.921, read as deleterious and probably damaging.
  • MutPred2 scores were 0.180 or lower for all variants. Gain of intrinsic disorder was predicted for p.A2351P (Pr=0.36, p=0.01) and p.G1771D (Pr=0.34, p=0.02). Loss of intrinsic disorder was predicted for p.R2034C (Pr=0.32, p=0.07). The authors treated p less than 0.10 as significant for these predictions.
  • No statistically significant associations were found between the BRCA1 or BRCA2 variants and demographic, histologic or clinicopathologic characteristics.
  • There was no statistically significant difference in survival between the BRCA2 mutant and non-mutant groups. All BRCA mutant patients were alive; two patients in the non-mutant group had died.
• The authors' conclusion: The authors concluded that somatic BRCA2 variants were much more common than BRCA1 variants in this small cohort, and that the BRCA2 variants localized more often to disordered regions of the protein and were predicted to alter the level of disorder.
• Limitations the authors state:
  • The sample was small, which the authors said might explain the lack of statistical significance for the survival finding.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Somatic Mutation.

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