Molecular characterization of diffuse malignant peritoneal mesothelioma

Our plain-English summary of Molecular characterization of diffuse malignant peritoneal mesothelioma, by Y.P. Hung, F. Dong, M. Torre, et al (Modern Pathology, 2020).

The study

• Authors: Y.P. Hung, F. Dong, M. Torre, C.P. Crum, R. Bueno, L.R. Chirieac
• Journal: Modern Pathology
• Published: 2020;33(11):2269-2279
• Cited by: 48 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant peritoneal mesothelioma is a rare aggressive tumor that arises from the peritoneal lining. While recurrent BAP1 mutations have been identified in a subset of mesotheliomas, molecular characteristics of peritoneal mesotheliomas, including those lacking BAP1 alterations, remain poorly understood. Using targeted next-generation sequencing, we examined the molecular features of 26 diffuse malignant peritoneal mesotheliomas. As part of an exploratory analysis, we analyzed an additional localized peritoneal mesothelioma and one well-differentiated papillary mesothelioma with invasive foci. Genomic characterization identified categories of diffuse malignant peritoneal mesotheliomas: The first group included 18 (69%) tumors with recurrent BAP1 alterations, with eight (31%) having more than one BAP1 alterations, and concomitant alterations in PBRM1 (46%) and SETD2 (35%). All tumors with complete loss of BAP1 expression by immunohistochemistry harbored BAP1 molecular alterations. PBRM1 alterations were significantly enriched in the BAP1-altered cohort. Frequent copy number loss of BAP1, ARID1B, PRDM1, PBRM1, SETD2, NF2, and CDKN2A was noted. The second group included eight (31%) BAP1-wild-type tumors: two with TP53 mutations, one with a TRAF7 activating mutation, one with a SUZ12 inactivating mutation, and three with ALK rearrangements that we previously published. One TP53-mutant biphasic mesothelioma showed evidence of genomic near-haploidization showing loss of heterozygosity of all chromosomes except 5, 7, 16, and 20. The localized peritoneal mesothelioma harbored a nonsense CHEK2 mutation, and the well-differentiated papillary mesothelioma with invasive foci harbored no reportable variants. In conclusion, we described the genetic categories of diffuse malignant peritoneal mesotheliomas, with BAP1-mutant and BAP1-wild-type groups. Our findings implicated DNA repair, epigenetics, and cell cycle regulation in the pathogenesis of peritoneal mesotheliomas, with identification of potential therapeutic targets.

In plain English

This study, from Brigham and Women's Hospital in Boston, used targeted gene sequencing of tumor tissue to describe the genetic changes in 26 diffuse malignant peritoneal mesotheliomas (cancers of the abdominal lining). Nine of these tumors had been published before. The patients were 16 women and 10 men, with a median age of 61. A history of asbestos exposure was documented in 8 patients (31%), and pleural plaques were seen on imaging in 12 (46%). Changes in the BAP1 gene were found in 18 of the 26 tumors (69%). All tumors that had completely lost BAP1 protein on staining carried BAP1 gene changes. BAP1 changes were associated with older age and worse overall survival. They showed no significant association with pleural plaques or asbestos exposure. Among the eight tumors without BAP1 changes, findings included TP53, TRAF7 and SUZ12 mutations and ALK rearrangements. One tumor showed evidence of genomic near-haploidization, seen as widespread loss of heterozygosity. The authors concluded that these tumors carry recurrent changes in BAP1 and other DNA repair, chromatin and cell-cycle genes. They noted small numbers and that inherited (germline) BAP1 status was not available.

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: Single-institution laboratory study (case series) using targeted next-generation sequencing of stored tumor tissue, plus immunohistochemistry and review of medical records
• Who was studied: 26 diffuse malignant peritoneal mesotheliomas (23 epithelioid, 3 biphasic) from the surgical pathology and consultation files of Brigham and Women's Hospital, Boston, MA. Patients were 16 women and 10 men, median age 61 years (range 17 to 81). For exploratory analysis, the study also included one localized peritoneal mesothelioma and one well-differentiated papillary mesothelioma with invasive foci.
• Exposure: Not an exposure study. Asbestos exposure and pleural plaques were taken from medical and radiologic records. A history of asbestos exposure was documented in 8 of 26 patients (31%). No fiber types or doses were reported. Two patients had prior therapeutic radiation to the abdomen.
• Main results:
  • BAP1 gene alterations were found in 18 of 26 diffuse malignant peritoneal mesotheliomas (69%). Eight tumors (31%) had more than one BAP1 alteration.
  • Immunohistochemistry showed complete loss of BAP1 protein in 13 tumors (50%). All tumors with complete loss carried BAP1 molecular alterations; the association had p = 0.001.
  • In patients with diffuse malignant peritoneal mesothelioma, the presence of BAP1 genomic alterations was associated with older age at diagnosis and worse overall survival. Details are in supplementary tables not included in the text.
  • No significant associations were observed between BAP1 molecular alterations and the presence of pleural plaques or asbestos exposure, or prior radiation.
  • Pleural plaques were seen radiographically in 12 patients (46%). Four of them later developed diffuse malignant pleural mesothelioma.
  • PBRM1 alterations were significantly more common in BAP1-altered tumors (p = 0.001). This association did not reach significance among epithelioid tumors only.
  • Single-nucleotide variants and/or copy number loss were found in PBRM1 in 12 tumors (52%), SETD2 in 9 (35%), NF2 in 5 (19%), TP53 in 4 (15%), and TSC1 in 3 (12%).
  • Among the eight BAP1-wild-type tumors, one epithelioid tumor had a TRAF7 activating mutation and one had a SUZ12 mutation. Two had TP53 mutations, and three had ALK rearrangements previously reported.
  • One TP53-mutant biphasic tumor showed evidence of genomic near-haploidization, with extensive loss of heterozygosity except chromosomes 5 and 20 and parts of chromosomes 7 and 16.
  • Among 24 patients with known follow-up (0.3 to 12.7 years, median 3.0), median overall survival was 4.1 years.
  • Median overall survival was 1.7 years for the three patients with biphasic mesothelioma, versus 5.9 years for those with epithelioid mesothelioma. The difference was not statistically significant (p = 0.26).
  • The single localized peritoneal mesothelioma carried a CHEK2 nonsense mutation.
  • The single well-differentiated papillary mesothelioma with invasive foci had one-copy loss of PRDM1 and low-copy gains of WT1 and TNFAIP3, but no reportable single-nucleotide variants.
• The authors' conclusion: The authors concluded that diffuse malignant peritoneal mesotheliomas carry recurrent alterations in BAP1 and other DNA repair, chromatin and cell cycle regulator genes, with one tumor showing genomic near-haploidization. They said this genetic diversity has implications for diagnosis and for selecting potential therapeutic targets.
• Limitations the authors state:
  • Too few biphasic tumors were examined for a definitive comparison with epithelioid tumors.
  • The localized and well-differentiated papillary tumors were single cases in an exploratory analysis. Definitive conclusions require larger cohorts.
  • Germline (inherited) BAP1 mutation status was not available.
  • The assay analyzed tumor samples only, so the authors could not determine whether some alterations were germline.
  • Because of the small number of cases, the authors could not address whether some alterations were mutually exclusive of BAP1 alterations.

Topics

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

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, BAP1, Mesothelioma, Next-Generation Sequencing (NGS), Well-Differentiated Papillary Mesothelioma, Immunohistochemistry, CDKN2A, Biphasic Mesothelioma.

Related studies

• Integrative Molecular Characterization of Malignant Pleural Mesothelioma — J. Hmeljak, F. Sanchez-Vega, et al. (2018)
• Molecular characterization of localized pleural mesothelioma — Y.P. Hung, F. Dong, et al. (2020)
• Molecular Analysis of a Patient With Neurofibromatosis 2 (NF2) and Peritoneal Malignant Mesothelioma — C. Glass, L.M. Sholl, et al. (2020)
• The value of BRCA-1-associated protein 1 expression and cyclin-dependent kinase inhibitor 2A deletion to distinguish peritoneal malignant mesothelioma from peritoneal location of carcinoma in effusion cytology specimens — W. Althakfi, S. Gazzo, et al. (2020)
• Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X — N.M. Joseph, Y.Y. Chen, et al. (2017)
• A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma — J. Lai, Z. Zhou, et al. (2016)

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