Correlation of methylthioadenosine phosphorylase (MTAP) protein expression with MTAP and CDKN2A copy number in malignant pleural mesothelioma

Our plain-English summary of Correlation of methylthioadenosine phosphorylase (MTAP) protein expression with MTAP and CDKN2A copy number in malignant pleural mesothelioma, by D.B. Chapel, A.M. Dubuc, J.L. Hornick, et al (Histopathology, 2021).

The study

• Authors: D.B. Chapel, A.M. Dubuc, J.L. Hornick, L.M. Sholl
• Journal: Histopathology
• Published: 2021;78(7):1032-1042
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Aims: Methylthioadenosine phosphorylase (MTAP) immunohistochemical expression is a specific marker of CDKN2A deletion in malignant mesothelioma. However, the relationship of MTAP expression with MTAP copy number remains unexplored.

Methods And Results: Forty malignant pleural mesotheliomas were characterised by targeted next-generation sequencing (29), single-nucleotide polymorphism microarray (seven), or both (four). MTAP and CDKN2A copy numbers were correlated with MTAP expression. Twenty-seven (68%) tumours showed CDKN2A deletion (14 heterozygous; 13 homozygous), of which 20 (74%) showed MTAP codeletion (15 heterozygous; five homozygous). No tumours showed MTAP deletion without CDKN2A codeletion. Loss of MTAP expression was seen in 16 (40%) tumours, and was 75% sensitive and 95% specific for MTAP deletion, and 59% sensitive and 100% specific for CDKN2A deletion. Nine of 40 (23%) tumours showed heterogeneous MTAP staining, and the percentage of tumour cells with MTAP loss correlated with molecular detection of MTAP deletion.

Conclusions: MTAP is frequently codeleted with CDKN2A in pleural mesothelioma. However, homozygous deletion of both genes occurs in a minority of tumours (5/40; 13%); CDKN2A deletion often co-occurs with heterozygous MTAP deletion or neutral MTAP copy number; and MTAP expression correlates inconsistently with heterozygous MTAP deletion. Correspondingly, MTAP immunohistochemistry is a highly specific but only moderately sensitive assay for CDKN2A deletion.

© 2021 John Wiley & Sons Ltd.

In plain English

This laboratory study looked at tumour samples from 40 patients with malignant pleural mesothelioma diagnosed between 2013 and 2018 at Brigham and Women's Hospital in Boston. The authors compared a tissue stain for the MTAP protein, which is used to help diagnose mesothelioma, with genetic tests showing whether the MTAP and CDKN2A genes had lost one copy or both. CDKN2A deletion was found in 27 of the 40 tumours, and MTAP was also deleted in 20 of those 27. Both copies of both genes were lost in 5 of 40 tumours. The stain showed MTAP loss in 16 tumours (40%). For MTAP deletion, the stain was 75% sensitive and 95% specific. For CDKN2A deletion, it was 59% sensitive and 100% specific. In other words, it missed many deletions but did not flag any tumour without a CDKN2A deletion. The authors concluded that stain loss is a specific stand-in for CDKN2A deletion, but its link to single-copy MTAP loss needs more study. They noted the small cohort, and that some tests were done on different tissue samples. The study did not examine asbestos exposure.

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 (pathology) study comparing MTAP immunohistochemistry with genetic copy-number testing (next-generation sequencing and/or SNP microarray) on previously diagnosed tumours
• Who was studied: 40 malignant pleural mesotheliomas from 40 patients diagnosed at Brigham and Women's Hospital, Boston, 2013 to 2018, chosen from 57 with genetic data. 33 patients were male, mean age 70 (range 30 to 81). There were 28 epithelioid, 10 biphasic and 2 sarcomatoid tumours.
• Exposure: Not studied. The article examines tumour tissue and genes; it does not assess asbestos or any other exposure.
• Main results:
  • Of 40 tumours, 20 (50%) had no MTAP copy-number change, 15 (38%) had heterozygous (single-copy) MTAP deletion and 5 (13%) had homozygous (two-copy) MTAP deletion
  • Among 27 tumours with CDKN2A deletion, MTAP was also deleted in 20 (74%)
  • Homozygous deletion of both CDKN2A and MTAP occurred in 5 (13%) of 40 tumours
  • Cytoplasmic MTAP staining was lost in 16 (40%) of 40 tumours and retained in 24 (60%)
  • Across all 40 tumours, loss of cytoplasmic MTAP staining was 75% sensitive and 95% specific for MTAP deletion
  • Across all 40 tumours, loss of cytoplasmic MTAP staining was 59% sensitive and 100% specific for CDKN2A deletion
  • 11 (46%) of the 24 tumours with retained MTAP staining had a CDKN2A deletion
  • MTAP staining was lost in 10 of 15 tumours with heterozygous MTAP deletion
  • 9 (23%) of 40 tumours showed MTAP loss in only some tumour cells. Six of these were tested on the same specimen. The three with loss in the highest share of cells (10%, 30% and 80%) had heterozygous MTAP deletion, while the three with the lowest share (1%, 5% and 5%) showed no MTAP copy-number change.
  • Faint versus strong MTAP staining was not significantly related to MTAP or CDKN2A copy number (P = 0.12 and P = 0.30); the authors note the small number of faint cases limits statistical power
• The authors' conclusion: The authors concluded that MTAP and CDKN2A are frequently deleted together in pleural mesothelioma, and that loss of cytoplasmic MTAP staining is a specific diagnostic stand-in for CDKN2A deletion. They found its sensitivity (59%) lower than in earlier studies, and said the relationship between MTAP staining and single-copy MTAP deletion needs further investigation.
• Limitations the authors state:
  • Staining and genetic tests were done on different surgical specimens in 9 of 40 tumours and on different tissue blocks in 29, which may limit direct comparison
  • The small cohort limits analysis of unusual deletion patterns
  • Only genetic changes were examined; the role of epigenetic changes was not studied
  • Only one tissue block per case was stained, so how often and where patchy MTAP staining occurs remains unclear

Topics

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

Medical terms in this study, explained in our Lexicon: MTAP, CDKN2A, Pleural Mesothelioma, Malignant Mesothelioma, Next-Generation Sequencing (NGS), Homozygous Deletion, Immunohistochemistry.

Related studies

• CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival — A.M. Krasinskas, D.L. Bartlett, et al. (2010)
• Usefulness of methylthioadenosine phosphorylase and BRCA-associated protein 1 immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens — K.B. Berg, A.M. Churg, et al. (2020)
• MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma — D.B. Chapel, J.J. Schulte, et al. (2020)
• Utility of Methylthioadenosine Phosphorylase Compared With BAP1 Immunohistochemistry, and CDKN2A and NF2 Fluorescence In Situ Hybridization in Separating Reactive Mesothelial Proliferations From Epithelioid Malignant Mesotheliomas — K.B. Berg, S. Dacic, et al. (2018)
• CDKN2A copy number and p16 expression in malignant pleural mesothelioma in relation to asbestos exposure — E. Kettunen, S. Savukoski, et al. (2019)
• Malignant mesothelioma in situ diagnosed by methylthioadenosine phosphorylase loss and homozygous deletion of CDKN2A: a case report — K. Minami, N. Jimbo, et al. (2020)

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