Correlation of MTAP Protein Expression with MTAP and CDKN2A Copy Number in Malignant Pleural Mesothelioma

Histopathology 2021 January 2 [Link]

David B Chapel, Adrian M Dubuc, Jason L Hornick, Lynette M Sholl


Aims: MTAP immunohistochemistry 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 characterized by targeted next-generation sequencing (29), single nucleotide polymorphism microarray (7), or both (4). Copy number status of MTAP and CDKN2A were correlated with MTAP immunohistochemistry. Twenty-seven (68%) tumours showed CDKN2A deletion (14 heterozygous, 13 homozygous), of which 20 (74%) showed MTAP co-deletion (15 heterozygous; 5 homozygous). No tumours showed MTAP deletion without CDKN2A co-deletion. Immunohistochemical loss of MTAP 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 co-deleted 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 immunohistochemistry correlates inconsistently with heterozygous MTAP deletion. Correspondingly, MTAP immunohistochemistry is a highly specific but only moderately sensitive assay for CDKN2A deletion.