Significance and Utility of Immunohistochemical MTAP Expression to Predict CDKN2A Genomic Status in Diffuse Large...

Recent genomic studies have delineated genetic subtypes of diffuse large B-cell lymphoma (DLBCL), and CDKN2A deletion has been reported as an adverse prognostic factor across several of these subtypes. Because MTAP, located adjacent to CDKN2A on 9p21, is frequently co-deleted, loss of MTAP protein expression may serve as a surrogate marker for CDKN2A homozygous deletion (HD) in a subset of malignancies. However, large cohort studies linking MTAP immunohistochemistry (IHC) with CDKN2A genomic status by fluorescence in situ hybridization (FISH) and/or next-generation sequencing (NGS) have been lacking. We therefore investigated the diagnostic significance of MTAP and p16 expression by IHC in relation to the genomic status of CDKN2A and MTAP (by FISH and NGS) in 238 DLBCL cases. Loss of MTAP expression was observed in 40 cases, of which 37 (92.5%) also showed concomitant loss of p16 expression. Among these 37 cases, 32 were identified as having CDKN2A HD by combined FISH/NGS analysis, whereas only 22 were detected by FISH alone. These findings indicate that loss of MTAP expression serves as a surrogate marker for CDKN2A HD, and that MTAP IHC is preferable to FISH for screening CDKN2A HD in DLBCL.