<i>MTAP</i> loss in primary kidney tumors: A comprehensive genomic profiling study.
Authors: Alexandra Goodman, Devashish Desai, Philippe E. Spiess, Roger Li, Petros Grivas, Ashish M. Kamat, Shilpa Gupta, Neeraj Agarwal, Adam E. Singer, Liang Cheng, Andrea Necchi, Joseph M Jacob, Mehdi Mollapour, Gennady Bratslavsky, Douglas I Lin, Dean Pavlick, Ole Gjoerup, Tamara Jamaspishvili, Jeffrey S. Ross, Alina Basnet
Journal: Journal of Clinical Oncology (2025)

564 Background: Kidney tumors (KT) comprises approximately 4% of all new cancer cases in US per year, with about a third being de-novo metastatic. 5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway &amp; has emerged as a putative biomarker for synthetic lethality-based trials testing Protein Arginine Methyltransferase 5 (PTMT5) &amp; Metastasis-associated protein 2 (MTA2) inhibitors. We compared the genomic landscape in KT with vs without MTAP loss (del). Methods: From 541,919 consecutive cases of clinically advanced cancers, 5,467 consecutive cases of recurrent &amp; metastatic KT underwent hybrid-capture based Comprehensive Genomic Profiling (CGP) to identify all classes of genomic alterations (GA), Microsatellite Instability (MSI) status, &amp; tumor mutation burden (TMB). Programmed Cell Death Ligand 1 (PD-L1) expression was determined by IHC (Dako 22C3). Results were evaluated using the Fisher Exact method. Results: The overall MTAP del frequency in all KT was 10.9%. At 26.3% MTAP del frequency was highest in urothelial carcinoma (uCA) followed by not otherwise specified renal cell carcinoma (nosRCC) (13.3%), collecting duct (cdRCC) (12.5%), sarcomatoid (srcRCC) (11.7%), papillary (papRCC) (7.3%) &amp; clear cell (ccRCC) (4.0%). Chromophobe &amp; medullary RCC were devoid of MTAP del cases. Tendencies for patients with MTAP del KT to be slightly older &amp; more often of male gender were noted. Across uCA &amp; the RCC subtypes, the frequencies of driver GA were higher in MTAP del vs MTAP intact cases (Table). CDKN2A was co-deleted in 99.6% &amp; CDKN2B in 92.8% cases of KT. For ccRCC the Von Hippel-Lindau ( VHL) GA was higher in MTAP intact than MTAP del (76.4% vs 67.0%; p=.029). Biomarkers that may correlate with immune-checkpoint inhibitor efficacy, including MSI-high status (0-4%) &amp; median TMB level (2.5-5 mutations/Mb), as well as PD-L1 low-high expression (29-69%), did not differ significantly by MTAP del status in all KT types. Conclusions: At 11% overall, MTAP del is a relatively common GA in advanced KT including uCA &amp; RCC cases. MTAPdel was more frequent in non-clear cell RCC, collecting duct carcinomas, &amp; sarcomatoid histology, generating hypotheses for targeted therapy clinical trials. Limitations include retrospective nature, lack of clinical data annotation, selection &amp; confounding biases. Further evaluation of KT, including uCA &amp; RCC, for MTAP del-enabled PTMT5 &amp; MTA2 inhibitor trials seem warranted. MTAPdel Top GA in MTAP del Top GA in MTAPi ntact uCA 26.3% FGFR3 34.7%, PIK3CA 20.4%, ERBB2 7.4% FGFR3 25.4%, PIK3CA 19.8%, ERBB2 13.0% nosRCC 13.3% NF2 25.6%, VHL 17.9%, PTEN 12.8% NF2 13.0%, VHL 27.6%, PTEN 5.1% ccRCC 4.0% VHL 67.0%, PBRM1 33.0%, BAP1 23.9% VHL 76.4%, PBRM1 45.9%, BAP1 14.6% papRCC 7.3% ERBB2 8.3%, MET 16.7%, NF2 5.6% ERBB2 1.7%, MET 11.5%, NF2 11.1% srcRCC 11.7% VHL 50.0%, NF2 30.8%, TP53 19.2% VHL 39.8%, NF2 18.9%, TP53 37.8% cdRCC 12.5% NF2 33.3%, SMARCB1 0%, TERT 44.4% NF2 25.4%, SMARCB1 17.5%, TERT 1.8%