MTAP loss in sarcomatoid renal cell carcinoma (srcRCC): A genomic landscape study

srcRCC is a rare, highly aggressive malignancy with poor prognosis, and thus further exploration of genomic profiling is essential in development of the targeted therapies. Recent evidence has emerged that novel anti-cancer treatments focused on synthetic lethality mechanisms may have efficacy in patients with clinically advanced malignancies. Methods: Using the FoundationOne CDx assay, 140 srcRCC underwent hybrid capture based comprehensive genomic profiling (CGP) to identify all classes of genomic alterations (GA). Microsatellite instability status (MSI) and tumor mutation burden (TMB) were determined from the sequencing data. PD-L1 expression was determined by immunohistochemistry (IHC) using the Dako TPS score (0% = negative; 1-49% = low positive and > 50% = high positive). Results: 36 (25.7%) of srcRCC featured whole or partial loss (homozygous deletion) of the MTAP gene. Of the 36 srcRCC with MTAP loss (MTAPloss+) there were 24 (66.7%) cases with 8/8 MTAP exons lost, 1 (2.8%) with 7/8 MTAP exons lost, 1 (2.8%) 6/8 MTAP exons lost, 5 (13.9%) with 4/8 MTAP exons lost and 5 (13.9%) with 3/8 MTAP exons lost. The srcRCC with MTAPloss+ were younger (median age of 60 vs 63 years; p < .0001) and more often male gender (75.0% vs 72.1%; NS), compared to MTAP wild type (MTAPloss-). Biomarkers of immunotherapy response in MTAPloss+ vs MTAPloss- srcRCC including MSI High status (2.8% vs 1.0%) and TMB 10-20 mutations/Mb (2.8% vs 3.8%; NS) were uncommon in both groups. At least 1% or higher PD-L1 expression was also similarly high in both groups (75.0) vs 71.4%; NS) in both groups. CDKN2A (100.0% vs 28.4%; p < .0001) and CDKN2B (97.2% vs 23.1%; p < .0001) were co-deleted with MTAP in the MTAPloss+ srcRCC. Other GA more frequent in the MTAPloss+ AM groups included NF2(38.9% vs 20.2%; NS) and TERT (30.6% vs 18.3%; NS). GA more frequent in the MTAPloss- srcRCC included RB1 (13.5% vs 0.0%; NS), and TP53 (16.7% vs 40.4%; NS). GA in the VHL gene were similar in both groups (44.4% vs 41.3%; NS). Conclusions: MTAP loss+ status occurs in 25.7% of srcRCC and is most often associated with loss of all 8 exons (66.7%) of the MTAP gene. Although the biomarkers associated with immunotherapy response (MSI, TMB, PD-L1) are similar in both groups, the genomic landscape of MTAPloss+ srcRCC is different from that in MTAPloss- srcRCC. Further study of MTAPloss+ srcRCC in the emerging era of PRMT5 and MAT2A inhibitor-based clinical development appears warranted.[Table presented]