<i>MTAP</i> loss in penile squamous cell carcinoma (penSCC): A genomic landscape study.

11 Background: Clinically advanced penSCC is a highly aggressive malignancy with poor prognosis, and thus further exploration of genomic profiling is essential in development of 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, 459 clinically advanced penRCC 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 &gt; 50% = high positive). Results: 30 (6.5%) of clinically advanced penSCC featured whole or partial loss (homozygous deletion) of MTAP gene. Of the 30 penSCC with MTAP loss ( MTAP loss+) there were 21 (70.0%) cases with 8/8 MTAP exons lost, 1 (3.3%) with 5/8 MTAP exons lost, 5 (16.7%) with 4/8 MTAP exons lost, 2 (6.6%) with 3/8 MTAP exons lost and 1 (3.3%) with 2/8 MTAP exons lost. The penSCC with MTAP loss+ group was of similar age (median age 64.5 vs 66 years; p &lt; .0001) vs MTAP wild type ( MTAP loss-) group. Genomic ancestry distributions were similar in both groups with European ancestry more frequent in the MTAP loss- group and African ancestry was more frequent in the MTAP loss+ group. APOBEC signature was more frequent in the MTAP loss+ group. A positive HRD signature was uncommon in both groups. The frequency of HPV detection was slightly higher in the MTAPloss- group (26.7% vs 33.3%; NS). Putative biomarkers of immunotherapy response including MSI High status and TMB &gt; 10mutations were uncommon in both groups. At least 1% PD-L1 expression was also similarly high in both groups (85.7% vs 76.7%; NS). CDKN2A (100% vs 39.2%; p &lt; .0001) and CDKN2B (90.0% vs 2.8%; p &lt; .0001) were co-deleted with MTAP in the MTAP loss+ group (Table). Conclusions: MTAP loss was identified in 6.5% of clinically advanced penSCC cases and was frequently associated with complete loss of all 8 exons (70%) of the MTAP gene. While biomarkers linked to immunotherapy response (MSI, TMB, PD-L1) and HPV positivity were comparable between groups, the genomic landscape of MTAP-loss+ penSCC showed notable distinctions from MTAP-loss– cases. Study limitations include its retrospective design, limited clinical annotation, and potential selection or confounding biases. Multi-tumor trials of PRMT5 and MAT2A inhibitors might consider allowing inclusion of patients with MTAP loss and PenSCC. PenSCC MTAP loss+ (N=30) MTAP loss- (N=429) P value CDKN2A 100.0% 39.2% &lt;.0001 CDKN2B 90.0% 2.8% &lt;.0001 EGFR 6.7% 12.1% NS FGFR1 6.7% 1.6% NS FGFR2 6.7% 0.7% NS NFE2L2 20.0% 5.8% 0.085 NOTCH1 26.7% 16.1% NS PIK3CA 33.3% 23.3% NS TP53 <jats:td c