MTAP loss in anal melanoma: A genomic landscape study.

4 Background: Anal melanoma (AM) 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 melanomas. Methods: Using the FoundationOne CDx assay, 211 AM 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: 35 (16.6%) of AM featured whole or partial loss (homozygous deletion) of the MTAP gene. Of the 35 AM with MTAP loss (MTAPloss+), there were 26 cases with 8/8 exons lost, 4 with 7/8 exons lost, 1 with 5/8 exons lost, 2 with 3 exons lost and 2 with 2 exons lost. The AM with MTAPloss+ were slightly younger (median age of 65 vs 68 years) and more often male gender (51.4% vs 39.8%), compared to MTAP wild type type (MTAPloss-), but these differences were not significant. Biomarkers of immunotherapy response including MSI High status (0.0% in both groups) and TMB (median 1.3 vs 2.5 mutations/Mb) were uncommon in both groups. Low level PD-L1 expression was also similar, but more frequent (30.8% vs 34.6%) in both groups. CDKN2A (100.0% vs 28.4%; p<.0001) and CDKN2B (85.3% vs 8.0%; p<.0001) were co-deleted with MTAP in the MTAPloss+ AM. Other GA more frequent in the MTAPloss+ AM groups included NF1 (41.2% vs 27.3%; p=.072), KIT (32.4% vs 27.8%; NS), TP53 (17.6% vs 10.2%; NS) and ATRX (11.8% vs 6.2%; NS). GA more frequent in the MTAPloss- AM included SF3B1 (39.8% vs 23.5%; p=.083), RAD21 (11.4% vs 0.0%), BRAF (13.1% vs 8.8%; NS) and KRAS (8.5% vs 2.9%; NS). Conclusions: MTAPloss+ status occurs in 16.6% of AM and is predominantly associated with loss of all 8 exons (74.2%) or 7 of 8 exons (11.4%) 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+ AM is different from that in MTAPloss- AM with higher frequencies of NF1 and KIT GA and a slightly lower frequency of BRAF GA. Further study of AM in the emerging era of PRMT5 and MAT2A inhibitor clinical development appears warranted. Genomic alterations in anal melanoma. MTAP Loss (35 cases) MTAP Wild Type (176 cases) P value SF3B1 23.5% 39.8% =0.083 CDKN2A 100.0% 28.4% <0.0001 KIT 32.4% 27.8% NS NF1 41.2% 27.3% =0.072 BRAF 8.8% 13.1% NS RAD21 0.0% 11.4% =0.051 CDKN2B 85.3% 8% <0.0001 ATRX 11.8% 6.2% NS PIK3CA 0.0% 5.7% NS