Abstract Introduction: MCC is a rare and highly aggressive cutaneous neuroendocrine carcinoma with increasing incidence over the last few decades. Cytotoxic chemotherapy and checkpoint inhibitors have provided modest treatment options, however, there are no approved or standard of care targeted treatment options. Here we surveyed the presence of targetable alterations in the AACR Project Genie Database Methods: Individual patient data were accessed from the cBioPortal. Variables of interest include demographic data, alterations annotated by OncoKB therapeutic evidence level, and TCGA PanCancer pathway alterations. Results: A total of 295 patients with MCC were cataloged in the database. Patients included were 34.6% (n=102) female with a median age of 71. Patients identified race as 91.2% (n=269) white, 2.4% (n=7) African American, and 0.4% (n=2) Asian. The median number of alterations was 3.00 (SD 21.4, Range 0-178). Oncogenic alterations represented 17.4% (n=660 of 3799) of mutations. Sampled tissue originated from primary tumor in 54% (n=161) verses metastases in 42.4% (n=125). NGS identified 18.5% (n=55) with an FDA approved drug for use in a biomarker approved indication or approved drug in another indication (Level 1-3). An additional 13.9% (n=41) had a Level 4 (L4) mutation. The most common Level 3B gene mutations include PIK3CA (4.1%, n=12), and BRCA1/2 (4.1%, n=12), HRAS (1.7%, n=5), TSC1/2 (1.7%, n=5). The most common L4 mutations include PTEN (4.4%, n=13), ARID1A (3.7%, n=11), and CDKN2A (2.4%, n=7). Only three fusions were identified; L3B fusions ATM-CDK12 and TSC2 along with Level 4 PTEN. Copy number alterations were identified in a small subset of patients. L3B CNAs include ATM, CHEK1 (n=1), BARD1 (n=1), BRCA2 (n=1), RAD51B (n=1), RAD51D (n=1). Level 4 CNAs identified CDKN2A (n=4) and PTEN (n=1). In 60.7% cases, PanCancer pathways were altered and 28.5% had alterations in multiple pathways. The most commonly altered pathways were RTK-RAS (37.6%, n=111), TP53 (33.9%, n=100), Cell Cycle (33.9, n=100), PI3K (32.2%, n=95) and NOTCH (30.8%, n=91). Additionally, oncogenic DNA damage repair gene alterations (BRCA1/2, CHEK1/2, ATM, PALB2, BRIP1, RAD51) were present in 7.5% (n=22) of cases. Conclusions: Here we identified a subset of patients with targetable mutations in MCC. The majority of patients had oncogenic alterations in cancer pathways which may support the investigation of kinase inhibitors as single agent or in combination with immunotherapy or cytotoxic chemotherapy in Merkel Cell Carcinoma. Citation Format: Danielle Brazel, Priyanka Kumar, Hung Doan, Justin T. Moyers. Survey of genomic alterations in Merkel cell carcinoma (MCC) in the AACR Project Genie real-world database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1185.