Abstract Introduction: Basal cell carcinoma (BCC) is the most common skin cancer, accounting for up to 90% of all skin cancers. However, locally advanced and metastatic disease, requiring systemic treatment, is rare. While most BCC is driven by the Hedgehog (Hh) pathway involving SMO and PTCH1 alterations, there is variation in BCC response to SMO inhibitors. Nearly 30% of tumors develop resistance to or relapse after treatment. We surveyed the GENIE database for targetable alterations in patients with BCC. Methods: Patient data were accessed via the GENIE database interface, cBioPortal. Individual demographic data, alterations with annotations by OncoKB therapeutic evidence level, and TCGA PanCancer pathway alterations were collected. Results: A total of 73 patients with BCC were identified. The median age at sequencing was 66 years (Range 26-88). Most patients were male 60.3% (n=44) and 89% (n=65) were white. The median number of alterations was 35.00 (SD 67.54, Range 0-525). The median number of oncogenic alterations was 6.00 (SD 6.86, Range 0-52). Sample tissue was collected from metastases and the primary tumor site in 34.2% (n=25) of cases and in 54.8% (n= 40) of cases respectively. NGS identified 77.0% (n=57) of samples with an FDA approved drug for use in a biomarker approved indication or approved drug in another indication (Evidence Level 1-3). Level 4 (L4) (potential biomarker) mutations were present in 71.6% (n=53) of cases. The most common Level 3B gene mutations were PTCH1 (63.5%, n=47), ATM (5.4%, n=4), CHEK2 (4.1%, n=3), PIK3CA (4.1%, n=3), ERCC2 (2.7%, n=2), and HRAS (2.7%, n=2). Common Level 4 (L4) mutations included ARID1A 17.6%, n=13), CDKN2A (9.5%, n=7), MTOR (4.1%, n=3), and NF1 (2.7%, n=2). No L1-L4 fusions were identified. L1-L4 copy number alterations (CNA) were identified in two cases. The only L4 CNA was CDKN2A (2.7%, n=3). PanCancer pathways were altered in 93.2% (n=68) of cases. The median number of altered pathways was 6.00 (SD 2.70, Range 0-9). Frequently altered pathways included RTK-RAS (76.7%, n=56), TP53 (71.2%, n=52), Cell Cycle (69.9%, n=51), PI3K (67.1%, n=49), and NOTCH (65.8%, n=48). Additionally, alterations in DNA damage repair genes (ATM, BRCA1, RAD51, CHEK2, ARID1A) occurred in 16 (22.9%) cases, of which 11 (14.9%) patients had concurrent DDR and PTCH1 alterations. 13.5% of patients (n=10) had alterations other than PTCH1 with L3 evidence for treatment. Among 57 patients with potentially actionable L3B/L4 genomic alterations, 45.6% (n=26) had PTCH1 as their lone alteration, while 36.8% (n=21) had other alterations concurrent with PTCH1 and 13.5% (n=10) had alterations without PTCH1 or Hh alterations. Conclusion: Survey of the GENIE database found most patients had targetable alterations in BCC. Targets other than PTCH1 were common and may support the use of targeted therapies other than SMO inhibitors or in combination with SMO inhibitors in BCC. Citation Format: Priyanka R. Kumar, Danielle M. Brazel, Hung T. Doan, Justin T. Moyers. Hedgehog and beyond: Genomic alterations in basal cell carcinoma (BCC) - A survey of 73 patients in the AACR 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 1186.