The genomic landscape of skin adnexal carcinomas in the AACR GENIE database: Implications for precision cancer medicine

Skin adnexal carcinomas (SAC) are rare and heterogeneous malignancies. These group of tumors differentiate from skin appendageal, such as hair follicles and sebaceous glands, and are molecularly and clinically distinct from keratinocyte carcinomas. Recurrent or metastatic SACs are aggressive tumors with poor survival outcomes, and limited available therapeutic options. Here we leveraged the AACR GENIE database to uncover the genomic landscape of SAC. Genomic data from samples classified as SAC according to the World Health Organization classification were selected from the AACR GENIE 1.8 dataset and annotated using the OncoKB TM database. Tumor mutation burden (TMB) values were provided by the AACR team, with classification defined as low (<2 mut/Mb), intermediate (2 to 16 mut/Mb), and high (>16 mut/Mb). Mutational signatures were generated and matched to the COMISC database. A total of 224 samples were retrieved, including primary (73.7%, n=165) and metastatic (26.3%, n=59) tumors. Clinicodemographic analysis revealed 53.6% (n=120) female and identified race distribution as white (73.2%; n=164), Asian (10.3%; n=23), black (5.4%; n=12) and non-specified (11.1%; n=25). Extramammary Paget disease was the most common subtype (48.7%; 109), followed by tumors with apocrine/eccrine (32.6%; n=73), sebaceous (17.4%; n=39), and follicular differentiation (1.3%; n=3). The median number of mutations per sample was 4 (IQR 2-3). The most frequently mutated genes were TP53 (45%), PIK3CA (20%), KMT2C (17%), ERBB2 (17%), and NOTCH1 (12%). The main altered pathways involved RTK-RAS (54.9%), TP53 (48.7%) and PI3K (37.1%). The most frequent copy number losses were in CDKN2A (11.8%) and CDKN2B (10.5%). The main copy number gains were observed in ERBB2 (8.7%) and MYC (8.1%). The most frequent actionable mutations annotated by OncoKB TM occurred in PIK3CA (Level 1; 17%), ERBB2 (Level 1; 12%), CDKN2A (Level 4, 4.9%), PTCH1 (Level 3A, 4.5%), and ARID1A (Level 4, 4%). Actionable BRAF mutations were detected in 2.2% of patients (0.4% Level 1 and 1.8% Level 2), whereas KRAS Level 1 mutations were observed in 3.6% of patients. The median TMB was 2.7 mut/Mb (IQR 0.85-6.83), 38.8% (n=87) samples had low TMB, 48.6% (n=109) had intermediate TMB, and 12.5% (n=28) had high TMB. Three COSMIC mutational signatures were matched: SBS2 (activity of APOBEC family of cytidine deaminases), SBS6 (defective DNA mismatch repair), and SBS7b (ultraviolet exposure), dominating 37.4%, 36.9%, and 25.7% of tumors, respectively. Our study profiled the largest cohort of SACs reported to date and identified a subset of patients with high TMB and actionable genomic alterations, including Level 1 alterations per OncoKB. These findings highlight the relevance of genomic profiling in SACs to inform clinical decision making, enable clinical trial matching, and improve the biological understanding of these rare malignancies.