Somatic alterations driving progression in cutaneous squamous cell carcinoma

Summary: Abstract Body: Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in the United States and can cause significant morbidity and mortality in advanced stages. The genetic drivers of disease progression, particularly in metastatic and aggressive (defined as T2b and T3 tumors, based on the Brigham and Women’s Hospital Tumor Classification System) tumors, remain poorly understood. This underscores a critical gap in knowledge of its biology and evolution. We conducted whole-exome sequencing on DNA extracted from formalin-fixed, paraffin-embedded tissue of surgically resected primary cSCCs that has aggressive features (agg-cSCC) or went on to metastasize (met-cSCC) and matched normal tissues. Tumor samples were identified from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohort using pathology and clinical data. We analyzed 66 tumor-normal pairs, including met-cSCC (n=22) and agg-cSCC (n=44), alongside 59 age-, sex-, and anatomic location-matched non-metastatic or non-aggressive cases. Our analysis revealed a high mutational burden consistent with UV-induced damage. We identified significantly mutated genes using dNdScv and MutSig2CV, considering the intersection of the identified genes as candidate drivers, including NOTCH1, FAT1, NOTCH2, ARID2, HRAS, TP53, CDKN2A, RIPK4, KMT2D, AJUBA, KNSTRN, KRT5, and CHUK, suggesting their pivotal roles in cSCC pathogenesis. In addition, we discovered novel candidate genes, COMMD8 and TMEM222, that warrant further investigation to assess their functional relevance. Our analysis of primary tumors validated known driver genes and identified candidate novel drivers, revealing key alterations associated with cSCC progression and potential clinical targets. Yuhree Kim¹, Vasuki Narasimha Swamy^{2, 3}, Lori Sakoda⁴, Ruth Foreman⁵, Claudia Chu^{2, 3}, Gaddy Getz^{2, 3}, Maryam Asgari¹ 1. Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States. 2. Broad Institute, Cambridge, MA, United States. 3. Massachusetts Institute of Technology, Cambridge, MA, United States. 4. Kaiser Permanente Northern California, Oakland, CA, United States. 5. Massachusetts General Hospital, Boston, MA, United States. Clinical Research: Epidemiology and Observational Research