Whole genome analysis reveals the genomic complexity in metastatic cutaneous squamous cell carcinoma

Metastatic cutaneous squamous cell carcinoma (cSCC) is associated with a high risk of recurrence and poor prognosis. There is limited published data exploring whole genome sequencing (WGS). The aim of this project was to provide the first comprehensive genomic understanding of the state of metastatic cSCC. In this study, we used WGS on matched tumor and blood DNA to detect somatic genetic alterations from 25 patients with regional metastases of head and neck cSCC. Our computational analyses interrogate clinical impacts of these genetic alterations on metastatic cSCC across the cohort for both the coding and non-coding genome. In the non-coding genome, 3UTR regions of EVC (48%), PPP1R1A (48%) and LUM (16%) were significantly functionally altered (Q-value < 0.05). Further, significant functional alterations are observed in the tumor suppressing lncRNA LINC01003 ( 68% of specimens, Q-value: 0.0158). In addition, significant recurrent copy number loss in tumor suppressor genes KANSL1 and PTPRD and gain in CALR, CCND1 and FGF3 was observed for coding regions. SNVs driver analyses predicted TP53, CDKN2A, as potential drivers of the metastasis cSCC (using 3 different tools). Indel signature analysis highlight dominance of ID signature 13 followed by ID8 & ID9. Interestingly, ID 9 has previously been shown to have no association with skin melanoma, unlike ID 13 and 8, suggesting some point of difference between these two skin-based diseases. The overall landscape of variation in metastatic cSCC is dominated by cell cycle and DNA repair disruption.