Abstract Introduction and aims Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers with metastatic potential. While only 1 in 20 cSCCs may proceed to metastasize, when this occurs it is can be as lethal as most other metastatic cancers. Previous studies have shown that primary cSCCs harbour a high mutational burden, but it remains unclear whether genetic events determine metastatic potential. This study aimed to characterize the genetic evolution of cSCC metastasis from their corresponding primary tumours. Methods Overall, 488 formalin-fixed paraffin-embedded samples were collected from a retrospective cohort of immunocompetent patients with cSCC, including primary tumours, metastatic lesions and normal perilesional skin. Primary tumours were classified as nonmetastasizing if patients had ≥ 3 years of follow-up without metastasis. Dermatopathologist-annotated samples underwent whole-exome sequencing. Following quality control filtering, we carried out an in-depth analysis of 62 primary tumours that did not metastasize, 30 primary tumours that did metastasize and 26 metastases from patients with matched perilesional skin. Using bioinformatic pipelines, we determined mutational burdens, mutational signatures, significantly mutated genes, clonality and copy number alterations. Results We found that primary tumours that metastasized and metastases had the highest mutational burden and contained more subclones. Ultraviolet-driven signatures dominated all sample groups. dNdSCV analysis identified 10 significantly mutated genes with mutation of TP53 and HRAS among others enriched in metastasizing tumours and their metastases. Copy number variation analysis revealed a remarkable increase in genomic complexity in primary tumours that metastasized and in metastases. Conclusions Primary tumours that metastasize are genomically distinct from primary tumours that do not metastasize and harbour a massive burden of copy number alteration. Metastases share this burden and may become even more genetically complex. Enrichment of driver gene combinations coupled with genetic instability may confer tumours with metastatic potential.
Campbell et al. (Tue,) studied this question.