# Genomic Insights into Cutaneous Squamous Cell Carcinoma

## TL;DR

This study identifies key genomic mutations in cutaneous squamous cell carcinoma, revealing disrupted pathways that could guide future diagnostics and treatments.

## Contribution

The study provides a comprehensive genomic profile of cSCC using a large dataset, highlighting novel mutation patterns and co-occurrence events.

## Key findings

- Frequent mutations in TP53, NOTCH1, KMT2D, and other genes disrupt DNA repair, cell cycle, and differentiation pathways.
- Recurrent co-occurring mutations suggest integrated pathway disruptions in cSCC.
- Exploratory analyses hint at possible race- and sex-based differences in mutation frequencies.

## Abstract

Cutaneous squamous cell carcinoma (cSCC) is one of the most common non-melanoma skin cancers, yet its genomic landscape remains incompletely defined despite its clinical significance. Using the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE), this study explores the mutational profile of cSCC in a large, diverse patient cohort. We found frequent mutations in TP53, NOTCH1, KMT2D, CDKN2A, TERT, ROS1, FAT1, NOTCH2, ERBB4, and KMT2A, which disrupt pathways controlling DNA damage response, cell-cycle checkpoints, keratinocyte differentiation, chromatin regulation, telomere stability, growth factor signaling, and cell adhesion. Recurrent co-occurring alterations were identified, and exploratory subgroup analyses suggested possible race- and sex-based differences requiring further validation. These findings expand our understanding of the molecular features driving cSCC and provide a framework for future studies aimed at improving diagnostic and therapeutic strategies for patients with this common yet genomically understudied skin cancer.

Background: Cutaneous squamous cell carcinoma (cSCC) represents one of the most common keratinocyte-derived malignancies encountered in clinical practice; however, its genomic landscape remains far less comprehensively characterized than that of other cutaneous cancers. This study aims to identify key molecular drivers and potential therapeutic targets by comprehensively characterizing the genomic landscape of cSCC using data from the American Association for Cancer Research (AACR) Project Genomics, Evidence, Neoplasia, Information, Exchange (GENIE) consortium. Methods: A retrospective cohort analysis of cSCC samples was performed utilizing AACR Project GENIE data accessed via the cBioPortal platform (v18.0-public) on 22 November 2025. Analyses included identification of recurrent somatic and copy-number alterations, pairwise gene–gene co-occurrence testing using Fisher’s exact tests with Benjamini–Hochberg False Discovery Rate (FDR) correction, and exploratory subgroup comparisons by sex and race, with statistical significance defined as p < 0.05. Results: Recurrent mutations were identified in TP53 (83.5%), NOTCH1 (56.3%), KMT2D (47.0%), CDKN2A (44.4%), TERT (41.4%), ROS1 (34.3%), FAT1 (33.3%), NOTCH2 (31.2%), ERBB4 (28.4%), and KMT2A (24.3%), reflecting disruption of the p53 pathway, cell-cycle control, Notch signaling, epigenetic regulation, telomere maintenance, RTK/MAPK pathways, and Wnt signaling. Statistically significant co-occurrence patterns were observed, and exploratory subgroup analyses evaluated mutation frequency differences by sex and race. Conclusions: This large, multi-institutional genomic analysis defines recurrent mutational and structural alterations in cSCC and highlights an integrated pattern of pathway disruption involving genomic integrity, differentiation, epigenetic control, and proliferative signaling. These findings enhance current understandings of the molecular architecture underlying this common yet genomically understudied malignancy and provide a foundation for future mechanistic studies and development of targeted diagnostic and therapeutic strategies.