# Short Tandem Repeat (STR) Somatic Mutation in Non-Melanoma Skin Cancer (NMSC): Association with Transcriptomic Profile and Potential Implications for Therapy

## TL;DR

This study explores DNA mutations in repetitive regions of non-melanoma skin cancer and finds they could help identify patients who may benefit from specific targeted treatments.

## Contribution

The study is the first to identify somatic STR mutations in NMSC and link them to potential precision therapies.

## Key findings

- STR somatic mutations in NMSC are associated with dysregulated cancer-related pathways like hedgehog and Wnt.
- These mutations can differentiate basal cell carcinoma from normal skin tissue using AI predictive models.
- Certain STR mutations suggest potential for targeted therapies such as hedgehog inhibitors and immune checkpoint inhibitors.

## Abstract

In a DNA sequence, there are some regions where a set of DNA bases is repeated right next to others (in tandem), called short tandem repeats (STRs). Sometimes, there are repeats of only one base (e.g., AAAAA or TTTTT). Mutations in such segments are not well studied. This study focused on these repetitive DNA changes in non-melanoma skin cancer (NMSC) across many cancer-related genes. The study identified changes that were only found in the cancerous tissue, not in normal skin. These mutations are associated with significant dysregulations of known cancer-related gene pathways. The findings suggest that these mutations can help identify NMSC patients who might benefit from personalized treatments, like hedgehog (Hh) inhibitors, immune checkpoint inhibitors (ICIs), and other precision therapies. This is the first study to find a new way of identifying and possibly treating skin cancer by looking at specific, previously ignored, repetitive patterns in tumor DNA.

Background: Studies on somatic mutations in cancer typically report single-nucleotide variants in coding regions, while mutations in short tandem repeats (STRs) are usually overlooked. Homopolymeric regions, a subset of STRs, are stretches of DNA where only a single nucleotide is repeated multiple times (e.g., AAAAA or TTTTT). Only recently have mutations in such STR regions been seen in colorectal cancer, where microsatellite instability (MSI) is common. In non-melanoma skin cancer (NMSC), MSI is rare. In this study, we focus on somatic mutations in such homopolymeric regions in NMSC and their functional implications. Methods: We performed targeted DNA sequencing (paired tissue and blood from the same individual), using more than 400 cancer-related genes from 32 NMSC patients as cases and non-lesional skin tissue from 16 independent individuals as controls. Results: We identified NMSC-associated STR somatic mutations. These are associated with the dysregulation of DNA damage and repair mechanisms. In artificial intelligence (AI) predictive modeling, these markers could successfully differentiate basal cell carcinoma (BCC) and non-lesional skin tissue. To our knowledge, we present the first study focusing on STR somatic mutations in multiple cancer-related genes in NMSC found only in tumor tissue and not in non-lesional skin tissue. Some of them (APC, BRAF) are associated with more pronounced dysregulation of relevant gene pathways (hedgehog, Notch signaling, and Wnt signaling). Conclusions: Our findings suggest that this STR somatic mutation status might potentially be used to select BCC patients who could benefit from certain precision therapy including hedgehog inhibitors, gamma-secretase inhibitors, anti-Vasuclar endothelial growth factor (VEGF), proteasome inhibitors, and immune check-point inhibitors.