# The genomic landscape and evolution of cutaneous squamous cell carcinoma

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $97,619

## Abstract

Project Summary/Abstract
Cutaneous squamous cell carcinoma is a form of skin cancer, originating from keratinocytes, that kills an
estimated 8000 people per year in the United States. Compared to other cancers with similar incidences, death
tolls, and/or economic burdens, our understanding of the genomic landscape and genetic evolution of
cutaneous squamous cell carcinoma is limited. The overarching goals of this grant are to define the driver
mutations in cutaneous squamous cell carcinomas, to delineate the genetic evolution of cutaneous squamous
cell carcinomas from precursor lesions, and to establish the earliest genetic alterations occurring in pre-
neoplastic keratinocytes. Towards these goals, in aim1, we will identify driver mutations in exome and genome
sequencing data covering cutaneous squamous cell carcinoma. This data will be aggregated from publicly
available sources as well as new sequencing data from our own institution, collectively comprising the largest
analysis of cutaneous squamous cell carcinoma sequencing data to date. In aim2, we will sequence cutaneous
squamous cell carcinomas and the remnant precursor lesions from which they arose. Most cutaneous
squamous cell carcinomas are discovered adjacent to benign precursor lesions known as actinic keratoses,
and here, we will analyze patient-matched lesions to reveal the mutations driving the transition from the benign
to the malignant state. In aim3, we will elucidate the earliest somatic alterations occurring in individual
keratinocytes from normal skin. Deep sequencing of normal skin has shown that keratinocytes can form
patches of related cells, sometimes harboring mutations known to drive cutaneous squamous cell carcinoma,
but no studies have truly genotyped keratinocytes at single-cell resolution, leaving gaps in our knowledge of
the incipient events that occur in pre-neoplastic keratinocytes. We have developed an innovative workflow to
call mutations in individual skin cells with high specificity and sensitivity, permitting us to catalog, for the first
time, the genomic alterations in human skin at single-cell resolution.
Similar lines of genomic studies have proven fundamental in advancing our understanding of other cancers by
revealing therapeutic points of intervention, biomarkers to measure disease progression, biomarkers to
estimate disease likelihood, and guidance on the best prevention tactics. Here, we will address these gaps in
knowledge for cutaneous squamous cell carcinoma. Taken together, completion of these studies will realize
longstanding goals within the field of dermatology, which will pave the way for new treatment strategies and
new preventions strategies to alleviate the public health burden posed by cutaneous squamous cell carcinoma.

## Key facts

- **NIH application ID:** 11064287
- **Project number:** 3R01CA265786-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Alan Hunter Shain
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $97,619
- **Award type:** 3
- **Project period:** 2022-09-22 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11064287

## Citation

> US National Institutes of Health, RePORTER application 11064287, The genomic landscape and evolution of cutaneous squamous cell carcinoma (3R01CA265786-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11064287. Licensed CC0.

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