Genomic and transcriptomic analysis of cutaneous squamous cell carcinoma arising in immunocompetent and immunosuppressed patients

Kristin P Bibee; Aditi Kulkarni; Sanghoon Lee; Johan Ho; Hatice Ulku Osmanbeyoglu; Robert L Ferris; Dan P Zandberg

doi:10.1016/j.oraloncology.2023.106582

Genomic and transcriptomic analysis of cutaneous squamous cell carcinoma arising in immunocompetent and immunosuppressed patients

Oral Oncol. 2024 Jan:148:106582. doi: 10.1016/j.oraloncology.2023.106582. Epub 2023 Nov 30.

Authors

Kristin P Bibee¹, Aditi Kulkarni², Sanghoon Lee³, Johan Ho⁴, Hatice Ulku Osmanbeyoglu⁵, Robert L Ferris², Dan P Zandberg²

Affiliations

¹ Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Electronic address: kbibee1@jhmi.edu.
² UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
³ UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁴ Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁵ UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh School of Engineering, Pittsburgh, PA, USA; Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.

PMID: 38039877
PMCID: PMC10917075 (available on 2025-01-01)
DOI: 10.1016/j.oraloncology.2023.106582

Abstract

Background: Cutaneous squamous cell carcinoma (cSCC) is the most common skin malignancy arising in immunocompromised patients such as solid organ transplant recipients. In addition to an abundance in number, the morbidity and mortality of these tumors in this patient population exceeds that of immune competent individuals. Here, we used whole exome and bulk RNA sequencing to analyze mutation profiles between tumors arising in immunocompetent and immunosuppressed patients.

Methods: DNA and RNA extracted from twenty formalin-fixed, paraffin embedded tumors and adjacent skin was sequenced. Bioinformatic analysis revealed tumor mutational burden, mutational signatures, microsatellite instability, and aberrant signaling pathways.

Results: Similar median tumor mutational burden was found in both the tumors from the immunocompetent and the immunosuppressed cohorts. Mutation signature analysis revealed UVR signatures and evidence of azathioprine exposure. 50% of tumors from the immunosuppressed patients have mutations consistent with microsatellite instability, yet mismatch repair protein expression was preserved in the samples analyzed. Additionally, frequently mutated genes in this cohort belong to the extracellular matrix receptor interaction and calcium signaling pathways, suggesting these may be targets for future treatments of this disease.

Conclusions: This study utilizes whole exome and bulk RNA sequencing to identify difference between cSCC arising in immunosuppressed and immunocompetent patients using the patient's photo exposed, but histologically normal appearing skin as the "germline" comparison. We demonstrate an enrichment in microsatellite instability in the tumors from immunosuppressed patients and differences in oxidative phosphorylation and epithelial-mesenchymal transition which may be targets for therapeutic intervention based on identification of mutations.

Keywords: Cutaneous squamous cell carcinoma; Genomics; Immunosuppression; Organ transplantation; Transcriptomics.

MeSH terms

Carcinoma, Squamous Cell* / pathology
Gene Expression Profiling
Genomics
Humans
Immunocompromised Host
Microsatellite Instability
Skin Neoplasms* / pathology

Abstract

MeSH terms

Grants and funding