Graduation Date

Winter 12-16-2022

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Cancer Research

First Advisor

Ashley Wysong, MD, MS

Abstract

Patients who are immunosuppressed, such as solid organ transplant recipients (SOTRs), are known to have a higher risk of developing cutaneous squamous cell carcinoma (cSCC). This population is at a higher risk of metastasis and worse disease-specific survival, with over 1 million cases and an estimated 3,932 to 8,791 deaths each year in the United States. Large cancer genomic databases have reported on genomic drivers for many cancer subtypes, yet cSCC has not been included. The immunosuppressed population is generally ineligible to receive immunotherapy which poses a challenge for treatment options in cases that develop metastasis. After we performed a PRISMA-compliant systematic review of metastatic cSCC cases in immunosuppressed patients, we found there to be a lack of systematic reporting in the literature revealing gaps in the characterization of metastatic cSCC specifically for this population. We hypothesized that a UNMC cohort of metastatic cSCC cases in immunosuppressed individuals will show worse rates of disease-specific death compared to immunocompetent matched controls and that these differences may correlate with different genetic drivers of disease.

A review of immunosuppressed patients with a diagnosis of cSCC seen at UNMC was conducted from 2010-2020. These patients were case matched with 3 other cohorts: immunosuppressed patients with a localized cSCC, immunocompetent patients with a confirmed lymph node metastasis, and immunocompetent patients with a localized cSCC. The majority of tumors for both immunosuppressed and immunocompetent metastatic cohorts were staged T3. These populations were also found to have the lowest probability of survival. A 40% decline in probability of survival from metastatic immunocompetent patients to immunosuppressed patients suggests that immunosuppression is an important risk factor in determining disease specific death.

We preformed whole exome sequencing on 26 samples of FFPE tissue from our previously created cohort to identify alterations that may be associated with oncogenesis in this patient population. Using this data, we found high UV exposure signatures consistent with previously published data and signatures of unknown etiology that may indicate new areas to study for tumor progression in cSCC patients. Possible cancer driver genes and genes regulating the tumor microenvironment were discovered. We also found a higher fraction of samples in the immunosuppressed metastatic cSCC cohort with mutated genes in the PI3K pathway, leading us to believe PI3K/mTOR inhibitors could be used as a possible treatment option. Clinical characteristics seen in our UNMC cohort and data from whole exome sequencing study could help increase treatment options and improve the prognosis of these individuals.

Comments

2022 Copyright, the authors

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