Author ORCID Identifier

Date Available


Year of Publication


Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation




Pharmaceutical Sciences

First Advisor

Dr. Jill M. Kolesar


Individuals residing in Appalachian regions have significant health disparities, including higher cancer incidence and mortality rates. Previous studies have addressed the impact of socioeconomic status and environmental risk factors on Appalachia cancer disparities, while few studies have evaluated genetic risk factors.

Germline whole exome sequencing samples from 7,078 individuals with cancer (759 Appalachians) were evaluated. Demographics and relatedness were assessed using KING. Ethnicity was verified by principal component analysis using TRACE, which included 6,034 individuals (85%) of European genetic ancestry. After QC filtering, 5,980 individuals were analyzed. To assess the overall predisposition of hereditary disease, gene level frequency of likely pathogenic or pathogenic variants (PGVs) located in ACMG genes were compared between Appalachian and non-Appalachian regions. Assessment of overall alternative allele frequencies and pathway analysis were also performed.

Appalachian individuals were predominantly non-Hispanic Caucasians (p < 0.001) with a significantly higher proportion of current smoking (p < 0.001) compared to non-Appalachian individuals.

We identified PGVs in 637 individuals, most commonly SNPs followed by deletions, duplications, microsatellites, insertions, and indels. The most frequently mutated genes were BRCA2 (83 [13.0%]), BRCA1 (56 [8.8%]), and LDLR (47 [7.4%]). In addition, we identified 43 (6.6%) individuals with heterozygous PGVs in a mismatch repair gene. When comparing Appalachian to non-Appalachian individuals, the OTC gene was more frequently mutated (0.85% vs. 0.043%, FDR = 0.001) in Appalachian individuals.

An additional 4,580 germline variants with significantly different alternative allele frequencies in Appalachian individuals were identified, which were enriched in functional networks, including RNA regulation, cancer development, cell proliferation, and regulation of adhesion.

More than 4 million germline variants in 5,980 cancer individuals with cancer were evaluated, identifying a clinically relevant gene with a significantly higher gene-level mutation rate in the Appalachian region, as well as 4580 germline variants with significantly different alternative allele frequencies that enriched in cancer-relevant pathways. This suggests the Appalachian population has a unique genetic landscape, which may predispose them to cancer and contribute to disparities in cancer development.

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