Head and neck squamous cell carcinoma (HNSCC) is an aggressive neoplasm primarily caused by tobacco consumption or human papillomavirus (HPV) infection. Incidence and mortality rates for HNSCC vary geographically. Appalachian residents consume tobacco products to a greater extent than national averages, a risk factor known to promote HPV-negative HNSCC through increased genomic instability. Male Appalachian patients display significantly worse relative survival than Appalachian females or non-Appalachian residents of either sex. Secondary analysis of available cancer registry outcome data from 2007-2013 indicates that white males with stage IV oral cavity/pharyngeal (OC/P) HNSCC are responsible for the decreased male survival observed within Appalachian regions. This disparity is seen in a subset of Appalachian states and is associated with lower relative survival in HPV-Associated subsites, suggesting a higher percentage of HPV-negative cancers occur in oral cavity regions typically associated with HPV infection. This increase is likely associated with higher smoking and smokeless tobacco usage in Appalachian states. An unbiased statistical analysis of gene copy number alterations (CNAs) from the Cancer Genome Atlas (TCGA)-HNSC national cohort indicates that smoking significantly correlates with amplification or deletions of genes found in several chromosomal cytobands. Of these, chromosome 11q13.3 and 11q13.4 (amplified) and chromosomes 9p21.3 and 9p24.1 (deleted) are the only altered segments that correlate with reduced overall survival in patients that smoked, independent of HPV status. 11q13 amplification is the most common CNA in HNSCC and enhances tumor progression and poor outcome due to protein overexpression. Transcriptome analysis of HNSCC with 11q13 amplification indicates that 13 out of 17 amplified genes are overexpressed, including the oncogenic cell gene CCND1 (cyclin D1). Recently, 3’UTRs of select mRNAs have been shown to function as positive regulators of cancer progression by sequestering tumor-suppressive microRNAs (miRNAs) as competing endogenous (ce)RNA. Thus, a novel mechanism of poor outcome in 11q13 amplified patients may be due to the 3’UTR regions of elevated 11q13 transcripts serving to titrate tumor-suppressive miRNAs, permitting increased oncogenic progression. The overall hypothesis of this dissertation is that HNSCC patients in Appalachia have lower survival due to a larger number of individuals harboring tumors with 11q13 amplification from tobacco-induced damage, resulting in increased transcript expression that downregulates tumor-suppressive miRNA functions. Predictive algorithms and secondary TCGA data analysis indicate that the CCND1 3’UTR contains multiple miRNA response elements expected to bind known tumor-suppressive miRNAs. Patient outcome data indicates that CCND1-amplified patients with 3’UTR containing transcripts have poorer overall survival than patients with CCND1 overexpression lacking the 3’UTR. Stratification by CCND1 expression reveals several altered protein targets including CCNB1, TYMS, and SERPINE1, that share miRNA response elements with CCND1 mRNA. Identification of tumor-promoting effects from 11q13 transcripts provides alternative avenues for therapeutic intervention in this most aggressive form of HNSCC by identifying novel druggable transcription targets that can augment protein-based precision medicine strategies or by facilitating stratification of patients for clinical trials in patients with smoking-induced 11q13 amplification in Appalachia or other regions of high tobacco use.