MicroRNA related genetic variation and head and neck cancer Head and neck squamous cell carcinoma (HNSCC) is a common and often disfiguring disease with a poor prognosis. Over 400,000 new cases of HNSCC are diagnosed annually worldwide, and most patients present with advanced disease. There is a recognized and incompletely described genetic susceptibility component in HNSCC genesis. Further, current prognostic models for HNSCC survival are based on staging and histopathologic criteria, are beginning to include HPV assessment, but lack robust genetic markers. This proposal will investigate the relationship between HNSCC risk and survival and a novel class of normal genetic variation, microRNA-related SNPs (miR-SNPs). MiR-SNPs include variation in miRNA target sites on mRNA transcripts, SNPs in miRNA genes, and SNPs in genes that participate in miRNA biogenesis and processing. While GWAS approaches have had some success, miR-SNPs have not been well represented on GWAS panels, and there is a very limited understanding of miRNA-related natural genetic variation. Almost exclusively non-coding, miR-SNPs clearly have critical regulatory capacity and the rapidly emerging literature has begun to demonstrate associations between candidate miR-SNPs and both risk and prognosis of human cancers including those of the head and neck. Recent and continued advances in miRNA target site prediction allows a more comprehensive cataloging and characterization of miR-SNPs that can be used for hypothesis testing in population studies. The primary aim of this work is to use proven epidemiologic resources to identify miR-SNPs associated with risk and prognosis of HNSCC, and to then validate identified associations in an independent population of HNSCC cases and controls. Previous work from our group has demonstrated a significant association between a SNP in the mature sequence of the miRNA gene MIR196A2 and risk of HNSCC, as well as the survival of patients with pharyngeal cancer. Separately, we observed a significant association between a let-7 miRNA target site in the 3'UTR of KRAS and survival of oral cancer patients. Further, in each of these reports on miR-SNPs and risk and survival of HNSCC we investigated the functional consequences of variant genotypes on expression of miRNAs and/or target gene transcripts. This proposal is a logical extension of our preliminary work and will extend well beyond candidate miR-SNP approaches by genotyping over 18,000 miR- SNPs. In our final aim, in conjunction with an extensive repertoire of molecular data from the parent study, we will use a systems genomics approach to explore the biological underpinnings and functional relevance of identified relationships between miR-SNPs and risk and prognosis of HNSCC. In addition, by integrating miR- SNP data with other molecular markers we will further refine identified markers of risk and prognosis to maximize their impact and translational potential.
Hundreds of thousands of new head and neck cancers are diagnosed each year and there remains an incomplete understanding of the genetic factors that contribute to risk and survival in this deadly disease. Our proposal will examine the relationship between as yet uncharacterized regulatory genetic variants and head and neck cancer risk and survival to identify biomarkers of disease risk and survival that may benefit both individuals at risk for this disease as well as patients.
|Thompson, Jeffrey A; Christensen, Brock C; Marsit, Carmen J (2018) Pan-Cancer Analysis Reveals Differential Susceptibility of Bidirectional Gene Promoters to DNA Methylation, Somatic Mutations, and Copy Number Alterations. Int J Mol Sci 19:|
|Wilkins, Owen M; Titus, Alexander J; Salas, Lucas A et al. (2018) MicroRNA-Related Genetic Variants Associated with Survival of Head and Neck Squamous Cell Carcinoma. Cancer Epidemiol Biomarkers Prev :|
|von Herrmann, Katharine M; Salas, Lucas A; Martinez, Eileen M et al. (2018) NLRP3 expression in mesencephalic neurons and characterization of a rare NLRP3 polymorphism associated with decreased risk of Parkinson's disease. NPJ Parkinsons Dis 4:24|
|Thompson, Jeffrey A; Christensen, Brock C; Marsit, Carmen J (2018) Methylation-to-Expression Feature Models of Breast Cancer Accurately Predict Overall Survival, Distant-Recurrence Free Survival, and Pathologic Complete Response in Multiple Cohorts. Sci Rep 8:5190|
|Salas, Lucas A; Wiencke, John K; Koestler, Devin C et al. (2018) Tracing human stem cell lineage during development using DNA methylation. Genome Res 28:1285-1295|
|Lundgren, Sara N; Madan, Juliette C; Emond, Jennifer A et al. (2018) Maternal diet during pregnancy is related with the infant stool microbiome in a delivery mode-dependent manner. Microbiome 6:109|
|Salas, Lucas A; Koestler, Devin C; Butler, Rondi A et al. (2018) An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray. Genome Biol 19:64|
|Johnson, Kevin C; Houseman, E Andres; King, Jessica E et al. (2017) Normal breast tissue DNA methylation differences at regulatory elements are associated with the cancer risk factor age. Breast Cancer Res 19:81|
|Wilkins, Owen M; Titus, Alexander J; Gui, Jiang et al. (2017) Genome-scale identification of microRNA-related SNPs associated with risk of head and neck squamous cell carcinoma. Carcinogenesis 38:986-993|
|Chen, Youdinghuan; Marotti, Jonathan D; Jenson, Erik G et al. (2017) Concordance of DNA methylation profiles between breast core biopsy and surgical excision specimens containing ductal carcinoma in situ (DCIS). Exp Mol Pathol 103:78-83|
Showing the most recent 10 out of 22 publications