The 5 year survival rate for patients with oral squamous cell carcinoma (SCC), at 40%, is among the worst of all sites in the body and has not improved over the past 40 years. Approximately 90% of oral SCC are preceded by clinically evident pre cancerous lesions with varying degrees of dysplasia (from mild, to moderate, to severe). Transformation to SCC is associated with 16% of mild and 55% of moderate/severe dysplasia. Improved understanding of the molecular basis of oral SCC progression and tumorigenesis can contribute to development of novel strategies for diagnosis, cancer risk assessment and classification, as well as targeted therapies for prevention and treatment. Genomic analysis is of particular utility, since it is generally accepted that oral SCC develop via accumulation of genetic and epigenetic changes in a multi step process. We have reported previously that oral squamous cell carcinoma genomes are characterized by recurrent copy number changes, including recurrent narrow amplicons spanning <3 Mb (1). We have recently found that these narrow amplicons are also present in oral epithelial dysplasia, suggesting that they may be early events in oral cancer progression. The amplicons focus attention on the genes they encompass as candidate oncogenes that contribute to oral cancer development. Here, we will begin the analysis of how genes mapping to narrow amplicons in oral epithelial dysplasia and oral SCC contribute to disease development and/or progression by focusing on three amplicons we found to be present in both dysplasia and oral SCC, including a novel amplicon mapping to 2q11, an amplicon at 11q22 encompassing the candidate oncogenes BIRC2, YAP1 and MMP7 and an amplicon at 20p12.2 harboring the candidate oncogene JAG1. We will first assess genes mapping to the novel 2q11 amplicon for their candidacy as driver oncogenes for amplification (Aim 1).
In Aim 2, we will determine how expression levels of the best candidate oncogenes from the 2q11 amplicon as well as BIRC2, YAP1, MMP7 and JAG1 are altered during disease progression and whether their expression patterns are predictive of progression of dysplasia to SCC or risk of metastasis. We will investigate possible mechanisms by which these genes contribute to oral cancer by evaluating the functional consequences of their overexpression (Aim 3). We will also determine whether aneuploidy as measured by array CGH (i.e. fraction of the genome at altered copy number, FGA) or specific aberrations including amplicons can be used to identify dysplasia patients at risk for progression to cancer (Aim 4). The 5 year survival rate for patients with oral squamous cell carcinoma is 40%, among the worst of all sites in the body. The most fundamental way to make progress toward improving diagnosis and treatment of oral cancer is to elucidate the specific genes and the interactions among genes that become abnormal as cancer develops.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA131286-03
Application #
7904120
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Kim, Kelly Y
Project Start
2008-09-15
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
3
Fiscal Year
2010
Total Cost
$270,000
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Iwai, Shoko; Weinmaier, Thomas; Schmidt, Brian L et al. (2016) Piphillin: Improved Prediction of Metagenomic Content by Direct Inference from Human Microbiomes. PLoS One 11:e0166104
Schmidt, Brian L; Kuczynski, Justin; Bhattacharya, Aditi et al. (2014) Changes in abundance of oral microbiota associated with oral cancer. PLoS One 9:e98741
Scheinin, Ilari; Sie, Daoud; Bengtsson, Henrik et al. (2014) DNA copy number analysis of fresh and formalin-fixed specimens by shallow whole-genome sequencing with identification and exclusion of problematic regions in the genome assembly. Genome Res 24:2022-32
Uchida, Kenichiro; Veeramachaneni, Ratna; Huey, Bing et al. (2014) Investigation of HOXA9 promoter methylation as a biomarker to distinguish oral cancer patients at low risk of neck metastasis. BMC Cancer 14:353
Bhattacharya, Aditi; Roy, Ritu; Snijders, Antoine M et al. (2011) Two distinct routes to oral cancer differing in genome instability and risk for cervical node metastasis. Clin Cancer Res 17:7024-34