Clinical Chemistry Fellow, University of Washington, Laboratory Medicine, 1990-1992.
Postdoc Research Associate, Fred Hutchinson Cancer Research Center, Molecular Virology, 1987-1990.
Postdoc Fellow, Fred Hutchinson Cancer Research Center, Biochemistry Oncology, 1983-1986.
Ph.D., University of Washington, Biochemistry, 1982.
M.S., Ohio State University, Botany, 1971.
B.S., National Taiwan University, Botany, 1968.
N.R.C.C., Clinical Chemistry, 1992.
D.A.B.C.C., Clinical Chemistry, 1992.
Prognostic Gene Signatures for Oral Cancer
Oral squamous cell carcinoma (OSCC), comprising malignancies of the oral cavity and oropharynx, is the 6th most common cancer world-wide, with an estimated 529,000 new cases in 2012. This disease is often fatal; the five-year survival has remained at about 50% for the past four decades. For those who survive, the disease and treatment often result in the loss of orofacial function, pain, and disfigurement.
Recent investigations all show HPV status to be an important and independent prognostic factor for oropharyngeal cancer (OPC). The 5-year survival under current standard of care regardless of the specific therapy given is about 80-85% for HPV-positive OPC patients, but was only about 30-35% for HPV-negative OPC patients.
For oral cavity cancers (OCC), in which HPV is relatively uncommon (10 to15%), the overall 5-year survival is about 70% for stage I or II disease, 45% for stage III disease and about 35% for stage IV disease (http://www.cancer.org). Unfortunately, studies to date indicate that HPV status is not likely to be useful as a prognostic marker in patients with OCC, and there are no other prognostic biomarkers that can reliably predict the survival of these patients to aid clinical management. At present, the classification of OCC to inform treatment or prognosis is heavily dependent on AJCC stage. Yet, the ability of staging to predict prognosis in OCC is limited; patients with tumors of the same clinical and pathologic staging have heterogeneous response to clinical treatment, and different probability of recurrence and survival. The treatment for OCC varies from uni-modality treatment (surgery or radiation) for early stage disease to multimodality treatments (some combination of surgery, radiation, and chemotherapy) for late stage disease. For those patients who present with early stage I/II disease treated with uni-modality therapy (i.e., surgery) and for whom open neck surgery to fully assess high-risk features (multiple positive lymph nodes, or extracapsular spread in positive lymph nodes) may not be warranted, more precise knowledge of whether a patient’s tumor is associated with a poor prognosis might justify treatment intensification with a second modality (i.e., radiation +/- chemotherapy). Although randomized clinical trials show that adding chemotherapy to radiation treatment improves prognosis in OSCC patients, we lack biomarkers to identify which patients with high risk features will respond to more aggressive treatment, and thus which patients could be spared significant treatment toxicity. Thus, an assay to improve the prediction of survival of OCC patients under the current standard of care could help physicians and patients to make better personalized treatment choices.
Building on our work using Affymetrix gene expression arrays to subclassify prospectively-collected fresh OSCC from the Oralchip study, we have identified a gene expression profile of 131 probesets (representing 108 unique known genes) which not only differentiate invasive OSCC from normal oral epithelium but also predict OSCC survival. Furthermore, we have identified a subset of 13 genes from this 131 probeset list for which the gene expression is strongly associated with OSCC-specific survival for patients with HPV-negative oral cavity and oropharyngeal cancer irrespective of treatment modalities, and validated the performance of this 13-gene signature in predicting survival of OCC patients using an external independent dataset This is the first demonstration of a gene set that provides prognostic information beyond AJCC stage for OCC patients. We are currently conducting an international multicenter study to convert the testing of this gene signature to a potentially useful clinical test to aid the management of patients with HPV-negative OCC using funds from a recent NIH award.
Etiology of Head and Neck Squamous Cell Cancer (HNSCC)
We have been investigating etiologic factors for HNSCC by pooling our results from our case-control study with those from investigators in the International Head and Neck Cancer Consortium (INHANCE), These efforts led to the following observations:
Etiology of Lung Cancer
In a nested case-control study comparing 746 lung cancer cases and 1,477 controls, all of whom were non-Hispanic white smokers in the β-Carotene and Retinol Efficacy Trial (CARET), we examined whether lung cancer risk is associated with single nucleotide polymorphisms (SNPs) in base-excision repair, nucleotide excision repair, mismatch repair, and homologous end joining DNA repair pathways and whether diet modifies the association, if any. We found that inherited variants in LIG1 and possibly other nucleotide excision repair genes may predispose to smoking-related lung cancer. We also found MSH5/BAT3 locus to be associated with increased lung cancer risk among smokers. We confirmed the reported relation between chromosome 15q24-25.1 variation and lung cancer risk and found diet has little influence on this relation. Our collaboration with investigators in the International Lung Cancer Consortium (ILCCO) and the Women’s Health Initiative (WHI) led to the following observations:
Etiology of Endometrial Cancer
We examined single-nucleotide polymorphisms (SNPs) in the NER genes in a population-based case-control study in Washington State, with 783 endometrial cancer cases and 795 controls. We found that certain ERCC5, LIG1, XPA, and XPC genotypes might influence endometrial cancer risk. A history of incomplete pregnancies was not associated with endometrial cancer risk to any appreciable degree. Older age at first birth was more strongly associated with decreased endometrial cancer risk than was older age at last birth. A long duration of use of continuous-combined estrogen-progestin therapy was associated with a reduced risk of endometrial cancer. Our collaboration with investigators in the Etiology of Endometrial Cancer Consortium (E2C2) and WHI has led to the following observations:
Chen C, Méndez E, Houck J, Fan W, Lohavanichbutr P, Doody D, Yueh B, Futran ND, Upton M, Farwell DG, Schwartz SM, Zhao LP. Gene expression profiling identifies genes predictive of oral squamous cell carcinoma. GEO Data Repository: GSE30784. Cancer Epidemiol Biomarkers Prev. 2008; 17(8):2152–62. PMID: 18669583, PMCID: PMC2575803.
Chen Y, Chen C. DNA copy number variation and loss of heterozygosity in relation to recurrence of and survival from head and neck squamous cell carcinoma: a review. Head Neck. 2008; 30(10):1361–83. PMID: 18642290, PMCID: PMC3220418.
Mendez E, Houck J, Doody D, Lohavanichbutr P, Fan W, Rue TC, Yueh B, Futran ND, Upton M, Farwell DG, Heagerty PJ, Zhao LP, Schwartz SM, Chen C. A genetic expression profile associated with oral cancer identifies a group of patients at high-risk of poor survival. Clin Cancer Res. 2009; 15(4):1353-61. PMID: 19228736, PMCID: PMC2683360.
Lohavanichbutr P, Houck J, Fan W, Yueh B, Mendez E, Futran N, Doody DR, Upton MP, Farwell DG, Schwartz SM, Zhao LP, Chen C. Genome-wide gene expression profiles of HPV-positive and HPV-negative oropharyngeal cancer: potential implications for treatment choices. Arch Otolaryngol Head Neck Surg. 2009; 135(2):180-8. PMID: 19221247, PMCID: PMC2761829.
Xu C, Liu Y, Wang P, Fan W, Rue TC, Upton MP, Houck JR, Lohavanichbutr P, Doody DR, Futran ND, Zhao LP, Schwartz SM, Chen C, Méndez E. Integrative analysis of DNA copy number and gene expression in metastatic oral squamous cell carcinoma identifies genes associated with survival. Mol Cancer. 2010; 9:143. PMID: 20537188, PMCID:
Mendez E, Lohavanichbutr P, Fan W, Houck JR, Rue TC, Doody DR, Futran ND, Upton MP, Yueh B, Zhao LP, Schwartz SM, Chen C. Can a metastasis gene expression profile outperform tumor size as a predictor of occult lymph node metastasis in oral cancer patients? Clin Cancer Res. 2011; 17(8):2466-73. PMID: 21300763, PMCID: PMC3078996.
Stott-Miller M, Houck JR, Lohavanichbutr P, Mendez E, Upton MP, Futran ND, Schwartz SM, Chen C. Tumor and salivary matrix metalloproteinase levels are strong diagnostic markers of oral squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev. 2011; 20(12):2628-36. PMID: 21960692, PMCID: PMC3237810.
Lohavanichbutr P, Houck J, Doody DR, Wang P, Mendez E, Futran N, Upton MP, Holsinger FC, Schwartz SM and Chen C. Gene expression in uninvolved oral mucosa of OSCC patients facilitates identification of markers predictive of OSCC outcomes. PLoS One. 2012; 7(9):e46575. PMID: 23029552, PMCID: PMC3460916.
Lohavanichbutr P, Méndez E, Holsinger FC, Rue TC, Zhang Y, Houck J, Upton MP, Futran N, Schwartz SM, Wang P, Chen C. A 13-gene signature prognostic of HPV-negative oral cavity cancer: discovery and external validation. GEO Data Repository: GSE41613. Clin Cancer Res. 2013; 19(5):1197-203. PMID: 23319825, PMCID: PMC3593802.
Chen C, Zhang Y, Loomis MM, Upton MP, Lohavanichbutr P, Houck JR, Doody DR, Mendez E, Futran N, Schwartz SM, Wang P. Genome-wide loss of heterozygosity and DNA copy number aberration in HPV-negative oral squamous cell carcinoma and their associations with oral cancer-specific survival. GEO Data Repository: GSE68717. PLoS One. 2015; 10(8):e0135074. PMID: 26247464; PMCID: PMC4527746.
Doherty JA, Sakoda LC, Loomis MM, Barnett, MJ, Julianto L, Thornquist MD, Neuhouser ML, Weiss NS, Goodman GE, Chen C. DNA repair genotype and lung cancer risk in the Beta-Carotene and Retinal Efficacy Trial. Int J Mol Epidemio Genet. 2013; 4(1):11-34. PMID: 23565320, PMCID: PMC3612452.
Luo J, Beresford S, Chen C, Chlebowski R, Garcia L, Kuller L, Regier M, Wactawski-Wende J, Margolis KL. Association between diabetes, diabetes treatment and risk of developing endometrial cancer. Br J Cancer. 2014; 111(7):1432-9. PMID: 25051408, PMCID:PMC4183842