Molecular Risk Factors for Oral Cancer

We are currently conducting studies to address hypotheses regarding the molecular basis for the development of oral squamous cell carcinoma (OSCC).

Genetic Susceptibility

Given the established role of tobacco and alcohol consumption as risk factors for these neoplasms, we are investigating whether polymorphisms in genes involved in the metabolism of tobacco and alcohol-derived carcinogens are related to OSCC risk. This work, which was funded by the National Institute of Dental and Craniofacial Research,  involved genotyping of DNA samples from over 300 cases and 500 controls from two population-based case-control studies conducted in the Seattle-Puget Sound region. The genes we are studying include those encoding glutathione S-transferases M1, P1, and T1, microsomal epoxide hydrolase, cytochrome p450 2E1, alcohol dehydrogenase type 3, N-acetyltransferase types 1 and 2, and NAD(P)H:quinone oxidoreductase. We have since expanded this study to examine genes for other factors likely to be relevant to the etiology of OSCC, such as those involved in DNA repair, immune response, and extra-cellular matrix biology. My principal collaborator is Dr. Chu Chen of the Fred Hutchinson Cancer Research Center, whose laboratory designs and performs the genotyping assays.

Human Papillomavirus Infection (HPV) and other Viral Factors

Although oncogenic strains of HPV are clearly central to the etiology of cervical and other anogenital carcinomas, the role of these agents in OSCC has been less-well studied. In 1998 we published the results of a population-based case-control study of HPV in relation to OSCC.  We found that 25% of OSCC patients had evidence of HPV infection (as measured by the presence of HPV DNA sequences by PCR) in their tumors, with the majority (16-17%) having evidence of oncogenic HPV infection. Using a sandwich ELISA developed by Dr. Denise Galloway's laboratory, we found that the risk of OSCC was increased more than two-fold greater among persons who had serologic evidence of antibody response to the HPV 16 L1 gene. Notably, the risk was nearly eight-fold for patients whose tumors contained HPV-16 DNA. We also found evidence of effect modification between HPV 16L1 antibody result, cigarette smoking, and OSCC risk.

More recently, we studied whether the detection of HPV in OSCC is associated with a favorable prognosis for OSCC patients. This represents the first population-based investigation of this hypothesis, which has been previously studied largely  in smaller, clinic-based settings.

There is also reason to suspect that other viral agents, in particular herpes simplex virus-1, might play a role in the etiology of some OSCC. Using specimens and data collected as part of the HPV-OSCC study, we have investigated this possibility.

Related Publications

Brennan P, Lewis S, Bell D, Boffetta P, Bouchardy C, Caparaso N, Chen C, Diehl S, Hayes RB, Olshan A, Schwartz SM, Sturgis E, Wei Q, Zavras AI, Benhamou S. Alcohol dehydrogenase3 genotype and risk of head an neck cancer—a pooled analysis of seven studies. Am J Epidemiol 2004; 159:1-16.

Starr JR, Daling JR, Fitzgibbons ED, Madeleine MM, Ashley R, Galloway DA, Schwartz SM. Serologic evidence of herpes simplex virus 1 infection and oral cancer risk. Cancer Research 2001;61:8459-64.

Schwartz SM, Doody DR, Fitzgibbons ED, Ricks S, Porter PL, Chen C. Oral squamous cell cancer risk in relation to alcohol consumption and alcohol dehydrogenase-3 genotypes. Cancer Epidemiol Biom Prev 2001;10:1137-44.

Chen C, Ricks S, Doody DR, Fitzgibbons ED, Porter PL, Schwartz SM. N-Acetyltransferase 2 polymorphisms, cigarette smoking and alcohol consumption, and oral squamous cell cancer risk. Carcinogenesis 2001;22:1993-99.

Schwartz SR, Yueh B, McDougall JK, Daling JR, Schwartz SM. Human papillomavirus infection and survival in oral squamous cell carcinoma: a population-based study. Otolaryngology – Head and Neck Surgery 2001;125:1-9.

Schwartz SM, Daling JR, Doody DR, Wipf GC, Carter JJ, Madeleine MM, Mao E-J, Fitzgibbons ED, Huang S, Beckmann AM, McDougall JK, Galloway DA. Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. JNCI 1998; 90:1626-36.

Mao E-J, Schwartz SM, Daling J, Oda D, Tickman L, Beckmann AM. Human papillomavirus and p53 mutations in normal, premalignant and malignant oral epithelia. Int J Cancer 1996; 69:152-158.