GENETIC SUSCEPTIBILITY TO HEAD AND NECK SQUAMOUS-CELL CARCINOMA

Background: In addition to influences of exposure to carcinogenic comp ounds, the development of cancer may depend on an individual intrinsic cancer susceptibility. Biomarkers for cancer susceptibility can be po werful additions to epidemiologic analyses. Purpose: This multicenter, case-control analysis combines previously published data and new data to substantiate the value of mutagen sensitivity as a biomarker of su sceptibility to head and neck squamous cell carcinoma and, more import antly, to gain insight into the interaction between susceptibility and exposure to carcinogens. Methods: Mutagen sensitivity (mean number of chromatid breaks per cell of cultured lymphocytes treated with bleomy cin in the late S-G(2) phase of the cell cycle) was determined in 313 patients with head and neck cancer and in 334 control subjects at two major U.S. medical institutions and one European institution, yielding a unique study population. The ages of the case and control subjects, as well as their history of use of tobacco and alcohol, were also rec orded. The relationships between variables were analyzed by use of Stu dent's t tests, Spearman's rank correlations, and multiple linear regr ession. For estimation of cancer risk, crude odds ratios (ORs) were me asured and multiple logistic regression was performed. All P values we re based on two-sided tests. Results: There were no differences across institutions in the distribution of mutagen sensitivity (Kruskal-Wall is test) for both case subjects and control subjects. Values for case subjects were consistently and significantly (P < .0001) higher than v alues for control subjects in the overall analyses. Age and tobacco or alcohol use did not influence the outcome in terms of mutagen-sensiti vity values for either the case or the control subjects. A mean number of breaks per cell dichotomized at 1.0 was found to be the best predi ctor of a hypersensitive phenotype. For nonsensitive, heavy smokers, t he OR was 11.5 (95% confidence interval [CI] = 5.0-26.6). This risk in creased dramatically in mutagen-hypersensitive, heavy smokers to 44.6 (95% CI = 17.4-114.0). Multiple logistic regression analysis confirmed these results, and a significant trend was found (P < .01) for the do se-dependent increase in cancer risk by smoking. The consumption of al cohol potentiated the effects of smoking, resulting in an OR of 57.5 ( 95% CI = 17.5-188.0) in hypersensitive persons. Conclusions: Mutagen s ensitivity was found to be a biomarker of cancer susceptibility. This study underscores the importance of utilizing both susceptibility mark ers and exposure data for the identification of persons at high risk o f developing cancer. Implications: More accurate risk estimation can d efine susceptible subgroups who might be targeted for intensive behavi oral interventions, surveillance through screening, and enrollment in chemoprevention programs.