Fiscal Year Peer Reviewed Cancer Research Program Topic Area: Kidney cancer.

Military Relevance Focus Area: Molecular mechanisms by which environmental influences associated with military exposures alter gene structure, stability, and expression.

Objective and Rationale: Kidney cancer occurs more frequently in males than females, and tobacco smoking is an established risk factor. The high prevalence of smoking in active military personnel and veterans means the male military population over age 40 years has a five- to sixfold greater rate of kidney cancer than non-military. However, there is very little information about the molecular mechanisms by which cigarette smoking promotes kidney cancer. We hypothesize that carcinogens from tobacco smoke cause distinctive changes in genes specifically in the kidney that promote tumor growth. To find these kidney-specific changes, we will perform a global analysis of gene sequences and activity in kidney tumors from male veterans who are heavy smokers (at least one pack of cigarettes a day for 20 years or longer), non-smokers (less than 100 cigarettes per lifetime), and data available for the general population of patients with kidney cancer, and compare the data from the three groups.

Applicability of the Research:

--By providing insight into the molecular mechanisms by which cigarette smoking promotes growth of kidney cancers, the data from this study will benefit all kidney cancer patients including those who smoke. Because of the high rate of smoking among veterans, veterans suffering from kidney cancer will benefit.

--Because of the discovery nature of this study (see below), the direct benefit will be in diagnosis of kidney cancer. However, this is a necessary first step toward achieving future novel chemotherapeutic strategies.

--This discovery phase study will collect data from a relatively small number of patients, although the number will be sufficient for statistical conclusions. Our future plans are to expand the number of patients, correlate clinical data and patterns of gene expression, and validate the results on additional, independent populations to achieve a comprehensive study.

--There is an increased understanding that within each type of cancer there are populations of patients with distinct affected genes that point to the most appropriate treatments. We expect to identify these genes or biomarkers in kidney cancer specific for heavy smokers, and this may lead to the development or applications of optimal treatments for these patients in the future.

Benefit to the Service Members: Cigarette smoking represents a major risk factor for development of kidney cancer in male veterans. This proposed research to investigating the effects of tobacco smoking on genes that affect the development and growth of kidney cancer will provide basic information about this disease. In the future, this work may be the basis for the development of specific, appropriate treatments for this fatal cancer in heavy smokers, including military personnel.