DESCRIPTION: (provided by Applicant) It is recognized that cigarette smoking
is a common risk factor for the development of cancers of the lung, larynx and
oral cavity. Although "pre-neoplastic" lesions are identified for these
smoking related cancers, not all lesions become malignant and currently there
is insufficient evidence to determine which features reliably predict
malignant potential of such lesions. We hypothesize that the conventional
histopathological examination of pre-neoplastic" lesions provides insufficient
information on prognosis, but genetic and epigenetic alterations in these
lesions may provide valuable information in this regard. It is also important
to focus on molecular alterations, which can be detected in 'pre-neoplastic"
lesions and could be clinically targeted with minimum adverse effects, since
primary prevention of smoking related cancers by elimination of tobacco abuse
may not be a realistic goal for everyone. We propose that alterations in
global DNA methylation in "pre-neoplastic" lesions is an important epigenetic
change to be validated because of its significance in the process of
carcinogenesis and the possibility of changing its status by nutritional
intervention. The primary hypothesis to be tested in this proposal is that
global DNA methylation status in 'pre-neoplastic" lesions (hyperplasia,
metaplasia, dysplasia and CIS) of the human lung, larynx and oral cavity of
subjects who have not developed cancers is higher compared to the methylation
status of the same "pre-neoplastic" lesions detected in subjects who have
developed cancers. To test this hypothesis, a retrospective follow-up study
will be conducted with subjects who were diagnosed with a "pre-neoplastic"
lesion of the lung, larynx or oral cavity. Subjects who have been followed
clinically for at least three years will be studied. Those who developed an
incident cancer vvill be compared to those who did not, with respect to the
degree of global methylation of DNA of the 'pre-neoplastic" lesions diagnosed
at the baseline. A newly developed and tested immunohistochemical technique,
which measures the degree of global methylation in intact and specific types
of cells, will be used to evaluate global DNA methylation in the proposed
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