DESCRIPTION (provided by applicant): A major concern for Hodgkin's Disease (HD) survivors is the development of recurrence or second primary tumors. Although factors responsible for the unfavorable outcomes and poor survival of HD patients remain incompletely understood, the population at highest risk seems to be genetically predisposed. In this proposal we propose to evaluate a panel of susceptibility biomarkers as predictors of disease outcome in an existing cohort of 254 HD patients for whom demographic, epidemiological, clinical data and pretreatment blood samples are available. We will test the hypothesis that unfavorable outcomes occur more frequently in patients with poor DNA repair capacity (measures by increase chromosome instability) and with adverse genotypes (polymorphisms in DNA repair and cell cycle control) as compared with patients with favorable outcome. Specifically we propose: 1) To collect follow-up information on health and vital status data to ascertain endpoints (recurrence or second primary tumors) for all the HD patients in the cohort; 2) To phenotypically characterize the role of background chromosomal instability (measured by chromosome aberrations and sister chromatid exchanges) in disease recurrence or development of SPTs. We hypothesize that patients with poor outcomes exhibit higher levels of baseline chromosomal damage than patients with favorable outcome. 3) To elucidate the role that specific polymorphisms in DNA repair capacity genes (XRCC1, XPD and XRCC3) and cell cycle control (p53 gene) play in the modulation of HD outcome. We hypothesize that individuals with DNA repair allelic variants have altered DNA repair capacity and increased risk of developing recurrence or SPT. Similarly, the allelic variants of p53 gene are associated with variant proteins that may alter cell cycle control encouraging progression either by inducing genomic instability and DNA misrepair or by permitting survival of mutants which will in turn have a negative impact on outcome; and 4) To analyze epidemiological and biomarker data independently and jointly as predictors of recurrence and development of SPTs. Identification of subgroups of HD patients who are at increased risk for recurrence or second primary tumor development has both clinical and prognostic relevance. The high risk population can be targeted for intensive preventive and early detection strategies.
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