To establish significant correlations between genetic polymorphisms and cancer, a largescale, systematic comparison of genetic alterations utilizing a case-control methodology is proposed. To date, such studies have been limited due to the large number of samples necessary for obtaining statistical significance, and the lack of rapid and accurate methods to screen for genetic polymorphisms. We propose to utilize an anonymized design to obtain DNA from residual material from routine diagnostic blood tests, to link these samples to a limited set of clinical variables, and to test for the frequency of candidate low-penetrance cancer susceptibility alleles. These data will be combined with similar data from a control group of age- and ethnically-matched volunteers for a related cohort study to be conducted separately. Polymorphisms to be screened for include those involving the genes PTEN, APC, TGF βR-I, BLM, CHK2, a p85 phosphoprotein, ATM, ER, PR, MCP-1, MPIF, CCR2/5, CCR3, and SULT1A1. Cancers to be included are breast, bladder, kidney,colon, testicular, lung, prostate, ovarian, lymphoid neoplasms, and head and neck carcinomas. Genes with SNPs known to be relevant for either the development or treatment of lymphoid malignancies will also be targeted. Specifically, candidate genes will be selected from 1) cytokine signaling, 2) DNA repair, and 3) apoptosis regulatory pathways.