Nathaniel Rothman

-

-

-

PLCO (Learn more about this study)

2005-0002

Aug 17, 2005

Chromosomal aberrations in cultured peripheral blood lymphocytes and subsequent risk of leukemia and lymphoma

Chromosomal aberrations (CA) in peripheral lymphocytes have been used to study the early biologic effects of genotoxic exposures for many decades in cross-sectional studies of healthy subjects exposed to a variety of genotoxic exposures. More recently, four small cohort studies have suggested that non-clonal chromosomal aberrations in peripheral lymphocytes of healthy individuals may also be predictive of subsequent risk of cancer (Hagmar et al., 1994; 1998; Bonassi et al., 1995; 2000; Liou et al., 1999; Smerhovsky et al., 2001). One study (Bonassi et al., 1995) has suggested that the association may be particularly strong for lymphoma and hematopoietic cancers. While the predictive capacity of these markers appears to be promising, these cohort studies are small and findings need to be validated for specific cancers and in different populations. The PLCO study has cryopreserved whole blood on more than 30,000 subjects in the screening arm of the trial and recent studies have shown that lymphocytes are viable (Hayes et al., 2002) and can be stimulated to grow to metaphase. There are almost no other cohorts in the world that have this type of resource. To explore the hypothesis that CA are predictive of future leukemia and lymphoma risk in the PLCO trial, we propose to carry out a nested case-control study of all cases of leukemia and lymphoma (n = 75) diagnosed one or more years after providing a cryopreserved blood sample, and controls matched on age, sex, center and amount of time the sample has been in storage. The proposal would use one vial of cryopreserved whole blood (ten vials were stored on average from each subject who participated in the T3 collection). We will use classic cytogenetic techniques, which were used in the four cohort studies described above, to assess chromosomal aberrations. This will be complimented by the evaluation of chromosomal aberrations by a fluorescent in situ hybridization (FISH) technique that has been optimized to detect specific chromosomal abnormalities relevant for leukemia and lymphoma (Zhang et al., 2005). Conceptually, this proposal evaluates non-clonal chromosomal aberrations as risk factors for future development of leukemia and lymphoma, not as early markers of disease itself. If validated for predicting future risk of these and other cancers, there could be important applications of this technology to screening the general population or high risk groups to estimate future cancer risk, as CA in peripheral lymphocytes function as general dosimeters that integrate both exogenous and endogenous genotoxic exposures and individual susceptibility. Potential interventions could include change in lifestyle, minimizing exposure to environmental and occupational genotoxic agents, and chemopreventive strategies designed to reduce risk of cancer in the future.