Hemopoietic stem cell transplant (HSCT) now offers curative therapy for a number of malignant and non-malignant disorders. However, survivors are at high risk for long-term adverse sequelae, including the development of second malignant neoplasms (SMNs). The etiology of SMNs is thought to involve genetic, treatment and environmental risk factors. HSCT patients are exposed to pretransplant chemotherapy or radiotherapy, to a cytotoxic preparative regimen and to immunosuppressive therapy. Patients may also be exposed to environmental carcinogens, such as UV light or tobacco, components of which are associated with increased risk of primary, and presumably SMNs. A large cohort (N=5806), with 381 patients with SMNs, treated at the Fred Hutchinson Cancer Research Center (FHCRC) is available for study. We have pertinent demographic and treatment information and stored pre-transplant biospecimens on patients, donors and family members. Follow-up is updated on an annual basis. We hypothesize that SMNs following HSCT occur in genetically predisposed individuals. Such predisposition may include increased radiation sensitivity of normal tissue and specific polymorphisms in enzymes related to tobacco metabolism, provision ofnucleotides and DNA repair. In patients with SMNs and in controls without SMN, treated with TBI, matched by race, primary diagnosis and who survived at least the elapsed period between the HSCT and the SMN of the case, we will: 1) investigate radiation sensitivity using in vitro chromosomal breakage assays on B-cell lymphoblastoid cell lines derived from cryopreserved pretransplant peripheral blood mononuclear cells; 2) examine polymorphisms in XRCC1, XRCC3, XPD, and XPG (DNA repair),methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) (folate metabolism), and glutathione-S-transferases (GSTT1, GSMT1, GSTM3, GSTP1) (tobacco metabolism/DNA repair) and microsomal epoxide hydrolase (mEH) (tobacco metabolism); 3) compare allelic frequencies between cases, controls and their first-degree relatives; 4) collect family history, tobacco use and UV light exposure information from self-report questionnaires, and explore relationship to genotype data. The information obtained from this research will provide insight into the role of common inherited variability in modifying susceptibility to SMN. As we learn more about the contributions of, and interactions among genetic susceptibility to second cancers and environmental risk factors, we can develop targeted preventive strategies for those recognized to be at highest risk.
