TelomereContentandRiskofSecondMalignantNeoplasmin Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study

Purpose: Shorter constitutional telomere length has been associated with increased cancer incidence. Furthermore, telomere shortening is observed in response to intensive chemotherapy and/or ionizing radiation exposure. We aimed to determine whether less telomere content was associated with treatmentrelated second malignant neoplasms (SMN) in childhood cancer survivors. Experimental Design: Using a nested case–control design, 147 cancer survivors with breast cancer, thyroidcancer,orsarcomadevelopingaftertreatmentforchildhoodcancer(cases)werematched(1:1)with childhood cancer survivors without a SMN (controls). Cases and controls were matched by primary cancer diagnosis, years since diagnosis, age at the time of sample collection, years of follow-up from childhood cancer diagnosis, exposure to specific chemotherapy agents, and to specific radiation fields. We performed conditional logistic regression using telomere content as a continuous variable to estimate ORs with corresponding95%confidence intervals(CI) fordevelopment ofSMN.ORswere alsoestimated forspecific SMN types, i.e., breast cancer, thyroid cancer, and sarcoma. Results: There was an inverse relationship between telomere content and SMN, with an adjusted OR of 0.3perunitchangeintelomerelengthtosingle-copygeneratio(95%CI,0.09–1.02;P ¼0.05).Patientswith thyroidcancerSMNwerelesslikelytohavemoretelomerecontent(OR,0.04;95%CI,0.00–0.55;P ¼0.01), but statistically significant associations could not be demonstrated for breast cancer or sarcoma. Conclusions: A relation between less telomere content and treatment-related thyroid cancer was observed, suggesting that shorter telomeres may contribute to certain SMNs in childhood cancer survivors. Clin Cancer Res; 20(4); 904–11. � 2013 AACR.