P53 MUTATIONS IN LUNG-CANCER FOLLOWING RADIATION-THERAPY FOR HODGKINS-DISEASE

High risks of lung cancer occur after successful treatment of Hodgkin' s disease. In addition to tobacco smoking, other risk factors include radiotherapy, chemotherapy, and immunosuppression, although the relati ve contributions of each are unknown, We conducted p53 mutational spec trum analysis in second lung cancers after radiation therapy for Hodgk in's disease in the Netherlands and in Ontario, Canada, Lung cancer ti ssues from 11 patients were analyzed by p53 immunohistochemistry and D NA sequence analysis. All were male cigarette smokers, all received ra diation therapy, and six also received chemotherapy. The lung cancers occurred 9.8 years (mean) after treatment, Radiation doses to lung lob es that developed the tumors averaged 5.7 Gy (range, 3.7-11.7 Gy), Seq uence analysis showed four missense and two silent p53 point mutations in five patients, There were four G:C --> A:T transitions; three of f our mutated deoxyguanines occurred on the coding strand, and one was a CPG site, There were two transversions: one G:C --> C:G and one A:T - -> C:G. Despite moderate or heavy smoking histories in all patients, t he mutational spectrum appears to differ from usual smoking-related lu ng cancers in which G:C --> T:A transversions predominate, The absence of G:C --> T:A mutations and the prominence of G:C --> A:T transition s, which are characteristic of radiation and oxidative damage, suggest that radiotherapy might have caused some of the p53 mutations, These data illustrate the potential of mutation analysis to determine causes of human cancer, If confirmed in a larger series, these results imply that some radiation-induced cancers can be distinguished from those c aused by other factors.