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Heterozygous Germline ATM Mutations Do Not Contribute to Radiation-Associated Malignancies After Hodgkin's Disease

From the Center for Cancer Risk Analysis, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA; Departments of Pediatric Oncology and Biostatistics, Dana-Farber Cancer Institute, Boston, MA; Joint Center for Radiation Therapy, Boston, MA; and Tohoku University, Sendai, Japan.

Address reprint requests to Daniel A. Haber, MD, PhD, Laboratory of Molecular Genetics, Massachusetts General Hospital Cancer Center, Building 149, 13th St, Charlestown, MA 02129; email haber@ helix.mgh.harvard.edu.

PURPOSE: The successful treatment of Hodgkin's disease has been associated with an increased incidence of secondary malignancies. To investigate whether genetic factors contribute to the development of secondary tumors, we collected family cancer histories and performed mutational analysis of the ataxia-telangiectasia (AT) gene, ATM, in a cohort of Hodgkin's disease survivors with secondary malignancies. ATM was chosen for evaluation because of the increased radiosensitivity of cells derived from AT patients and obligate heterozygotes and the epidemiologic observation that AT carriers are at increased risk for radiation-induced breast cancer.

PATIENTS AND METHODS: Fifty-two patients who developed one or more neoplasms after treatment for Hodgkin's disease participated in this study. Personal and family histories of cancer were obtained through patient interviews and review of medical records. ATM mutational analysis was performed using a yeast-based protein truncation assay.

RESULTS: Seventy-six secondary neoplasms were observed in this cohort of 52 Hodgkin's disease survivors, with 18 patients (35%) developing more than one secondary neoplasm. Positive family histories of cancer were present in 11 (21%) of 52 patients, compared with three (4%) of 68 Hodgkin's disease patients in a comparison cohort who did not develop secondary neoplasms (P = .008; Fisher's exact test). No germline ATM mutations were identified, resulting in an estimated AT carrier frequency in this population of 0% (90% confidence interval, 0% to 4%).

CONCLUSION: Analysis of the number of tumors per individual and the family history of cancer in our cohort suggests that genetic factors may contribute to development of secondary neoplasms in a subset of Hodgkin's disease survivors. Mutational analysis, however, does not support a significant role for heterozygous truncating ATM mutations. Future studies evaluating other genes involved in DNA damage response pathways are warranted.

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