Severe reaction to radiotherapy for breast cancer as the presenting feature of ataxia telangiectasia

• Published in: British journal of cancer Vol. 106; no. 2; pp. 262 - 268
• Main Authors: Byrd, P J, Srinivasan, V, Last, J I, Smith, A, Biggs, P, Carney, E F, Exley, A, Abson, C, Stewart, G S, Izatt, L, Taylor, A M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-01-2012; Nature Publishing Group
• Subjects: Apoptosis; Ataxia; Ataxia Telangiectasia - complications; Ataxia Telangiectasia - diagnosis; Ataxia Telangiectasia - genetics; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - complications; Breast Neoplasms - genetics; Breast Neoplasms - radiotherapy; Cancer Research; Cell cycle; Cell Cycle Proteins - genetics; Clinical Study; DNA-Binding Proteins - genetics; Drug Resistance; Epidemiology; Female; Fibroblasts; Gynecology. Andrology. Obstetrics; Humans; Kinases; Laboratories; Lymphocytes; Mammary gland diseases; Medical research; Medical sciences; Middle Aged; Molecular Medicine; Mutagenesis; Mutation; Oncology; Patients; Protein Serine-Threonine Kinases - genetics; Proteins; Radiation therapy; Radiation Tolerance; Tumor Suppressor Proteins - genetics; Tumors; United Kingdom > UK; ataxia telangiectasia; radiotherapy; breast cancer; radiosensitivity; Immunopathology; Skin disease; Nervous system diseases; Breast disease; Radiosensitivity; Cardiovascular disease; Breast cancer; Malignant tumor; Radiotherapy; Genetic disease; Vascular disease; Mammary gland diseases; Eye disease; Cancerology; Treatment; Ataxia telangiectasia; ATM; Cancer; Tumor suppressor gene
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2011.534

Background:
Severe early and late radiation reaction to radiotherapy is extremely rare in breast cancer patients. Such a reaction prompted an investigation into a 44-year-old mother (patient A-T213).
Methods:
A neurological examination was performed and blood lymphocytes and skin fibroblasts were assessed for radiosensitivity chromosomally and by colony-forming assay. The
ATM
gene was sequenced and
ATM
mutations modelled by site-directed mutagenesis. The ATM kinase activity was also assessed.
Results:
Patient A-T213 was normally ambulant with no ataxia and minimal other neurological features. T lymphocytes and skin fibroblasts were unusually radiosensitive, although less sensitive than in classical ataxia telangiectasia (A-T). A lymphoblastoid cell line and skin fibroblasts expressed ATM protein with some retained kinase activity. One missense
ATM
mutation c.8672G>A (p.Gly2891Asp) and a c.1A>G substitution were identified. In the modelling system, the p.Gly2891Asp mutant protein was expressed and shown to have residual ATM kinase activity.
Conclusion:
Patient A-T213 has a milder form of A-T with biallelic
ATM
mutations, which may have contributed to breast cancer development, and certainly caused the severe radiation reaction. Ataxia telangiectasia should be investigated as a potential cause of untoward severe early and late radiation reactions in breast cancer patients.