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

Abstract

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.

Genotype, extrapyramidal features, and severity of variant ataxia‐telangiectasia

“…31 Disease severity was moderate or severe, except in the individual described above and 2 pediatric patients aged 11 and 15 years. Nineteen individuals (33%) were in Group A.…”

“…31 Patients with these mutations have been noted to have a milder clinical course, 24 and there is some uncertainty of ATM activity associated with these mutations. These mutations allow expression of a very low level of truncated protein.…”

Newborn Screening for SCID Identifies Patients with Ataxia Telangiectasia

“…Thus, although screening programs are designed to identify newborns with diseases for which there are treatments, the early diagnosis of AT as a secondary target of TREC screening for SCID can provide important information for family and genetic counseling. Patients should avoid undue irradiation and should be monitored for malignancy as well as protected from infection, while carriers of ATM mutations should be made aware of their own increased risk of cancer, and any anti-cancer therapy they require should be tailored in light of their increased sensitivity to radiation [41]. A diagnosis of AT by newborn screening can also help parents plan for the care of the affected child and obtain genetic counseling when considering future pregnancies.…”

ATM Mutations in Cancer: Therapeutic Implications

“…Radiosensitivity and chemosensitivity and ATM Radiosensitivity is also a hallmark of the A-T syndrome (35,36). Increased toxicity to radiotherapy has been reported in patients with A-T syndrome and heterozygous carriers of ATM mutations, probably due to defective DNA repair and genomic instability in normal tissues (37)(38)(39)(40). However, heterozygous germ-line mutations apparently do not contribute to secondary cancers following radiotherapy (41)(42)(43).…”