Severe reaction to radiotherapy provoked by hypomorphic germline mutations in ATM (ataxia-telangiectasia mutated gene)

Background: A minority of breast cancer (BC) patients suffer from severe reaction to adjuvant radiotherapy (RT). Although, deficient DNA double-strand break repair is considered the main basis for the reactions, pretreatment identification of high-risk patients has been challenging.

Methods: To retrospectively determine the etiology of severe local reaction to RT in a 39-year-old woman with BC, we performed next-generation sequencing followed by further clinical and functional studies.

Results: We found a -4 intronic variant (c.2251-4A>G) in trans with a synonymous (c.3576G>A) variant affecting the ATM DNA-repair gene (NG_009830.1, NM_000051.3) which is linked to autosomal recessive ataxia-telangiectasia (A-T). We verified abnormal transcripts resulting from both variants, next to a minor wild-type transcript leading to a residual ATM kinase activity and genomic instability. Follow-up examination of the patient revealed no classic sign of A-T but previously unnoticed head dystonia and mild dysarthria, a family history of BC and late-onset ataxia segregating with the variants. Additionally, her serum level of alpha-fetoprotein (AFP) was elevated similar to A-T patients.

Conclusion: Considering the variable presentations of A-T and devastating impact of severe reactions to RT, we suggest a routine measurement of AFP in RT-candidate BC patients followed by next-generation sequencing with special attention to non-canonical splice site and synonymous variants in ATM.

Keywords: ATM; ataxia-telangiectasia; breast cancer; hypomorphic variants; normal tissue overreaction; radiotherapy; splice site variants.