Asadollahi, Reza ORCID: https://orcid.org/0000-0002-1497-0564, Britschgi, Christian, Joset, Pascal, Oneda, Beatrice, Schindler, Detlev ORCID: https://orcid.org/0000-0003-2451-8165, Meier, Urs R. and Rauch, Anita ORCID: https://orcid.org/0000-0003-2930-3163 (2020) Severe reaction to radiotherapy provoked by hypomorphic germline mutations in ATM (ataxia–telangiectasia mutated gene). Molecular Genetics and Genomic Medicine, 8 (10):e1409. ISSN 2324-9269 (Online) (doi:10.1002/mgg3.1409)

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Abstract

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 synony-mous (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-fetopro-tein (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.

Item Type:	Article
Uncontrolled Keywords:	ATM; ataxia-telangiectasia; breast cancer; radiotherapy; hypomorphic variants
Subjects:	Q Science > QH Natural history > QH426 Genetics
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science Faculty of Engineering & Science > School of Science (SCI)
Last Modified:	27 Jun 2022 11:47
URI:	http://gala.gre.ac.uk/id/eprint/36704

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