Severe reaction to radiotherapy provoked by hypomorphic germline mutations in ATM (ataxia-telangiectasia mutated gene).
Adult
Ataxia Telangiectasia
/ etiology
Ataxia Telangiectasia Mutated Proteins
/ genetics
Breast Neoplasms
/ radiotherapy
Cells, Cultured
Female
Genetic Predisposition to Disease
Genetic Testing
Genomic Instability
Germ-Line Mutation
Humans
Pedigree
RNA Splicing
Radiation Injuries
/ etiology
Radiotherapy, Adjuvant
/ adverse effects
alpha-Fetoproteins
/ metabolism
ATM
ataxia-telangiectasia
breast cancer
hypomorphic variants
normal tissue overreaction
radiotherapy
splice site variants
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
03
02
2020
accepted:
05
06
2020
pubmed:
5
8
2020
medline:
1
6
2021
entrez:
5
8
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32748564
doi: 10.1002/mgg3.1409
pmc: PMC7549565
doi:
Substances chimiques
alpha-Fetoproteins
0
ATM protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1409Informations de copyright
© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
Références
Breast Cancer Res. 2011 Jul 25;13(4):R73
pubmed: 21787400
Radiother Oncol. 1998 May;47(2):125-8
pubmed: 9683358
Genome Integr. 2010 Jun 24;1(1):9
pubmed: 20678261
Nat Cell Biol. 2012 Aug;14(8):882-90
pubmed: 22772081
Eur J Hum Genet. 2012 Mar;20(3):305-12
pubmed: 22071889
BMC Cancer. 2019 Jun 3;19(1):535
pubmed: 31159747
Am J Hum Genet. 1998 Mar;62(3):551-61
pubmed: 9497252
PLoS One. 2019 Nov 22;14(11):e0225685
pubmed: 31756226
Lancet. 2011 Nov 12;378(9804):1707-16
pubmed: 22019144
Ann Oncol. 2015 Sep;26 Suppl 5:v8-30
pubmed: 26314782
Am J Hum Genet. 1998 Feb;62(2):334-45
pubmed: 9463314
Radiother Oncol. 2003 Nov;69(2):155-60
pubmed: 14643952
Hum Genet. 1993 Aug;92(1):61-8
pubmed: 8365728
Mol Cancer Ther. 2016 Aug;15(8):1781-91
pubmed: 27413114
Neuromolecular Med. 2013 Sep;15(3):447-57
pubmed: 23632773
Br J Cancer. 1997;76(12):1546-9
pubmed: 9413938
Breast Cancer Res Treat. 2016 Sep;159(2):245-56
pubmed: 27553368
Radiother Oncol. 2011 Apr;99(1):97-8
pubmed: 21354641
J Cell Biol. 2009 Dec 28;187(7):977-90
pubmed: 20026654
Am J Med Genet A. 2015 Aug;167A(8):1937-9
pubmed: 25914063
Prog Mol Biol Transl Sci. 2019;162:199-212
pubmed: 30905450
Nat Rev Mol Cell Biol. 2003 Jun;4(6):435-45
pubmed: 12778123
Curr Protoc Cytom. 2017 Oct 2;82:7.5.1-7.5.20
pubmed: 28967991
Int J Radiat Oncol Biol Phys. 2016 Mar 1;94(3):450-60
pubmed: 26867874
Curr Oncol. 2018 Apr;25(2):e176-e180
pubmed: 29719442
Br J Cancer. 2012 Jan 17;106(2):262-8
pubmed: 22146522
Clin Oncol (R Coll Radiol). 2015 Oct;27(10):579-87
pubmed: 26166774
Breast Cancer Res. 2018 Apr 17;20(1):28
pubmed: 29665859
Nat Rev Mol Cell Biol. 2010 Mar;11(3):208-19
pubmed: 20177396
Nat Rev Cancer. 2009 Feb;9(2):134-42
pubmed: 19148183
Med Phys. 2018 Nov;45(11):e1111-e1122
pubmed: 30421807
Int J Radiat Oncol Biol Phys. 2002 Mar 1;52(3):606-13
pubmed: 11849780
Eur J Surg Oncol. 2009;35 Suppl 1:1-22
pubmed: 19299100
J Med Genet. 2017 Nov;54(11):732-741
pubmed: 28779002
Mol Genet Genomic Med. 2020 Oct;8(10):e1409
pubmed: 32748564
Hum Mutat. 2012 Mar;33(3):561-71
pubmed: 22213089
Int J Radiat Oncol Biol Phys. 2006 Mar 1;64(3):776-83
pubmed: 16338099
Int J Radiat Oncol Biol Phys. 2015 Apr 1;91(5):1090-8
pubmed: 25832699
Nat Med. 2012 May;18(5):783-90
pubmed: 22466704
Acta Oncol. 2005;44(8):801-15
pubmed: 16332587
Radiother Oncol. 2004 Sep;72(3):319-23
pubmed: 15450731
J Med Genet. 2019 May;56(5):308-316
pubmed: 30819809
Neurology. 2019 Jan 1;92(1):e19-e29
pubmed: 30504431
PLoS One. 2011 Jan 26;6(1):e16422
pubmed: 21298066
Biochem Pharmacol. 2003 Jul 15;66(2):225-37
pubmed: 12826265
Neurology. 2009 Aug 11;73(6):430-7
pubmed: 19535770
Ann Neurol. 2004 Jun;55(6):891-5
pubmed: 15174027
Lancet Oncol. 2015 Jan;16(1):47-56
pubmed: 25500422
Nat Rev Cancer. 2006 Sep;6(9):702-13
pubmed: 16929324
Int J Radiat Oncol Biol Phys. 2019 Nov 15;105(4):698-712
pubmed: 31381960