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Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers.
- Source :
-
Breast cancer research : BCR [Breast Cancer Res] 2018 Apr 17; Vol. 20 (1), pp. 28. Date of Electronic Publication: 2018 Apr 17. - Publication Year :
- 2018
-
Abstract
- Background: The ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management.<br />Methods: To characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours. Morphology of ATM-associated tumours was compared with that of 599 patients with no BRCA1 and BRCA2 mutations from a hospital-based series, as well as with data from The Cancer Genome Atlas. Absolute copy number and loss of heterozygosity (LOH) profiles were obtained from the OncoScan SNP array. In addition, we performed whole-genome sequencing on four tumours from ATM loss-of-function variant carriers with available frozen material.<br />Results: We found that ATM-associated tumours belong mostly to the luminal B subtype, are tetraploid and show LOH at the ATM locus at 11q22-23. Unlike tumours in which BRCA1 or BRCA2 is inactivated, tumours arising in ATM deleterious variant carriers are not associated with increased large-scale genomic instability as measured by the large-scale state transitions signature. Losses at 13q14.11-q14.3, 17p13.2-p12, 21p11.2-p11.1 and 22q11.23 were observed. Somatic alterations at these loci may therefore represent biomarkers for ATM testing and harbour driver mutations in potentially 'druggable' genes that would allow patients to be directed towards tailored therapeutic strategies.<br />Conclusions: Although ATM is involved in the DNA damage response, ATM-associated tumours are distinct from BRCA1-associated tumours in terms of morphological characteristics and genomic alterations, and they are also distinguishable from sporadic breast tumours, thus opening up the possibility to identify ATM variant carriers outside the ataxia-telangiectasia disorder and direct them towards effective cancer risk management and therapeutic strategies.
- Subjects :
- Adult
Aged
Ataxia Telangiectasia complications
Ataxia Telangiectasia genetics
Ataxia Telangiectasia pathology
BRCA2 Protein genetics
Breast Neoplasms classification
Breast Neoplasms complications
Breast Neoplasms pathology
Breast Neoplasms, Male classification
Breast Neoplasms, Male complications
Breast Neoplasms, Male pathology
DNA Damage genetics
DNA Repair genetics
Female
Genetic Testing
Genomics
Germ-Line Mutation genetics
Humans
Loss of Heterozygosity genetics
Male
Middle Aged
Sequence Deletion genetics
Ataxia Telangiectasia Mutated Proteins genetics
BRCA1 Protein genetics
Breast Neoplasms genetics
Breast Neoplasms, Male genetics
Genetic Predisposition to Disease
Subjects
Details
- Language :
- English
- ISSN :
- 1465-542X
- Volume :
- 20
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Breast cancer research : BCR
- Publication Type :
- Academic Journal
- Accession number :
- 29665859
- Full Text :
- https://doi.org/10.1186/s13058-018-0951-9