Breast Cancer Research volume 20 , Article number: 28 Cite this article. Metrics details. 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.
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. In addition, we performed whole-genome sequencing on four tumours from ATM loss-of-function variant carriers with available frozen material.
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 13q 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.
Ataxia-telangiectasia A-T is a rare autosomal recessive disorder caused by biallelic inactivating variants in the ataxia-telangiectasia mutated ATM gene. The phenotype is characterised by progressive neuronal degeneration, immunological deficiency, genetic instability, hypersensitivity to ionising radiation and agents that cause DNA double-strand breaks, and a predisposition to malignancies, particularly lymphoid tumours [ 1 , 2 , 3 ].
Epidemiological studies on A-T families showed that heterozygous ATM deleterious variant carriers hereafter referred to as HetAT are also at increased risk of other cancer types [ 4 , 5 , 6 ], notably of breast cancer BC in female relatives [ 7 , 8 ].
