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Breast Cancer Research
Published in: Breast Cancer Research 1/2018

Open Access 01-12-2018 | Research Article

Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers

Authors: Anne-Laure Renault, Noura Mebirouk, Laetitia Fuhrmann, Guillaume Bataillon, Eve Cavaciuti, Dorothée Le Gal, Elodie Girard, Tatiana Popova, Philippe La Rosa, Juana Beauvallet, Séverine Eon-Marchais, Marie-Gabrielle Dondon, Catherine Dubois d’Enghien, Anthony Laugé, Walid Chemlali, Virginie Raynal, Martine Labbé, Ivan Bièche, Sylvain Baulande, Jacques-Olivier Bay, Pascaline Berthet, Olivier Caron, Bruno Buecher, Laurence Faivre, Marc Fresnay, Marion Gauthier-Villars, Paul Gesta, Nicolas Janin, Sophie Lejeune, Christine Maugard, Sébastien Moutton, Laurence Venat-Bouvet, Hélène Zattara, Jean-Pierre Fricker, Laurence Gladieff, Isabelle Coupier, Georgia Chenevix-Trench, Janet Hall, Anne Vincent-Salomon, Dominique Stoppa-Lyonnet, Nadine Andrieu, Fabienne Lesueur, CoF-AT, GENESIS, kConFab

Published in: Breast Cancer Research | Issue 1/2018

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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.

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.

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.

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.
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Metadata
Title
Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers
Authors
Anne-Laure Renault
Noura Mebirouk
Laetitia Fuhrmann
Guillaume Bataillon
Eve Cavaciuti
Dorothée Le Gal
Elodie Girard
Tatiana Popova
Philippe La Rosa
Juana Beauvallet
Séverine Eon-Marchais
Marie-Gabrielle Dondon
Catherine Dubois d’Enghien
Anthony Laugé
Walid Chemlali
Virginie Raynal
Martine Labbé
Ivan Bièche
Sylvain Baulande
Jacques-Olivier Bay
Pascaline Berthet
Olivier Caron
Bruno Buecher
Laurence Faivre
Marc Fresnay
Marion Gauthier-Villars
Paul Gesta
Nicolas Janin
Sophie Lejeune
Christine Maugard
Sébastien Moutton
Laurence Venat-Bouvet
Hélène Zattara
Jean-Pierre Fricker
Laurence Gladieff
Isabelle Coupier
Georgia Chenevix-Trench
Janet Hall
Anne Vincent-Salomon
Dominique Stoppa-Lyonnet
Nadine Andrieu
Fabienne Lesueur
CoF-AT
GENESIS
kConFab
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2018
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-018-0951-9

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