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. 2018 Apr 17;20(1):28.
doi: 10.1186/s13058-018-0951-9.

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

Anne-Laure Renault  1   2   3   4 , Noura Mebirouk  1   2   3   4 , Laetitia Fuhrmann  5 , Guillaume Bataillon  5 , Eve Cavaciuti  1   2   3   4 , Dorothée Le Gal  1   2   3   4 , Elodie Girard  1   2   3   4 , Tatiana Popova  2   3   6 , Philippe La Rosa  1   2   3   4 , Juana Beauvallet  1   2   3   4 , Séverine Eon-Marchais  1   2   3   4 , Marie-Gabrielle Dondon  1   2   3   4 , Catherine Dubois d'Enghien  7 , Anthony Laugé  7 , Walid Chemlali  8 , Virginie Raynal  9 , Martine Labbé  1   2   3   4 , Ivan Bièche  8 , Sylvain Baulande  9 , Jacques-Olivier Bay  10 , Pascaline Berthet  11 , Olivier Caron  12 , Bruno Buecher  7 , Laurence Faivre  13   14 , Marc Fresnay  15 , Marion Gauthier-Villars  7 , Paul Gesta  16 , Nicolas Janin  17 , Sophie Lejeune  18 , Christine Maugard  19   20 , Sébastien Moutton  21 , Laurence Venat-Bouvet  22 , Hélène Zattara  23 , Jean-Pierre Fricker  24 , Laurence Gladieff  25 , Isabelle Coupier  26   27 ; CoF-AT; GENESIS; kConFab; Georgia Chenevix-Trench  28 , Janet Hall  29   30   31 , Anne Vincent-Salomon  5 , Dominique Stoppa-Lyonnet  6   7   32 , Nadine Andrieu  1   2   3   4 , Fabienne Lesueur  33   34   35   36
Affiliations

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

Anne-Laure Renault et al. Breast Cancer Res. .

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.

Keywords: ATM; Breast tumour; Copy number; Genetic instability; Genomic signature; Loss of heterozygosity; OncoScan array; Pathology.

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Conflict of interest statement

Ethics approval and consent to participate

Written informed consent for genetic studies and use of medical records for the present analyses was obtained from all participants enrolled in the Retro-AT, CoF-AT, GENESIS and kConFab research programs. The appropriate local ethics committee (Comité de Protection des Personnes [CCP] Ile-de-France III 2002/2006) and the French data protection authority (Commission Nationale de l’Informatique et des Libertés [CNIL]) approved the individual resource collections; Retro-AT, CoF-AT, and GENESIS study protocols; and the specific study on tumour material of ATM carriers. The kConFab resource collection and the specific study on tumour material of ATM carriers were approved by the Peter MacCallum Cancer Centre Ethics Committee and the Queensland Institute of Medical Research Human Research Ethics Committee.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Distribution of molecular subtypes in the ataxia-telangiectasia mutated (ATM) series and in the three control series. PAM50 classification was used for The Cancer Genome Atlas (TCGA) data, which explains the absence of luminal B/Human epidermal growth factor receptor 2-positive (HER2+) tumours in this series. Fisher’s exact test was used to assess difference between ATM series and control series. PICBIM Programme incitatif et collaboratif - Cancer du sein: invasion et motilité series
Fig. 2
Fig. 2
Copy number variation profiles of ataxia-telangiectasia mutated (ATM)-associated tumours analysed with the OncoScan array. a Genome-wide view of cumulative copy number variations present in the 23 ATM-associated tumours. Gains are indicated in red, losses in blue, and loss of heterozygosity (LOH) in orange. b Cluster dendrogram and genomic regions altered in ≥ 70% of the 23 analysed tumours. Tumours from Ataxia-telangiectasia (A-T) children are indicated by asterisks. c Cluster dendrogram and genomic regions altered in ≥ 70% of the 16 tumours with confirmed biallelic inactivation of ATM. Tumours from A-T children are indicated by asterisks. Loss The two alleles are present in the tumour, Loss/LOH Only one allele is present in the tumour, Loss/LOH or Loss Consecutive segmental regions characterised as either ‘Loss/LOH’ or ‘Loss’, HBOC Hereditary breast and ovarian cancer, HER2 Human epidermal growth factor receptor 2
Fig. 3
Fig. 3
Copy number variation and single-nucleotide variant (SNV) profiles of ataxia-telangiectasia mutated (ATM)-associated tumours obtained by deep whole-genome sequencing (WGS). a Cumulative profiles of copy number gains, losses and of loss of heterozygosity (LOH) regions obtained from WGS of four ATM-associated tumours. Black boxes indicate the genomic regions identified in the OncoScan analysis; green boxes indicate the new genomic regions identified by WGS. b Venn diagram representing the number of somatic SNVs and indels shared between the four tumours. c Venn diagram representing the number of genes altered and shared between the four tumours
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References

    1. Micol R, Ben Slama L, Suarez F, Le Mignot L, Beaute J, Mahlaoui N, Dubois d’Enghien C, Lauge A, Hall J, Couturier J, et al. Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype. J Allergy Clin Immunol. 2011;128(2):382–9.e1. doi: 10.1016/j.jaci.2011.03.052. - DOI - PubMed
    1. Suarez F, Mahlaoui N, Canioni D, Andriamanga C, Dubois d’Enghien C, Brousse N, Jais JP, Fischer A, Hermine O, Stoppa-Lyonnet D. Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: a report from the French national registry of primary immune deficiencies. J Clin Oncol. 2015;33(2):202–208. doi: 10.1200/JCO.2014.56.5101. - DOI - PubMed
    1. Taylor AM, Metcalfe JA, Thick J, Mak YF. Leukemia and lymphoma in ataxia telangiectasia. Blood. 1996;87(2):423–438. - PubMed
    1. Borresen AL, Andersen TI, Tretli S, Heiberg A, Moller P. Breast cancer and other cancers in Norwegian families with ataxia-telangiectasia. Genes Chromosomes Cancer. 1990;2(4):339–340. doi: 10.1002/gcc.2870020412. - DOI - PubMed
    1. Swift M, Chase CL, Morrell D. Cancer predisposition of ataxia-telangiectasia heterozygotes. Cancer Genet Cytogenet. 1990;46(1):21–27. doi: 10.1016/0165-4608(90)90004-T. - DOI - PubMed

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