Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers
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...
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BMC
2018-04-01
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Series: | Breast Cancer Research |
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Online Access: | http://link.springer.com/article/10.1186/s13058-018-0951-9 |
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language |
English |
format |
Article |
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DOAJ |
author |
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 CoF-AT GENESIS kConFab Georgia Chenevix-Trench Janet Hall Anne Vincent-Salomon Dominique Stoppa-Lyonnet Nadine Andrieu Fabienne Lesueur |
spellingShingle |
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 CoF-AT GENESIS kConFab Georgia Chenevix-Trench Janet Hall Anne Vincent-Salomon Dominique Stoppa-Lyonnet Nadine Andrieu Fabienne Lesueur Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers Breast Cancer Research ATM Breast tumour Pathology Genetic instability OncoScan array Copy number |
author_facet |
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 CoF-AT GENESIS kConFab Georgia Chenevix-Trench Janet Hall Anne Vincent-Salomon Dominique Stoppa-Lyonnet Nadine Andrieu Fabienne Lesueur |
author_sort |
Anne-Laure Renault |
title |
Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers |
title_short |
Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers |
title_full |
Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers |
title_fullStr |
Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers |
title_full_unstemmed |
Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers |
title_sort |
morphology and genomic hallmarks of breast tumours developed by atm deleterious variant carriers |
publisher |
BMC |
series |
Breast Cancer Research |
issn |
1465-542X |
publishDate |
2018-04-01 |
description |
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. |
topic |
ATM Breast tumour Pathology Genetic instability OncoScan array Copy number |
url |
http://link.springer.com/article/10.1186/s13058-018-0951-9 |
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doaj-b1d561356ed34398951c09ca8284ba312021-03-02T08:40:49ZengBMCBreast Cancer Research1465-542X2018-04-0120111810.1186/s13058-018-0951-9Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriersAnne-Laure Renault0Noura Mebirouk1Laetitia Fuhrmann2Guillaume Bataillon3Eve Cavaciuti4Dorothée Le Gal5Elodie Girard6Tatiana Popova7Philippe La Rosa8Juana Beauvallet9Séverine Eon-Marchais10Marie-Gabrielle Dondon11Catherine Dubois d’Enghien12Anthony Laugé13Walid Chemlali14Virginie Raynal15Martine Labbé16Ivan Bièche17Sylvain Baulande18Jacques-Olivier Bay19Pascaline Berthet20Olivier Caron21Bruno Buecher22Laurence Faivre23Marc Fresnay24Marion Gauthier-Villars25Paul Gesta26Nicolas Janin27Sophie Lejeune28Christine Maugard29Sébastien Moutton30Laurence Venat-Bouvet31Hélène Zattara32Jean-Pierre Fricker33Laurence Gladieff34Isabelle Coupier35CoF-AT36GENESIS37kConFab38Georgia Chenevix-Trench39Janet Hall40Anne Vincent-Salomon41Dominique Stoppa-Lyonnet42Nadine Andrieu43Fabienne Lesueur44INSERM, U900INSERM, U900Service de Pathologie, Institut CurieService de Pathologie, Institut CurieINSERM, U900INSERM, U900INSERM, U900Institut CurieINSERM, U900INSERM, U900INSERM, U900INSERM, U900Service de Génétique, Institut CurieService de Génétique, Institut CurieUnité de Pharmacogénomique, Institut CurieInstitut Curie Genomics of Excellence (ICGex) Platform, Institut CurieINSERM, U900Unité de Pharmacogénomique, Institut CurieInstitut Curie Genomics of Excellence (ICGex) Platform, Institut CurieCHU Estaing, CHU Clermont-FerrandUnité de Pathologie Gynécologique, Centre François BaclesseService d’Oncologie Génétique, Gustave RoussyService de Génétique, Institut CurieInstitut GIMI, CHU de Dijon, Hôpital d’EnfantsDépartement d’Hématologie et d’Oncologie Médicale, CLCC Antoine LacassagneService de Génétique, Institut CurieService d’Oncogénétique Régional Poitou-Charentes, Centre Hospitalier Georges-RenonService de Génétique, Clinique Universitaire Saint-LucService de Génétique Clinique Guy Fontaine, Hôpital Jeanne de FlandreLaboratoire de Diagnostic Génétique, UF1422 Oncogénétique Moléculaire, Hôpitaux Universitaires de StrasbourgLaboratoire Maladies Rares: Génétique et Métabolisme, CHU de Bordeaux-GH PellegrinService d’Oncologie Médicale, Hôpital Universitaire DupuytrenDépartement de Génétique, Hôpital de la TimoneUnité d’Oncogénétique, Centre Paul StraussIUCT Oncopole, Institut Claudius RegaudService de Génétique Médicale et Oncogénétique, Hôpital Arnaud de Villeneuve, CHU de MontpellierINSERM, U900INSERM, U900Research Department, Peter MacCallum Cancer CentreDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research InstituteUMR INSERM 1052Service de Pathologie, Institut CurieINSERM U830INSERM, U900INSERM, U900Abstract 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.http://link.springer.com/article/10.1186/s13058-018-0951-9ATMBreast tumourPathologyGenetic instabilityOncoScan arrayCopy number |