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

Breast Cancer Research

Jacques-Olivier Bay¹  Georgia Chenevix-Trench²  Hélène Zattara³  Marc Fresnay⁴  Dominique Stoppa-Lyonnet⁵  Juana Beauvallet⁶  Anne-Laure Renault⁶  Dorothée Le Gal⁶  Eve Cavaciuti⁶  Fabienne Lesueur⁶  Nadine Andrieu⁶  CoF-AT⁶  Elodie Girard⁶  Noura Mebirouk⁶  Philippe La Rosa⁶  GENESIS⁶  Martine Labbé⁶  Séverine Eon-Marchais⁶  Marie-Gabrielle Dondon⁶  Laurence Gladieff⁷  Virginie Raynal⁸  Sylvain Baulande⁸  Tatiana Popova⁹  Laurence Faivre^1,10  Sébastien Moutton^1,11  Christine Maugard^1,12  kConFab^1,13  Sophie Lejeune^1,14  Isabelle Coupier^1,15  Nicolas Janin^1,16  Marion Gauthier-Villars^1,17  Catherine Dubois d’Enghien^1,17  Bruno Buecher^1,17  Anthony Laugé^1,17  Laetitia Fuhrmann^1,18  Anne Vincent-Salomon^1,18  Guillaume Bataillon^1,18  Paul Gesta^1,19  Olivier Caron^2,20  Laurence Venat-Bouvet^2,21  Janet Hall^2,22  Pascaline Berthet^2,23  Walid Chemlali^2,24  Ivan Bièche^2,24  Jean-Pierre Fricker^2,25 

[1] CHU Estaing, CHU Clermont-Ferrand;Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute;Département de Génétique, Hôpital de la Timone;Département d’Hématologie et d’Oncologie Médicale, CLCC Antoine Lacassagne;INSERM U830;INSERM, U900;IUCT Oncopole, Institut Claudius Regaud;Institut Curie Genomics of Excellence (ICGex) Platform, Institut Curie;Institut Curie;Institut GIMI, CHU de Dijon, Hôpital d’Enfants;Laboratoire Maladies Rares: Génétique et Métabolisme, CHU de Bordeaux-GH Pellegrin;Laboratoire de Diagnostic Génétique, UF1422 Oncogénétique Moléculaire, Hôpitaux Universitaires de Strasbourg;Research Department, Peter MacCallum Cancer Centre;Service de Génétique Clinique Guy Fontaine, Hôpital Jeanne de Flandre;Service de Génétique Médicale et Oncogénétique, Hôpital Arnaud de Villeneuve, CHU de Montpellier;Service de Génétique, Clinique Universitaire Saint-Luc;Service de Génétique, Institut Curie;Service de Pathologie, Institut Curie;Service d’Oncogénétique Régional Poitou-Charentes, Centre Hospitalier Georges-Renon;Service d’Oncologie Génétique, Gustave Roussy;Service d’Oncologie Médicale, Hôpital Universitaire Dupuytren;UMR INSERM 1052;Unité de Pathologie Gynécologique, Centre François Baclesse;Unité de Pharmacogénomique, Institut Curie;Unité d’Oncogénétique, Centre Paul Strauss;

关键词: ATM;    Breast tumour;    Pathology;    Genetic instability;    OncoScan array;    Copy number;   

DOI  :  10.1186/s13058-018-0951-9

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown