GENESIS: a French national resource to study the missing heritability of breast cancer

Dondon, Marie-Gabrielle; Eon-Marchais, Séverine; Damiola, Francesca; Barjhoux, Laure; Marcou, Morgane; Verny-Pierre, Carole; Sornin, Valérie; Toulemonde, Lucie; Beauvallet, Juana; Gal, Dorothée Le; Mebirouk, Noura; Belotti, Muriel; Caron, Olivier; Gauthier‐Villars, Marion; Coupier, Isabelle; Bruno, Benedetto; Lortholary, Alain; Dugast, Catherine; Gesta, Paul; Fricker, Jean-Pierre; Noguès, Catherine; Faivre, Laurence; Luporsi, É.; Berthet, Pascaline; Bonadona, Valérie; Maugard, Christine M.; Pujol, Pascal; Lasset, Christine; Longy, Michel; Bignon, Yves‐Jean; Adenis, Claude; Venat-Bouvet, Laurence; Demange, L.; Dreyfus, Hélène; Frénay, Marc; Gladieff, Laurence; Mortemousque, Isabelle; Audebert‐Bellanger, Séverine; Soubrier, Florent; Giraud, Sophie; Lejeune-Dumoulin, S.; Chevrier, Annie; Limacher, Jean‐Marc; Chiésa, Jean; Fajac, Anne; Floquet, Anne; Eisinger, François; Tinat, Julie; Colas, Chrystelle; Fert‐Ferrer, Sandra; Penet, Clotilde; Frébourg, Thierry; Collonge‐Rame, Marie‐Agnès; Barouk-Simonet, Emmanuelle; Layet, Valérie; Leroux, Dominique; Cohen-Haguenauer, Odile; Prieur, Fabienne; Mouret-Fourme, Emmanuelle; Cornélis, François; Jonveaux, Philippe; Béra, Odile; Cavaciuti, Eve; Tardivon, A.; Lesueur, Fabienne; Mazoyer, Sylvie; Stoppa‐Lyonnet, Dominique; Andrieu, Nadine

doi:10.1186/s12885-015-2028-9

Cited by 16 publications

(18 citation statements)

References 24 publications

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“…The study population consisted of women participating in GENESIS (GENE SISters), a French resource for familial BC research . In summary, 1,721 women affected with infiltrating mammary or ductal adenocarcinoma, not carrying a pathogenic variant in BRCA1 and BRCA2, and having a sister with BC were enrolled in GENESIS between 2007 and 2013 through the national network of cancer genetics clinics (http://www.unicancer.fr/en/unicancer-group).…”

Section: Participants Materials and Methodsmentioning

confidence: 99%

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Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Girard

Eon-Marchais

Olaso

et al. 2018

Intl Journal of Cancer

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Pathogenic variants in BRCA1 and BRCA2 only explain the underlying genetic cause of about 10% of hereditary breast and ovarian cancer families. Because of cost‐effectiveness, multigene panel testing is often performed even if the clinical utility of testing most of the genes remains questionable. The purpose of our study was to assess the contribution of rare, deleterious‐predicted variants in DNA repair genes in familial breast cancer (BC) in a well‐characterized and homogeneous population. We analyzed 113 DNA repair genes selected from either an exome sequencing or a candidate gene approach in the GENESIS study, which includes familial BC cases with no BRCA1 or BRCA2 mutation and having a sister with BC ( N = 1,207), and general population controls ( N = 1,199). Sequencing data were filtered for rare loss‐of‐function variants (LoF) and likely deleterious missense variants (MV). We confirmed associations between LoF and MV in PALB2 , ATM and CHEK2 and BC occurrence. We also identified for the first time associations between FANCI , MAST1 , POLH and RTEL1 and BC susceptibility. Unlike other associated genes, carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (OR LoF = 17.4 vs. OR MV = 1.6; p Het = 0.002). Hence, our approach allowed us to specify BC relative risks associated with deleterious‐predicted variants in PALB2 , ATM and CHEK2 and to add MAST1 , POLH , RTEL1 and FANCI to the list of DNA repair genes possibly involved in BC susceptibility. We also highlight that different types of variants within the same gene can lead to different risk estimates.

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Section: Participants Materials and Methodsmentioning

confidence: 99%

“…The study population consisted of women participating in GEN-ESIS (GENE SISters), a French resource for familial BC research. 22 In summary, 1,721 women affected with infiltrating 2 Age at diagnosis for cases and age at inclusion for controls. 3 Number after excluding GENESIS index case and one affected sister.…”

Section: Study Participantsmentioning

confidence: 99%

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Girard

Eon-Marchais

Olaso

et al. 2018

Intl Journal of Cancer

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“…Breast tumour samples were selected from carriers of a deleterious ATM variant from four different research resources: the French retrospective study on A-T families (Retro-AT) [ 19 ], the French prospective cohort on women related to an A-T child (CoF-AT) [ 8 ], the GENESIS study [ 20 ] and the Kathleen Cuningham Foundation Consortium for research into Familial Breast Cancer (kConFab) study [ 21 ]. Briefly, Retro-AT [ 19 ] was carried out between 1994 and 1997 to assess cancer risk in A-T families living in France.…”

Section: Methodsmentioning

confidence: 99%

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

Mebirouk

Fuhrmann

et al. 2018

Breast Cancer Res

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BackgroundThe 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.MethodsTo 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.ResultsWe 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.ConclusionsAlthough 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.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-0951-9) contains supplementary material, which is available to authorized users.

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“…15 The index cases are women diagnosed with infiltrating mammary adenocarcinoma who attended a cancer genetics clinic in France and were found negative for BRCA1/2 pathogenic variants after extensive diagnostic screening (BRCA1/2 coding sequences and intron-exon boundaries screening and search for large gene rearrangements). The index cases were selected on the basis of a family history of breast cancer consisting of at least one sister with a breast cancer.…”

Section: Study Subjectsmentioning

confidence: 99%

Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

et al. 2016

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Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, that regulate BRCA1, and the 3ʹ-untranslated regions (3ʹ-UTRs) of BRCA1 and BRCA2 in the GENESIS French national case/control study (BRCA1-and BRCA2-negative breast cancer cases with at least one sister with breast cancer and matched controls). We identified one rare variant in MIR146A, four in MIR146B, five in BRCA1 3ʹ-UTR and one in BRCA2 3ʹ-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant MIR146A/MIR146B variants affected the pre-miR sequences. The potential causality of the four relevant BRCA1/BRCA2 3ʹ-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of BRCA2 3ʹ-UTR in a large series of familial breast cancer cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity.

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GENESIS: a French national resource to study the missing heritability of breast cancer

Cited by 16 publications

References 24 publications

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

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

Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

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