Breast tumors from ATM pathogenic variant carriers display a specific genome-wide DNA methylation profile
Abstract Background The ataxia-telangiectasia mutated (ATM) kinase phosphorylates and activates several downstream targets that are essential for DNA damage repair, cell cycle inhibition and apoptosis. Germline biallelic inactivation of the ATM gene causes ataxia-telangiectasia (A-T), and heterozygo...
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BMC
2025-03-01
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| Series: | Breast Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13058-025-01988-w |
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| author | Nicolas M. Viart Anne-Laure Renault Séverine Eon-Marchais Yue Jiao Laetitia Fuhrmann Sophia Murat El Houdigui Dorothée Le Gal Eve Cavaciuti Marie-Gabrielle Dondon Juana Beauvallet Virginie Raynal Dominique Stoppa-Lyonnet Anne Vincent-Salomon Nadine Andrieu Melissa C. Southey Fabienne Lesueur |
| author_facet | Nicolas M. Viart Anne-Laure Renault Séverine Eon-Marchais Yue Jiao Laetitia Fuhrmann Sophia Murat El Houdigui Dorothée Le Gal Eve Cavaciuti Marie-Gabrielle Dondon Juana Beauvallet Virginie Raynal Dominique Stoppa-Lyonnet Anne Vincent-Salomon Nadine Andrieu Melissa C. Southey Fabienne Lesueur |
| author_sort | Nicolas M. Viart |
| collection | DOAJ |
| description | Abstract Background The ataxia-telangiectasia mutated (ATM) kinase phosphorylates and activates several downstream targets that are essential for DNA damage repair, cell cycle inhibition and apoptosis. Germline biallelic inactivation of the ATM gene causes ataxia-telangiectasia (A-T), and heterozygous pathogenic variant (PV) carriers are at increased risk of cancer, notably breast cancer. This study aimed to investigate whether DNA methylation profiling can be useful as a biomarker to identify tumors arising in ATM PV carriers, which may help for the management and optimal tailoring of therapies of these patients. Methods Breast tumor enriched DNA was prepared from 2 A-T patients, 27 patients carrying an ATM PV, 6 patients carrying a variant of uncertain clinical significance and 484 noncarriers enrolled in epidemiological studies conducted in France and Australia to investigate genetic and nongenetic factors involved in breast cancer susceptibility. Genome-wide DNA methylation analysis was performed using the Illumina Infinium HumanMethylation EPIC and 450K BeadChips. Correlation between promoter methylation and gene expression was assessed for 10 tumors for which transcriptomic data were available. Results We found that the ATM promoter was hypermethylated in 62% of tumors of heterozygous PV carriers compared to the mean methylation level of ATM promoter in tumors of noncarriers. Gene set enrichment analyses identified 47 biological pathways enriched in hypermethylated genes involved in neoplastic, neurodegenerative and metabolic-related pathways in tumor of PV carriers. Among the 327 differentially methylated promoters, promoters of ARHGAP40, SCGB3A1 (HIN-1), and CYBRD1 (DCYTB) were hypermethylated and associated with a lower gene expression in these tumors. Moreover, using three different deep learning algorithms (logistic regression, random forest and XGBoost), we identified a set of 27 additional biomarkers predictive of ATM status, which could be used in the future to provide evidence for or against pathogenicity in ATM variant classification strategies. Conclusions We showed that breast tumors that arise in women who carry an ATM PV display a specific genome-wide DNA methylation profile. Specifically, the methylation pattern of 27 key gene promoters was predictive of ATM PV status of the women. These genes may also represent new medical prevention and therapeutic targets for these women. |
| format | Article |
| id | doaj-art-ec1ee47d7458464baf16e74d969c3de2 |
| institution | DOAJ |
| issn | 1465-542X |
| language | English |
| publishDate | 2025-03-01 |
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| series | Breast Cancer Research |
| spelling | doaj-art-ec1ee47d7458464baf16e74d969c3de22025-08-20T03:02:19ZengBMCBreast Cancer Research1465-542X2025-03-0127111610.1186/s13058-025-01988-wBreast tumors from ATM pathogenic variant carriers display a specific genome-wide DNA methylation profileNicolas M. Viart0Anne-Laure Renault1Séverine Eon-Marchais2Yue Jiao3Laetitia Fuhrmann4Sophia Murat El Houdigui5Dorothée Le Gal6Eve Cavaciuti7Marie-Gabrielle Dondon8Juana Beauvallet9Virginie Raynal10Dominique Stoppa-Lyonnet11Anne Vincent-Salomon12Nadine Andrieu13Melissa C. Southey14Fabienne Lesueur15Inserm, U1331, Institut Curie, PSL University, Mines ParisTechInserm, U1331, Institut Curie, PSL University, Mines ParisTechInserm, U1331, Institut Curie, PSL University, Mines ParisTechInserm, U1331, Institut Curie, PSL University, Mines ParisTechService de Pathologie, Institut CurieInserm, U1331, Institut Curie, PSL University, Mines ParisTechInserm, U1331, Institut Curie, PSL University, Mines ParisTechInserm, U1331, Institut Curie, PSL University, Mines ParisTechInserm, U1331, Institut Curie, PSL University, Mines ParisTechInserm, U1331, Institut Curie, PSL University, Mines ParisTechICGex Next-Generation Sequencing Platform, Institut Curie, PSL UniversityService de Génétique, Institut Curie, Université Paris CitéService de Pathologie, Institut CurieInserm, U1331, Institut Curie, PSL University, Mines ParisTechMonash University, Clayton, VIC; University of MelbourneInserm, U1331, Institut Curie, PSL University, Mines ParisTechAbstract Background The ataxia-telangiectasia mutated (ATM) kinase phosphorylates and activates several downstream targets that are essential for DNA damage repair, cell cycle inhibition and apoptosis. Germline biallelic inactivation of the ATM gene causes ataxia-telangiectasia (A-T), and heterozygous pathogenic variant (PV) carriers are at increased risk of cancer, notably breast cancer. This study aimed to investigate whether DNA methylation profiling can be useful as a biomarker to identify tumors arising in ATM PV carriers, which may help for the management and optimal tailoring of therapies of these patients. Methods Breast tumor enriched DNA was prepared from 2 A-T patients, 27 patients carrying an ATM PV, 6 patients carrying a variant of uncertain clinical significance and 484 noncarriers enrolled in epidemiological studies conducted in France and Australia to investigate genetic and nongenetic factors involved in breast cancer susceptibility. Genome-wide DNA methylation analysis was performed using the Illumina Infinium HumanMethylation EPIC and 450K BeadChips. Correlation between promoter methylation and gene expression was assessed for 10 tumors for which transcriptomic data were available. Results We found that the ATM promoter was hypermethylated in 62% of tumors of heterozygous PV carriers compared to the mean methylation level of ATM promoter in tumors of noncarriers. Gene set enrichment analyses identified 47 biological pathways enriched in hypermethylated genes involved in neoplastic, neurodegenerative and metabolic-related pathways in tumor of PV carriers. Among the 327 differentially methylated promoters, promoters of ARHGAP40, SCGB3A1 (HIN-1), and CYBRD1 (DCYTB) were hypermethylated and associated with a lower gene expression in these tumors. Moreover, using three different deep learning algorithms (logistic regression, random forest and XGBoost), we identified a set of 27 additional biomarkers predictive of ATM status, which could be used in the future to provide evidence for or against pathogenicity in ATM variant classification strategies. Conclusions We showed that breast tumors that arise in women who carry an ATM PV display a specific genome-wide DNA methylation profile. Specifically, the methylation pattern of 27 key gene promoters was predictive of ATM PV status of the women. These genes may also represent new medical prevention and therapeutic targets for these women.https://doi.org/10.1186/s13058-025-01988-wBreast cancerATM geneEpigeneticsDNA methylationBiomarkerMolecular testing |
| spellingShingle | Nicolas M. Viart Anne-Laure Renault Séverine Eon-Marchais Yue Jiao Laetitia Fuhrmann Sophia Murat El Houdigui Dorothée Le Gal Eve Cavaciuti Marie-Gabrielle Dondon Juana Beauvallet Virginie Raynal Dominique Stoppa-Lyonnet Anne Vincent-Salomon Nadine Andrieu Melissa C. Southey Fabienne Lesueur Breast tumors from ATM pathogenic variant carriers display a specific genome-wide DNA methylation profile Breast Cancer Research Breast cancer ATM gene Epigenetics DNA methylation Biomarker Molecular testing |
| title | Breast tumors from ATM pathogenic variant carriers display a specific genome-wide DNA methylation profile |
| title_full | Breast tumors from ATM pathogenic variant carriers display a specific genome-wide DNA methylation profile |
| title_fullStr | Breast tumors from ATM pathogenic variant carriers display a specific genome-wide DNA methylation profile |
| title_full_unstemmed | Breast tumors from ATM pathogenic variant carriers display a specific genome-wide DNA methylation profile |
| title_short | Breast tumors from ATM pathogenic variant carriers display a specific genome-wide DNA methylation profile |
| title_sort | breast tumors from atm pathogenic variant carriers display a specific genome wide dna methylation profile |
| topic | Breast cancer ATM gene Epigenetics DNA methylation Biomarker Molecular testing |
| url | https://doi.org/10.1186/s13058-025-01988-w |
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