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Background <p>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 <i>ATM</i> 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 <i>ATM</i> PV carriers, which may help for the management and optimal tailoring of therapies of these patients.</p> Methods <p>Breast tumor enriched DNA was prepared from 2&#xa0;A-T patients, 27 patients carrying an <i>ATM</i> 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.</p> Results <p>We found that the <i>ATM</i> promoter was hypermethylated in 62% of tumors of heterozygous PV carriers compared to the mean methylation level of <i>ATM</i> 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 <i>ARHGAP40</i>, <i>SCGB3A1</i> (<i>HIN-1</i>), and <i>CYBRD1</i> (<i>DCYTB</i>) 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 <i>ATM</i> status, which could be used in the future to provide evidence for or against pathogenicity in <i>ATM</i> variant classification strategies.</p> Conclusions <p>We showed that breast tumors that arise in women who carry an <i>ATM</i> PV display a specific genome-wide DNA methylation profile. Specifically, the methylation pattern of 27 key gene promoters was predictive of <i>ATM</i> PV status of the women. These genes may also represent new medical prevention and therapeutic targets for these women.</p>

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Breast tumors from ATM pathogenic variant carriers display a specific genome-wide DNA methylation profile

  • 期刊论文

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  • 发表日期：

    2025年3月11日

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  • 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

摘要

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.