Methylation profiling in promoter sequences of ATM and CDKN2A (p14ARF/p16INK4a) genes in blood and cfDNA from women with impalpable breast lesions

Delmonico, Lucas; Costa, Mauricio Augusto Silva Magalhães; Gomes, Romario José; Vieira, Pâmella De Oliveira; Silva, Ana Beatriz Passos Da; Fournier, Marcia V.; Scherrer, Luciano Rios; Azevedo, Carolina Maria de; Ornellas, Maria Helena; Alves, Gilda

doi:10.3892/ol.2020.11382

Cited by 7 publications

(7 citation statements)

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“…A small number of studies have explored the Oncomine cfDNA Assay in breast cancer; one was limited to advanced disease, 28 whereas another was used to determine whether mutations could be identified in cfDNA from serum stored for 30 years. 29 We also investigated the prevalence of CHIP-derived mutations in ctDNA, normal hemopoietic cells accumulating somatic mutations during the aging process in the absence of cancer. 14 Such mutations can potentially arise in highly sensitive next-generation sequencing data because of inaccurate variant calling, sequencing artifacts, and somatic tumor-relevant SNPs.…”

Section: Discussionmentioning

confidence: 99%

“…Since the inception of this study, several groups have reported different assays potentially capable of helping in the differential diagnosis of breast diseases, and thus are candidate blood tests for use as a part of a screening strategy. These include DNA methylation analysis, 29 ctDNA fragmentation assays, 22 and a multianalyte platform. 23 Our results show that screening with the assay could be used in combination with other such strategies, and future studies could focus on developing technologies to improve sensitivity, determining the added value of measuring other analytes, 23 and the application of machine learning 22 in improving diagnostic accuracy.…”

Section: Discussionmentioning

confidence: 99%

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Circulating Tumor DNA Profiling From Breast Cancer Screening Through to Metastatic Disease

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Martinson

Fernández-García

et al. 2021

JCO Precision Oncology

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PURPOSE We investigated the utility of the Oncomine Breast cfDNA Assay for detecting circulating tumor DNA (ctDNA) in women from a breast screening population, including healthy women with no abnormality detected by mammogram, and women on follow-up through to advanced breast cancer. MATERIALS AND METHODS Blood samples were taken from 373 women (127 healthy controls recruited through breast screening, 28 ductal carcinoma in situ, 60 primary breast cancers, 47 primary breast cancer on follow-up, and 111 metastatic breast cancers [MBC]) to recover plasma and germline DNA for analysis with the Oncomine Breast cfDNA Assay on the Ion S5 platform. RESULTS One hundred sixteen of 373 plasma samples had one or more somatic variants detected across eight of the 10 genes and were called ctDNA-positive; MBC had the highest proportion of ctDNA-positive samples (61; 55%) and healthy controls the lowest (20; 15.7%). ESR1, TP53, and PIK3CA mutations account for 93% of all variants detected and predict poor overall survival in MBC (hazard ratio = 3.461; 95% CI, 1.866 to 6.42; P = .001). Patients with MBC had higher plasma cell-free DNA levels, higher variant allele frequencies, and more polyclonal variants, notably in ESR1 than in all other groups. Only 15 individuals had evidence of potential clonal hematopoiesis of indeterminate potential mutations. CONCLUSION We were able detect ctDNA across the breast cancer spectrum, notably in MBC where variants in ESR1, TP53, and PIK3CA predicted poor overall survival. The assay could be used to monitor emergence of resistance mutations such as in ESR1 that herald resistance to aromatase inhibitors to tailor adjuvant therapies. However, we suggest caution is needed when interpreting results from a single plasma sample as variants were also detected in a small proportion of HCs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Circulating Tumor DNA Profiling From Breast Cancer Screening Through to Metastatic Disease

Page

Martinson

Fernández-García

et al. 2021

JCO Precision Oncology

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“…Breast cancer is the most common cancer associated with high mortality rates among women worldwide [3]. The silencing of tumor suppressor genes by hypermethylation is an essential epigenetic mechanism in breast tumorigenesis [20]. Epigenetic alterations differ from genetic ones primarily in their greater frequency, incomplete reversibility, and their location in fixed genome regions.…”

Section: Discussionmentioning

confidence: 99%

SCGB3A1 gene DNA methylation status is associated with breast cancer in Egyptian female patients

Nomair

Ahmed

Mohammed

et al. 2021

Egypt J Med Hum Genet

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Background In recent years, hypermethylation of gene promoters has emerged as one of the fundamental mechanisms for the inactivation of tumor suppressor genes and has a potential role in the early detection of breast cancer. The present study is a case-control study aimed to quantify the methylation levels in the promoters of secretoglobin 3A1 (SCGB3A1), and ataxia-telangiectasia mutated (ATM) genes and evaluate their relation to clinicopathological features of the tumor in a cohort of Egyptian female patients with breast cancer. Methods Genomic deoxyribonucleic acid (DNA) was extracted from 100 tissue samples, 50 breast cancer tissues and 50 adjacent non-cancerous breast tissues, then, it was subjected to bisulfite conversion. The converted DNA was amplified by real-time PCR; then, pyrosequencing was performed to quantify DNA methylation levels in four CpG sites in ATM and SCGB3A1 gene promoters. The methylation data were presented as the percentage of average methylation of all the observed CpG sites and were calculated for each sample and each gene. Results The percentage of DNA methylation of the SCGB3A1 promoter was significantly higher in the tumor group than in the normal group (P= 0.001). However, a non-statistical significance difference was found in the DNA methylation percentage of the ATM promoter in the tumor group compared to the normal group (P = 0.315). The SCGB3A1 promoter methylation frequency was significantly associated with estrogen receptors (ER) and progesterone receptors (PR) positive tumors, lymph node metastasis, and lymphovascular invasion. However, no association was found between ATM methylation status and the different clinicopathological features of the tumor. Conclusions The findings of this work showed that the SCGB3A1 promoter methylation was significantly higher in the tumor group and was significantly associated with different clinicopathologic features in breast cancer. It may be considered as a suitable biomarker for diagnosis and prognosis. However, the promoter methylation levels of the ATM gene in breast cancer cases were unable to distinguish between breast cancer tissues and adjacent normal tissues, and there is no evidence that epigenetic silencing by ATM methylation has a role in breast cancer pathogenesis.

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“…Delmonico et al investigated plasma cfDNA from women with and without impalpable breast lesions to detect the epigenetic alterations and observed that ATM and p14 ARF showed higher methylation rates in samples from women with malignant lesions and older than 50 years. 38 Thus, the authors described the potential detection of epigenetic changes in liquid biopsy to monitor the impalpable breast lesions.…”

Section: Methylation Signature In Cfdnamentioning

confidence: 99%

Tracking the history of circulating nucleic acids for cancer research in Brazil: A systematic review

Chantre-Justino

Delmonico²,

Lage

et al. 2022

BJHBS

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Introduction: Circulating nucleic acids can be obtainedby minimally invasive procedures based on liquid biopsy,which has emerged as a promising area of investigation forscreening and monitoring cancer treatment. Currently, testsbased on circulating nucleic acid analysis, specifically cellfreeDNA (cfDNA), are commercially available for diagnosticand prognostic investigation of a number of neoplasms. Objective:To describe the research on circulating nucleic acidmarkers for cancer prospecting in Brazil, since this area hasadvanced rapidly in recent years. Methods: In this systematicreview, we surveyed Brazilian publications in cancer researchfocused on cfDNA and cfRNA present in different fluids. BothMEDLINE-PUBMED and EMBASE databases were inspectedusing terms such as “circulating nucleic acids”, “cancer”, and“Brazil”. Results: The search returned 326 articles, in which28 Brazilian translational studies were eligible. Differentmethodologies were reported for different types of cancer,in which cfDNA from plasma was the most investigatedbiological material. Molecular investigations included quantification,somatic mutation, RNA expression, genotyping,microsatellites, blood protein interaction, and methylation.Discrepancies in the regional distribution of the studies werealso observed. Conclusion: Studies on circulating nucleic acidmarkers have advanced significantly in the oncology field,but many others are needed to better address the clinicalpractice in Brazil.

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Methylation profiling in promoter sequences of ATM and CDKN2A (p14ARF/p16INK4a) genes in blood and cfDNA from women with impalpable breast lesions

Cited by 7 publications

References 44 publications

Circulating Tumor DNA Profiling From Breast Cancer Screening Through to Metastatic Disease

Circulating Tumor DNA Profiling From Breast Cancer Screening Through to Metastatic Disease

SCGB3A1 gene DNA methylation status is associated with breast cancer in Egyptian female patients

Tracking the history of circulating nucleic acids for cancer research in Brazil: A systematic review

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