BRCA1 methylation in newborns: genetic disposition, maternal transfer, environmental influence, or by chance only?

Lønning, Per Eystein; Knappskog, Stian

doi:10.1186/s13148-018-0566-0

Cited by 5 publications

(4 citation statements)

References 14 publications

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“…Interestingly, Al-Moghrabi and colleagues reported a potential association between BRCA1 methylation status in mothers and their newborns [154]. While the data did not allow for formal statistical assessment, their explorative analysis indicated a moderate correlation, albeit not in accordance with Mendelian dominant inheritance [155]. Importantly, their findings do not define whether there was a paternal or maternal transfer of methylation.…”

Section: Brca1 Promoter Hypermethylation May Be a Constitutional Evenmentioning

confidence: 99%

Constitutional Mosaic Epimutations – a hidden cause of cancer?

Lønning¹,

Eikesdal²,

Løes³

et al. 2019

CST

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Silencing of tumor suppressor genes by promoter hypermethylation is a key mechanism to facilitate cancer progression in many malignancies. While promoter hypermethylation can occur at later stages of the carcinogenesis process, constitutional methylation of key tumor suppressors may be an initiating event whereby cancer is started. Constitutional BRCA1 methylation due to cis -acting germline genetic variants is associated with a high risk of breast and ovarian cancer. However, this seems to be a rare event, restricted to a very limited number of families. In contrast, mosaic constitutional BRCA1 methylation is detected in 4-7% of newborn females without germline BRCA1 mutations. While the cause of such methylation is poorly understood, mosaic normal tissue BRCA1 methylation is associated with a 2-3 fold increased risk of high-grade serous ovarian cancer (HGSOC). As such, BRCA1 methylation may be the cause of a significant number of ovarian cancers. Given the molecular similarities between HGSOC and basal-like breast cancer, the findings with respect to HGSOC suggest that constitutional BRCA1 methylation could be a risk factor for basal-like breast cancer as well. Similar to BRCA1 , some specific germline variants in MLH1 and MSH2 are associated with promoter methylation and a high risk of colorectal cancers in rare hereditary cases of the disease. However, as many as 15% of all colorectal cancers are of the microsatellite instability (MSI) “high” subtype, in which commonly the tumors harbor MLH1 hypermethylation. Constitutional mosaic methylation of MLH1 in normal tissues has been detected but not formally evaluated as a potential risk factor for incidental colorectal cancers. However, the findings with respect to BRCA1 in breast and ovarian cancer raises the question whether mosaic MLH1 methylation is a risk factor for MSI positive colorectal cancer as well. As for MGMT , a promoter variant is associated with elevated methylation across a panel of solid cancers, and MGMT promoter methylation may contribute to an elevated cancer risk in several of these malignancies. We hypothesize that constitutional mosaic promoter methylation of crucial tumor suppressors may trigger certain types of cancer, similar to germline mutations inactivating the same particular genes. Such constitutional methylation events may be a spark to ignite cancer development, and if associated with a significant cancer risk, screening for such epigenetic alterations could be part of cancer prevention programs to reduce cancer mortality in the future.

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Section: Brca1 Promoter Hypermethylation May Be a Constitutional Evenmentioning

confidence: 99%

Constitutional Mosaic Epimutations – a hidden cause of cancer?

Lønning¹,

Eikesdal²,

Løes³

et al. 2019

CST

Self Cite

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“…shows that epimutations like promoter hypermethylation can be passed on through generations and can lead to cancer predisposition [36][37][38]. Recent studies have also shown the presence of BRCA1 hypermethylation in pregnant adults and its maternal transfer to their newborns [39,40]. Another recent report suggests that constitutive BRCA1 hypermethylation may be responsible for early onset breast cancers [41].…”

Section: Discussionmentioning

confidence: 99%

BRCA1 Hypermethylation In Sporadic Breast Cancers: Discovering A Novel Pathway To Tumorigenesis Via Coordinate NBR2 Deregulation And TNBC Transformation

Patra

Varghese

Jaikumar

et al. 2022

Preprint

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Women with a family history of mutations in the Breast cancer susceptibility gene, BRCA1 will have an increased risk of developing breast neoplasms. However, majority of the breast cancers are sporadic where BRCA1 mutations are very rare. Instead, 5-65% of sporadic cases manifest BRCA1 promoter hypermethylation and 30-40% of such cases are develop into Triple Negative Breast Cancers. Even then, the molecular mechanism of BRCA1 hypermethylation mediated breast tumorigenesis has remained an enigma till date. Here, we present a novel tumorigenesis pathway for breast cancers that engenders from BRCA1 hypermethylation by using a modified version of CRISPR technology.We report that induction of site-specific methylation on BRCA1 promoter α effectuates a downregulation in BRCA1 expression via alteration in the balance between its alternate transcripts β and α. Induced BRCA1 hypermethylation is also responsible for the attenuation of a long noncoding RNA, NBR2 (Neighbour of BRCA1 gene 2), which is transcribed through the bidirectional BRCA1 promoter α in the reverse direction. Downregulation of NBR2 activates a feedback loop by leading to further downregulation of BRCA1 which is more evident under glucose starvation conditions and is associated with an impaired DNA damage repair pathway. Further, BRCA1 hypermethylation also results in significant overexpression of β-hCG (human chorionic gonadotrophin), which was found to be associated with highly aggressive and drug-resistant forms of BRCA1 mutated breast cancers invitro & in vivo in our previous study. Finally, we report a variation in the hormone receptor levels as the tumor progresses which suggests how BRCA1 deficient cells modulate their expression of ER-α and ER-β to promote their proliferation in early stages of tumor development and at later stages, transform to a basal tumor subtype by shedding down the expression of ER-α & PR.GRAPHICAL ABSTRACT

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“…Our observation of a significant level of BRCA1 methylation in healthy controls is consistent with its previous observation in the white blood cells of healthy women 54,55 , suggesting the origin of this signal may be from hematopoietic cells rather than ctDNA. Whether this is an inherited epimutation that represents a risk factor for the development of breast cancer 56,57 , or is a spontaneous event that may represent a "first hit" 58 , has not been resolved 57 . Its relatively weak association in our control population with an abnormal mammogram and previous breast biopsy indicates further study will be needed to determine its role as a marker of a benign or pre-cancerous state.…”

Section: Nfic-a Nfic-b Nr5a2-b Otx2-a Pax6-a Pbdmrta Trim Pbscand Trim Pbtal Trim Pdx1exp-b Phox2b-a Ppfia3-a Prdm13 Prkcb-a Prkcb-c Prssmentioning

confidence: 99%

A DNA methylation-based liquid biopsy for triple-negative breast cancer

et al. 2021

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Here, we present a next-generation sequencing (NGS) methylation-based blood test called methylation DETEction of Circulating Tumour DNA (mDETECT) designed for the optimal detection and monitoring of metastatic triple-negative breast cancer (TNBC). Based on a highly multiplexed targeted sequencing approach, this assay incorporates features that offer superior performance and included 53 amplicons from 47 regions. Analysis of a previously characterised cohort of women with metastatic TNBC with limited quantities of plasma (<2 ml) produced an AUC of 0.92 for detection of a tumour with a sensitivity of 76% for a specificity of 100%. mDETECTTNBC was quantitative and showed superior performance to an NGS TP53 mutation-based test carried out on the same patients and to the conventional CA15-3 biomarker. mDETECT also functioned well in serum samples from metastatic TNBC patients where it produced an AUC of 0.97 for detection of a tumour with a sensitivity of 93% for a specificity of 100%. An assay for BRCA1 promoter methylation was also incorporated into the mDETECT assay and functioned well but its clinical significance is currently unclear. Clonal Hematopoiesis of Indeterminate Potential was investigated as a source of background in control subjects but was not seen to be significant, though a link to adiposity may be relevant. The mDETECTTNBC assay is a liquid biopsy able to quantitatively detect all TNBC cancers and has the potential to improve the management of patients with this disease.

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BRCA1 methylation in newborns: genetic disposition, maternal transfer, environmental influence, or by chance only?

Cited by 5 publications

References 14 publications

Constitutional Mosaic Epimutations – a hidden cause of cancer?

Constitutional Mosaic Epimutations – a hidden cause of cancer?

BRCA1 Hypermethylation In Sporadic Breast Cancers: Discovering A Novel Pathway To Tumorigenesis Via Coordinate NBR2 Deregulation And TNBC Transformation

A DNA methylation-based liquid biopsy for triple-negative breast cancer

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