Genetic Versus Epigenetic BRCA1 Silencing Pathways

Sun, Tingting; Ruscito, Ilary; Dimitrova, Desislava; Chekerov, Radoslav; Kulbe, Hagen; Baron, Udo; Blanchard, Véronique; Panici, Pierluigi Benedetti; Darb‐Esfahani, Silvia; Sehouli, Jalid; Olek, Sven; Braicu, Elena Ioana

doi:10.1097/igc.0000000000001071

Cited by 9 publications

(4 citation statements)

References 38 publications

(24 reference statements)

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“…Although some studies have reported that BRCA1/RAD51C methylation is associated with a good prognosis, 35 , 36 , 37 other studies have described contradictory findings and poor reliability of this as a biomarker for PARPi response. 35 , 38 , 39 In a recent study of TCGA samples, epigenetically modified HRD cases were noted to have a similarly poor prognosis as HRD-negative cases. 26 …”

Section: Selecting Patients For Parpis: How Can We Best Identify Hrd?mentioning

confidence: 99%

The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?

Ngoi

Tan

2021

ESMO Open

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The recognition of homologous recombination deficiency (HRD) as a frequent feature of high-grade serous ovarian cancer (HGSOC) has transformed treatment paradigms. Poly(ADP-ribose) polymerase inhibitors (PARPis), developed based on the rationale of synthetic lethality that predicates antitumor efficacy in tumors harboring underlying HRD, now represents an important class of therapy for HGSOC. Recent data have drawn attention to the assessment of homologous recombination DNA repair (HRR) as a prognostic and predictive biomarker in HGSOC, leading to increasing debate on the optimal means of defining and evaluating HRD, both genotypically and phenotypically. At present, clinical-grade assays such as myChoice CDx and FoundationOne CDx are approved companion diagnostics which can identify patients with HRD-positive HGSOC by diagnosing a 'genomic scar' reflecting underlying genomic instability. Yet despite the rapid maturation of this field, tumoral HRD status has been recognized to be dynamic over time and with treatment pressure. In practice, this means that restoration of HRR through mechanisms of platinum and PARPi resistance are not adequately represented by genomic scar assays, and contribute toward discordance with clinical PARPi response, or lack-thereof. It is thus critical that HRD testing is optimized to address the controversies of diverse HRD testing methodology, appropriate thresholds for HRD identification, and relevant timepoints for HRD testing, in order to realize the potential for PARPis to maximally benefit patients with HGSOC. Here, we discuss the premise of HRD testing in HGSOC, current methodologies for HRD identification and their performance in the clinic, highlight upcoming strategies, and discuss the challenges faced in moving this field forward.

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Section: Selecting Patients For Parpis: How Can We Best Identify Hrd?mentioning

confidence: 99%

The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?

Ngoi

Tan

2021

ESMO Open

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“…BRCA1 methylation is detected in 9-15% of spontaneous cases of serous ovarian cancer, but does not seem to occur in concert with germline mutations [97, 120, 121]. Notably, ovarian cancer tissue methylation for the BRCA1 promoter, similar to germline BRCA1 mutation status, was associated with the high-grade serous cancer subtype and young age at diagnosis [122, 123]. In contrast to the frequencies reported in BRCA1 , methylation of BRCA2 occurs in <1% of ovarian cancers [124–126].…”

Section: Brca1 and Brca2 Epimutations In Breast And Ovarian Cancer Timentioning

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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“…Absent or reduced BRCA1 expression in tumors without BRCA1 pathogenic variants appears to be linked to hypermethylation of the BRCA1 promoter region [18], a condition reported in 9.1-37% of sporadic BCs and associated with infiltrating ductal carcinoma type, high tumor grade (grade II-III), ER negativity, basal marker expression, younger age at diagnosis, and poor prognosis [18][19][20][21][22][23][24][25][26][27][28][29]. Thus, BRCA1 promoter hypermethylation could be a marker of BRCA1 deficiency in the absence of BRCA1 mutation, as these two events appear to be almost mutually exclusive [23,[30][31][32][33][34], outside of the recently described association between a dominantly inherited 5' UTR variant, classified as likely pathogenic, and BRCA1 promoter hypermethylation [35]. In contrast, no BRCA2 promoter methylation is implicated in breast carcinogenesis and rarely so in ovarian cancer [36].…”

Section: Introductionmentioning

confidence: 99%

BRCA1 Promoter Hypermethylation is Associated with Good Prognosis and Chemosensitivity in Triple-Negative Breast Cancer

Jacot

Lopez-Crapez

Mollévi

et al. 2020

Cancers

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The aberrant hypermethylation of BRCA1 promoter CpG islands induces the decreased expression of BRCA1 (Breast Cancer 1) protein. It can be detected in sporadic breast cancer without BRCA1 pathogenic variants, particularly in triple-negative breast cancers (TNBC). We investigated BRCA1 hypermethylation status (by methylation-specific polymerase chain reaction (MS-PCR) and MassARRAY® assays), and BRCA1 protein expression using immunohistochemistry (IHC), and their clinicopathological significance in 248 chemotherapy-naïve TNBC samples. Fifty-five tumors (22%) exhibited BRCA1 promoter hypermethylation, with a high concordance rate between MS-PCR and MassARRAY® results. Promoter hypermethylation was associated with reduced IHC BRCA1 protein expression (p = 0.005), and expression of Programmed death-ligand 1 protein (PD-L1) by tumor and immune cells (p = 0.03 and 0.011, respectively). A trend was found between promoter hypermethylation and basal marker staining (p = 0.058), and between BRCA1 expression and a basal-like phenotype. In multivariate analysis, relapse-free survival was significantly associated with N stage, adjuvant chemotherapy, and histological subtype. Overall survival was significantly associated with T and N stage, histology, and adjuvant chemotherapy. In addition, patients with tumors harboring BRCA1 promoter hypermethylation derived the most benefit from adjuvant chemotherapy. In conclusion, BRCA1 promoter hypermethylation is associated with TNBC sensitivity to adjuvant chemotherapy, basal-like features and PD-L1 expression. BRCA1 IHC expression is not a good surrogate marker for promoter hypermethylation and is not independently associated with prognosis. Association between promoter hypermethylation and sensitivity to Poly(ADP-ribose) polymerase PARP inhibitors needs to be evaluated in a specific series of patients.

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Genetic Versus Epigenetic BRCA1 Silencing Pathways

Cited by 9 publications

References 38 publications

The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?

The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: do we need it?

Constitutional Mosaic Epimutations – a hidden cause of cancer?

BRCA1 Promoter Hypermethylation is Associated with Good Prognosis and Chemosensitivity in Triple-Negative Breast Cancer

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