Promoter Hypermethylation and BRCA1 Inactivation in Sporadic Breast and Ovarian Tumors

Esteller, Manel; Silva, José María; Domínguez, Gemma; Bonilla, Félix; Matías‐Guiu, Xavier; Lerma, Enrique; Bussaglia, Elena; Prat, Jaime; Harkes, I. Clara; Repasky, Elizabeth A.; Gabrielson, Edward; Schutte, Mieke; Baylin, Stephen B.; Herman, James G.

doi:10.1093/jnci/92.7.564

Cited by 1,069 publications

(738 citation statements)

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“…Promoter hypermethylation of TS genes can serve as the first and/or the second hit in Knudson's model of tumor development. Approximately 20% of sporadic, in particular triple‐negative breast cancers33, 34 and a subset of ovarian cancers35 display BRCA1 promoter hypermethylation. It seems plausible to assume that the few hypermethylated alleles that were observed in some BC and control samples represent stochastic or environmentally induced somatic epimutations.…”

Section: Discussionmentioning

confidence: 99%

Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation‐negative early‐onset and high‐risk breast cancer patients

Böck

Appenzeller

Haertle

et al. 2018

Intl Journal of Cancer

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To evaluate the role of constitutive epigenetic changes in normal body cells of BRCA1/BRCA2‐mutation negative patients, we have developed a deep bisulfite sequencing assay targeting the promoter regions of 8 tumor suppressor (TS) genes (BRCA1, BRCA2, RAD51C, ATM, PTEN, TP53, MLH1, RB1) and the estrogene receptor gene (ESR1), which plays a role in tumor progression. We analyzed blood samples of two breast cancer (BC) cohorts with early onset (EO) and high risk (HR) for a heterozygous mutation, respectively, along with age‐matched controls. Methylation analysis of up to 50,000 individual DNA molecules per gene and sample allowed quantification of epimutations (alleles with >50% methylated CpGs), which are associated with epigenetic silencing. Compared to ESR1, which is representative for an average promoter, TS genes were characterized by a very low (< 1%) average methylation level and a very low mean epimutation rate (EMR; < 0.0001% to 0.1%). With exception of BRCA1, which showed an increased EMR in BC (0.31% vs. 0.06%), there was no significant difference between patients and controls. One of 36 HR BC patients exhibited a dramatically increased EMR (14.7%) in BRCA1, consistent with a disease‐causing epimutation. Approximately one third (15 of 44) EO BC patients exhibited increased rates of single CpG methylation errors in multiple TS genes. Both EO and HR BC patients exhibited global underexpression of blood TS genes. We propose that epigenetic abnormalities in normal body cells are indicative of disturbed mechanisms for maintaining low methylation and appropriate expression levels and may be associated with an increased BC risk.

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Section: Discussionmentioning

confidence: 99%

Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation‐negative early‐onset and high‐risk breast cancer patients

Böck

Appenzeller

Haertle

et al. 2018

Intl Journal of Cancer

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“…As described by others [Cancer Genome Atlas Research, 2011], hypermethylation was mutually exclusive with germline and somatic BRCA1 and BRCA2 mutations. In line with previous reports [Esteller et al., 2000], we noticed that LOH of BRCA1 was observed in all OCs with methylation of the BRCA1 promoter, suggesting that the hypermethylation is driving the tumourigenesis and will probably lead to homologous recombination‐deficient tumors. Therefore, patients who develop OCs with hypermethylation of the BRCA1 promoter are predicted to benefit from PARP‐inhibitor treatments [Stefansson et al., 2012; Veeck et al., 2010].…”

Section: Discussionmentioning

confidence: 99%

NovelBRCA1andBRCA2Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas

et al. 2016

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With the recent introduction of Poly(ADP‐ribose) polymerase inhibitors, a promising novel therapy has become available for ovarian carcinoma (OC) patients with inactivating BRCA1 or BRCA2 mutations in their tumor. To select patients who may benefit from these treatments, assessment of the mutation status of BRCA1 and BRCA2 in the tumor is required. For reliable evaluation of germline and somatic mutations in these genes in DNA derived from formalin‐fixed, paraffin‐embedded (FFPE) tissue, we have developed a single‐molecule molecular inversion probe (smMIP)‐based targeted next‐generation sequencing (NGS) approach. Our smMIP‐based NGS approach provides analysis of both strands of the open reading frame of BRCA1 and BRCA2, enabling the discrimination between real variants and formalin‐induced artefacts. The single molecule tag enables compilation of unique reads leading to a high analytical sensitivity and enabling assessment of the reliability of mutation‐negative results. Multiplex ligation‐dependent probe amplification (MLPA) and Methylation‐specific multiplex ligation‐dependent probe amplification (MS‐MLPA) were used to detect exon deletions of BRCA1 and methylation of the BRCA1 promoter, respectively. Here, we show that this combined approach allows the rapid and reliable detection of both germline and somatic aberrations affecting BRCA1 and BRCA2 in DNA derived from FFPE OCs, enabling improved hereditary cancer risk assessment and clinical treatment of ovarian cancer patients.

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“…It is possible that other epigenetic changes might play a role in inactivating SAFB. Inactivations of tumour suppressor genes through methylation (Merlo et al, 1995;Esteller et al, 2000;Simpson et al, 2000), through altered ubiquitin degradation (Pagano et al, 1995;Tam et al, 1997;Scheffner, 1998;Zaika et al, 1999), and through mislocalization are increasingly recognized as alternative inactivating mechanisms. Our own Western blot analyses have demonstrated variations in the abundance of SAFB in breast tumour specimens -in 16% of the tumours (10/61), no SAFB protein was detectable even after prolonged exposure of X-ray films, and in an additional 3% (2/61), SAFB appeared to be truncated (Townson et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

High rates of loss of heterozygosity on chromosome 19p13 in human breast cancer

et al. 2001

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The oestrogen receptor (ER) is a nuclear steroid receptor that upon activation by its ligands (e.g. oestrogen) initiates a cascade of events resulting in increased cellular proliferation in its target tissues (Warner et al, 1999). Since oestrogen is one of the most potent mitogens for breast cancer cells, it is no surprise that ER is the most important target for endocrine therapy of breast cancer (Osborne, 1998). Recently, a number of factors which regulate nuclear hormone receptor activity have been identified. Cofactors capable of increasing receptor action, termed coactivators, include transcriptional intermediary factor 1 (TIF1), nuclear receptor interacting protein (NRIP1), nuclear receptor coactivator 2 (TIF2), steroid receptor coactivator 1 (SRC1), amplified in breast cancer 1 (AIB1), the cyclic AMP (cAMP)-response element binding protein (CREB) binding protein (CBP) (Glass et al, 1997;Shibata et al, 1997) and many more. The family of corepressors (negative regulators) of ER is smaller; the best characterized ones being the nuclear receptor corepressor (N-CoR) (Horlein et al, 1995;Shibata et al, 1997) the silencing mediator of retinoid and thyroid receptors (SMRT) (Chen and Evans, 1995;Sande and Privalsky, 1996) and the repressor of ER activity (REA) (Montano et al, 1999). The overexpression of coactivators or the loss of corepressors could lead to deregulation of oestrogen-dependent pathways related to mammary epithelial cell proliferation, and thus to breast tumorigenesis. And indeed, some of the ER cofactors have recently been characterized as playing major roles in breast tumorigenesis (Horlein et al, 1995;Anzick et al, 1997;Shibata et al, 1997). The ER coactivator AIB1 was cloned during a search on the long arm of chromosome 20 for genes whose expression and copy number are elevated in human breast cancer, and subsequent analysis in 105 breast tumour specimens confirmed its overexpression (Anzick et al, 1997). Interestingly, the breast/ovarian tumour suppressor gene BRCA1 has recently been characterized as an ER corepressor (Fan, 1999) again suggesting that ER coregulators are crucial in breast tumorigenesis. Thus, it might be expected that other ER coactivators and corepressors might play similar important roles in breast cancer development and progression.The nuclear matrix protein SAFB (Renz, 1996;Oesterreich, 1997) has been shown to be an ER corepressor . ER and SAFB interact in in-vitro binding assays (Glutathione-S-Transferase [GST]-pulldown assays) and in cell lines (co-immunoprecipitation experiments). In cell lines, there is binding of SAFB to ER in the presence or absence of oestradiol; however, binding is significantly increased by the antioestrogen tamoxifen. Overexpression of SAFB results in repression of oestrogen-mediated transactivation of gene expression by the ER. Furthermore, as a result of SAFB overexpression, the antagonist activity of tamoxifen on ER can be enhanced, and the agonist activity of tamoxifen can be inhibited.These results led us to investigate whether the ER corep...

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Promoter Hypermethylation and BRCA1 Inactivation in Sporadic Breast and Ovarian Tumors

Abstract: Silencing of the BRCA1 gene by promoter hypermethylation occurs in primary breast and ovarian carcinomas, especially in the presence of LOH and in specific histopathologic subgroups. These findings support a role for this tumor suppressor gene in sporadic breast and ovarian tumorigenesis.

Cited by 1,069 publications

References 30 publications

Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation‐negative early‐onset and high‐risk breast cancer patients

Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation‐negative early‐onset and high‐risk breast cancer patients

NovelBRCA1andBRCA2Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas

High rates of loss of heterozygosity on chromosome 19p13 in human breast cancer

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