BRCA Methylation Implicated in Breast Cancer Carcinogenesis

Tunisian women who had no family history of breast cancer or BRCA mutation were investigated for the methylation status of BRCA1 and BRCA2 promoters using methylation-specific PCR. Breast cancer is the most common malignancy among women in Tunisia, and breast cancer in Tunisia is characterized by its increased incidence of a younger age at onset and a more aggressive tumor phenotype.

Study examines methylation status of Tunisian women with no family history of breast cancer or BRCA mutation. By: Dr. Lise Alschuler

Reference
Ben Gacem, Hachana M, Ziadi S, et al. Contribution of epigenetic alteration of BRCA1 and BRCA2 genes in breast carcinomas in Tunisian patients. Cancer Epidemiol. 2011 Oct 4. [Epub ahead of print].

Design
A paired retrospective cohort study

Participants
Breast carcinoma tissues from 117 Tunisian women diagnosed and treated for invasive breast cancer in Farhat Hached Hospital in Sousse, Tunisia, from 1995 to 2007 and paired normal breast tissues (available from 65 patients) were matched with 21 frozen non-tumor breast tissue specimens from women without carcinoma (16 fibroadenomas and 5 cases of mastopathies) as controls. The age of patients at diagnosis ranged from 31 to 87 years, with a median of 47. The selection criteria included: the availability of frozen breast carcinoma tissue samples obtained at the time of primary surgery, no preoperative treatment, and no family history of breast cancer.

Study Parameters Assessed
Tunisian women who had no family history of breast cancer or BRCA mutation were investigated for the methylation status of BRCA1 and BRCA2 promoters using methylation-specific PCR.

Key Findings
Breast cancer is the most common malignancy among women in Tunisia, and breast cancer in Tunisia is characterized by its increased incidence of a younger age at onset and a more aggressive tumor phenotype. The familial contribution to the breast cancer by genetic mutation does not represent more than 10% of cases, but epigenetic alterations appear to contribute to risk. Based upon the findings of this analysis, methylation of CpG island cell repair genes, namely BRCA1 and BRCA2, was increased in cancerous tissue over healthy tissue.

This study indicates that women without these inherited mutations can acquire some degree of this risk by epigenetically silencing their genes via methylation.

Methylation of BRCA1 was found in 71 (60.7%) cases of the 117 tumors examined, and BRCA2 methylation was found in 81 (69.2%) cases. Both BRCA1 and BRCA2 genes were simultaneously methylated in 52 cases (44.4%). Additionally, there was a bimodal pattern to the methylation such that BRCA1 methylation was detected in 73% of the patients below the age of 37 and in 72% of the patients over the age of 55 (P=0.04). This was compared to 50% of patients between the ages of 37 and 55 displaying BRCA1 methylation. Additionally, there was a significant correlation between BRCA1 methylation and triple negative (ER-, PR-, HER2-) tumors (P=0.01) and higher histological grade tumors [70% in grade III and 61% in grades I and II (P=0.08)]. BRCA2 methylation, on the other hand, was not correlated with grade, tumor size, or receptor stat

Practice Implications

Overall, the high prevalence of methylated BRCA1 and BRCA2 suggests that methylation of these repair genes plays an important role in breast carcinogenesis. In effect, methylation of BRCA1 and/or BRCA2 is an epigenetic corollary of inherited mutations of BRCA1 and BRCA2. Mutation carriers have a significant lifetime risk of developing breast and ovarian cancer. This study indicates that women without these inherited mutations can acquire some degree of this risk by epigenetically silencing their genes via methylation.

This finding provides additional support to the importance of epimutagenetics in the risk of developing cancer. Methylation of CpG islands, segments of promoter DNA upstream to cell repair and tumor suppressor genes, is characteristic of many cancer types. Methylation of the CpG islands is considered to be a late, but critical, feature of carcinogenesis. Methylated CpG islands lead to transcriptional silencing of the adjacent gene, leaving the cell vulnerable to increasing cellular instability, aneuploidy, and ultimately malignancy. Various medical and lifestyle strategies are being investigated for their impact on methylation patterns. An emerging body of evidence points to the importance of dietary polyphenols, epigallocatechin gallate in particular, in reversing hypermethylation of CpG islands.1

One seemingly paradoxical finding of this study was that, after adjustment for covariates, patients with one or both methylated BRCA1 and BRCA2 had significantly better survival than those with unmethylated tumors (P=0.002). This survival benefit was postulated to be the result of the fact that methylation of BRCA1 and BRCA2 diminishes cell repair capacity in response to chemotherapy agents. This, in turn, increases sensitivity to chemotherapy. This suggests that while CpG island cell repair gene methylation is implicated in carcinogenesis, this same inhibition of cell repair facilitates the cytotoxic action of chemotherapy.

Limitations

This study was relatively small, and the results may not be generalizable to women outside of Tunisia.

Reference

1. Yang CS, Fang M, Lambert JD, Yan P, Huang TH. Reversal of hypermethylation and reactivation of genes by dietary polyphenolic compounds. Nutr Rev. 2008;66(suppl.1):S18-S20.