Approximately 50% of breast cancers arise in women without discernible risk factors apart from gender (female) and age (over 40 years). While a family history of breast cancer elevates the risk, the majority of women diagnosed with breast cancer lack a documented familial predisposition to the disease. Scientists are exploring various factors, including genes and the environment, to comprehend the etiology of cancer. A noteworthy area of research is ‘epimutations,’ referring to changes in the regulation of genes, determining whether they are activated or deactivated.
Recently, researchers from the University of Bergen and the US Women’s Health Initiative collaborated on a study that identified a connection between specific epimutations of the BRCA1 gene and an increased risk of triple-negative breast cancer (TNBC). Published in the journal Genome Medicine, this new study revealed that breast cancer may stem from a small group of normal tissue cells carrying an epimutation in the BRCA1 gene. This discovery is expected to contribute to the development of more effective treatments for TNBC, currently one of the most challenging forms of breast cancer to address.
Nikolaienko and colleagues conducted a comprehensive analysis of the methylation status of BRCA1 in breast cancer tissue and matched WBCs from 408 patients with 411 primary breast cancers. The study, which included 66 cases of TNBCs, employed a highly sensitive sequencing assay enabling allele-resolved methylation assessment. Furthermore, they examined umbilical cord blood samples from 1260 newborn girls and 200 newborn boys to understand the timing and characteristics of normal cell BRCA1 methylation. Lastly, the team investigated the BRCA1 methylation status in 575 mothers and 531 fathers of girls, comparing those with (n = 102) and without (n = 473) BRCA1 methylation.
According to the study, 10 out of 66 patients with TNBC and four out of six patients with estrogen receptor (ER) had low expression tumors, the researchers found concordant tumor and mosaic WBC BRCA1 epimutations (a total of 14 out of 72, which is 19.4% with a 95% CI of 11.1–30.5). However, in contrast, they only found concordant WBC and tumor methylation in three out of 220 patients with 221 ER ≥ 10% tumors and zero out of 114 patients with 116 human epidermal growth factor receptor 2 (HER2)-positive tumors. The researchers found that intra-individually, BRCA1 epimutations affected the same allele in normal and tumor cells. In addition, the study found mosaic, predominantly monoallelic BRCA1 epimutations in umbilical WBCs from girls, with qualitative features similar to those in adults, in 113/1260 (9.0%) of individuals, but no correlation to BRCA1 methylation status either in mothers or fathers. The study also found that a significantly lower fraction of newborn boys carried BRCA1 methylation (9/200; 4.5%) compared to girls (P = 0.038). Similarly, WBC BRCA1 methylation was less common among fathers (16/531; 3.0%) as compared to mothers (46/575; 8.0%; P = 0.0003).
Consistent with this study, Lonning et al. (2022) observed a significant association between constitutional normal tissue BRCA1 promoter methylation and the risk of developing TNBC and high-grade serous ovarian cancers. This discovery carries potential implications for predicting the occurrence of these cancer types.
The researchers have concluded that prenatal BRCA1 epimutations may be the underlying cause of around 20% of TNBC and breast cancers with low estrogen receptor expression. The constitutional mosaic BRCA1 methylation observed is likely a result of gender-related mechanisms in utero, operating independently of Mendelian inheritance. This discovery underscores the importance of considering epigenetic factors in the prenatal environment when exploring the origins of certain breast cancers.
References
- Nikolaienko O, Eikesdal HP, Ognedal E, Gilje B, Lundgren S, Blix ES, et al. Prenatal BRCA1 epimutations contribute significantly to triple-negative breast cancer development. Genome Medicine. 2023 Dec 6;15(1):104.
- Lønning PE, Nikolaienko O, Pan K, Kurian AW, Eikesdal HP, Pettinger M, et al. Constitutional BRCA1 Methylation and Risk of Incident Triple-Negative Breast Cancer and High-grade Serous Ovarian Cancer. JAMA Oncology. 2022 Nov 1;8(11):1579–87.