PrenatalBRCA1epimutations contribute significantly to triple-negative breast cancer development

Abstract

AbstractBackgroundNormal cellBRCA1epimutations have been associated with increased risk of triple-negative breast cancer (TNBC). However, the fraction of TNBCs that may haveBRCA1epimutations as their underlying cause is unknown.MethodsTo address this question, we analyzedBRCA1methylation status in breast cancer tissue and matched white blood cells (WBC) from 411 patients with primary breast cancer, including 66 TNBCs, applying a highly sensitive sequencing assay, allowing allele-resolved methylation assessment. Further, to assess the time of origin and the characteristics of normal cellBRCA1methylation, we analyzed umbilical cord blood of 1260 newborn girls.ResultsWe found concordant tumor and mosaic WBCBRCA1epimutations in 10 out of 66 patients with TNBC and in four out of six patients with estrogen receptor (ER)-low expression (<10%) tumors (combined: 14 out of 72; 19.4%; 95% CI 11.1–30.5). In contrast, we found concordance in only three out of 221 patients with ER≥10% tumors and zero out of 116 patients with HER2-positive tumors. Intraindividually,BRCA1epimutations affected the same allele in normal and tumor cells. AssessingBRCA1methylation in umbilical WBCs from girls, we found mosaic, predominantly monoallelicBRCA1epimutations, with qualitative features similar to those in adults, in 113/1260 (9.0%) of individuals.ConclusionsOur findings reveal prenatalBRCA1epimutations to be the underlying cause of around 20% of TNBC and low-ER expression breast cancers.