High-level tumour methylation of BRCA1 and RAD51C is required for homologous recombination deficiency in solid cancers

TL;DR

This study explores how methylation of BRCA1 and RAD51C genes affects homologous recombination deficiency in various solid cancers, suggesting their potential as biomarkers for PARP inhibitors.

Contribution

The study identifies high-level methylation of BRCA1 and RAD51C as a novel biomarker for homologous recombination deficiency across multiple cancer types.

Findings

BRCA1 methylation is associated with reduced gene expression, LOH, TP53 mutations, and HRD features in endometrial and other cancers.

RAD51C methylation is common in some cancers but only leads to HRD features when combined with high-level methylation and LOH.

RAD51C methylation is frequently linked to CpG island methylator phenotype in certain cancers.

Abstract

In ovarian and breast cancer, promoter methylation of BRCA1 or RAD51C is a promising biomarker for PARP inhibitor response, as high levels lead to homologous recombination deficiency (HRD). Yet the extent and role of such methylation in other cancers is not clear. This study comprehensively investigated promoter methylation of eight homologous recombination repair genes across 23 solid cancer types. Here, we showed that BRCA1 methylated cancers were associated with reduced gene expression, loss of heterozygosity (LOH), TP53 mutations and genomic features of HRD. We identified BRCA1 methylation in 3% of the copy-number high subtype of endometrial cancer, and as a rare event in six other cancer types, including lung squamous cell, pancreatic, bladder and stomach cancer. RAD51C promoter methylation was widespread across multiple cancer types, but HRD features were only observed for cases which contained high-level tumour methylation and LOH of RAD51C. While RAD51C methylation was frequent in stomach adenocarcinoma (6%) and low-grade glioma (2.5%), it was mostly detected at a low tumour level, suggestive of heterozygous methylation, and was associated with CpG island methylator phenotype. Our findings indicate that high-level tumour methylation of BRCA1 and RAD51C should be explored as a PARP inhibitor biomarker across multiple cancers.

Graphical Abstract

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