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

In ovarian and breast cancer, promoter methylation of or 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 methylated cancers were associated with reduced gene expression, loss of heterozygosity (LOH), mutations and genomic features of HRD. We identified 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. 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 . While 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 and should be explored as a PARP inhibitor biomarker across multiple cancers.