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Variant Linked to BRCA1 Silencing Found in Two Families Affected by Breast, Ovarian Cancer

NEW YORK (GenomeWeb) – Researchers have uncovered a variant that leads to the epigenetic silencing of the BRCA1 gene in families affected by breast and ovarian cancer.

Germline mutations in BRCA1 and BRCA2 are found in about 20 percent of families in which multiple members are affected by early-onset breast and ovarian cancer. But for other families, the cause of their breast and ovarian cancer has been unclear.

Researchers from the University of Manchester screened nearly 50 individuals from affected families and uncovered two women with hypermethylated BRCA1 promoters. As they reported yesterday in the American Journal of Human Genetics, the researchers found that these two families harbored a dominantly inherited 5'UTR variant that leads to epigenetic silencing of BRCA1.

"This means that by testing this area outside of the gene and this on/off switch into our existing genetic testing could allow us to identify more women who are at greater risk of developing breast and ovarian cancer and look at preventative treatment and also rule out those at lower risk," first author Gareth Evans from the NIHR Manchester Biomedical Research Center said in a statement.

Promoter hypermethylation, the researchers noted, is present in about 10 percent of sporadic breast cancers and is also found in the breast tumors of women with germline pathogenic variants.

In this study, they screened lymphocyte-derived DNA from 49 unrelated individuals from families with multiple members affected by breast and ovarian cancer using a methylation assay. All the individuals screened had previously been assessed though Sanger sequencing and an MLPA assayof the BRCA1 and BRCA2 coding exons but no pathogenic single-nucleotide or copy-number variant was detected.

Two women in the cohort had hypermethylated BRCA1 promoters. One had been diagnosed with breast cancer at the age of 39 and ovarian cancer at 48, while the other woman was diagnosed with breast cancer at the age of 38 and at again 46.

The methylation assay results, the researchers noted, was consistent with BRCA1 promoter hypermethylation across 10 CpG dinucleotides, which they said indicated that one allele was fully methylated. They repeated this analysis using DNA extracted from buccal mucosa and hair samples and found the same pattern.

When the researchers expanded their analysis to the women's family members, they found hypermethylation in individuals affected by cancer and in healthy individuals. RNA sequencing oflymphocyte-derived RNA further indicated allelic imbalance and that one allele is not expressed.

The researchers also performed Sanger sequencing of the gene region and uncovered a heterozygous variant in a region upstream of the BRCA1 translation start site in one woman from each family. This c._107A>T variant segregated with the hypermethylated BRCA1 allele in all family members the researchers tested and was absent from those without it, indicating that it was in a cis state.

According to the researchers, this variant is not present in the gnomAD or BRCA Exchange databases, nor was it present in the other families in the analysis cohort. In both of these families, the researchers found the variant on an ancestral B1 haplotype, indicating they could share a common ancestry.

Just how this variant leads to BRCA1 methylation isn't yet clear, though the researchers said they are now working to find out. Still, they noted that this mechanism could explain some of the missing heritability in familial breast and ovarian cancer.

"This research could eventually allow us to offer additional screening to those who have a strong family history of breast cancer but do not have the mutated BRCA gene," Lester Barr, the chair of Prevent Breast Cancer, said in a statement. "This could potentially save thousands of women and men from developing genetic breast cancers."