New BRCA1 variant found to be associated with familial breast/ovarian cancer
A dominantly inherited 5′ UTR variant causing methylation-associated silencing of BRCA1 as a cause of breast and ovarian cancer.
American Journal of Human Genetics
Elke M. van Veen, D. Gareth R. Evans, Helen J. Byers, Andrew J. Wallace, Jamie M. Ellingford, Glenda Beaman, Javier Santoyo-Lopez, Timothy J. Aitman, Diana M. Eccles, Fiona I. Lalloo, Miriam J. Smith, William G. Newman
Researchers from NIHR Manchester Biomedical Research Centre have identified a new mechanism which switches off a gene in families affected by breast and ovarian cancer.
Researchers at The University of Manchester have found a new genetic change that results in familial breast and ovarian cancer.
Currently, cancer-causing variations in BRCA1 or BRCA2 are identified in around one of five families with multiple women with early-onset breast and ovarian cancer. Angelina Jolie was found to carry a variant in the BRCA1 gene associated with her own increased family risk.
However, for many women, the cause of breast and ovarian cancer in their families remains unknown. In this study, the researchers screened families with a high chance of having a genetic cause for their cancer. They looked in the regions around the BRCA1 gene to see if there were any possible changes that could explain the diagnosis.
This is the first research to identify a variant just before the start of BRCA1 to cause breast and ovarian cancer in two families. This variant is seen together with another modification that switches off the gene from working. This is called an 'epigenetic silencing' mechanism and has never been seen before in patients with inherited breast cancer.
Although this might be a rare mechanism, it may be the explanation for some families with early-onset breast and ovarian cancer.
- Genetic changes can be inherited from generation to generation and increase the risk of breast cancer and other disorders.
- Sometimes changes outside the gene can switch a gene off and stop it from working. This on-off switch (called the promoter) has been turned off in these families and passed from generation to generation.
- Tests for BRCA1 and BRCA2 should include testing of the upstream region of at least 120 nucleotides before the start of the gene.
- Families that look very typical for a BRCA1 family with triple negative breast cancer or high grade serous ovarian cancer that have previously tested negative should be tested for the variant and promotor methylation (epigenetic silencing).
- This is the first time this mechanism called an epigenetic change has been shown for women with inherited breast cancer. This mechanism may be important for other types of inherited cancer.
- Manchester University NHS Foundation Trust
- Faculty of Medicine, University of Southampton
- Edinburgh Genomics, University of Edinburgh
- Manchester BRC: Researchers identify a novel type of genetic change resulting in inherited breast cancer
- Prevent Breast Cancer: Epigenetic silencing and what it means for inherited breast cancer
- Genome Web: Variant Linked to BRCA1 Silencing Found in Two Families Affected by Breast, Ovarian Cancer
- News Medical: Researchers discover new mechanism linked to inherited breast, ovarian cancer