A large international team of researchers led by the Mayo Clinic in the US has discovered that some individuals whose risk of breast cancer may be increased by carrying a variant of the BRCA1 gene may also possess other gene variants that can modify that risk, bringing closer the day when it will be possible to determine individual risk for breast cancer in carriers of BRCA1.
You can read about the findings that led to this discovery, and other insights, in a paper published online on 19 September in the journal Nature Genetics.
Among the 180 co-authors who contributed as individuals and as members of several consortia are first author Dr Antonis Antoniou of the Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care at the University of Cambridge in the UK, and senior study investigator Dr Fergus Couch of the Department of Laboratory Medicine and Pathology, at the Mayo Clinic in Rochester, Minnesota, in the US.
People who carry certain mutations of the BRCA1 gene are known to have a higher risk of developing breast cancer.
Couch told the media that their findings should be “useful in helping determine individual risk for breast cancer in BRCA1 carriers”.
“It also provides insights into hormone-receptor-negative breast cancer in the general population,” he added.
For the study, Couch and colleagues conducted four phases of genome-wide association studies (GWAS) that altogether involved 20 research centers in 10 North American and European countries and Israel.
For the first phase, to identify candidate gene variants, they scanned the genomes of 1,193 carriers of BRCA1 mutations who were under 40 and had invasive breast cancer and compared them to scans of about the same number of controls: BRCA1 carriers of similar age who did not have breast cancer.
In comparing the genomes from the two populations the researchers examined over half a million genetic alterations. They found 96 pieces of DNA called SNPs, or “snips”, short for single nucleotide polymorphisms, that they thought would be likely candidates because they differed between the two populations.
To narrow down the list, they moved into the second phase of the study, where they looked at just the 96 SNPs in another two groups: one of about 3,000 BRCA1 carriers with breast cancer and a matched group of carriers without breast cancer. From this second phase they narrowed the 96 SNPs down to five linked to breast cancer. The five SNPs were all in a region of chromosome 19p13.
In a third phase, where the researchers examined the genomes of 6,800 breast cancer patients who did not have the cancer-linked BRCA1 mutations, they found links between the newly discovered five SNPs and estrogen-receptor-negative (ER-) disease (ER- cancer is where the tumors don’t possess estrogen receptors).
And in a fourth phase, the researchers found that the same five SNPs were also linked to another aggressive form of breast cancer known as triple-negative breast cancer, which occurs in around 12 per cent of breast cancers. For this phase they scanned the genomes of 2,300 triple-negative cases and 3,949 controls. (Triple negative breast cancer tumors don’t express genes for estrogen or progesterone receptors or Her2/neu).
The researchers also determined that the five SNPs were not linked to higher risk of ovarian cancer among carriers of the breast cancer-prone variants of BRCA1.
The researchers concluded that by identifying these five SNPs, we are in a better position to understand the mechanisms behind the development of breast cancer, and if further risk-modifying SNPs are found (the team is continuing the search), it may one day be possible to identify which BRCA1 carriers are at lower risk of developing breast cancer, and who may be at higher risk, giving them the opportunity to change their approach to cancer prevention.
Funds from the Breast Cancer Research Foundation, Susan G. Komen for the Cure, the National Institutes of Health, all in the US, and Cancer Research UK paid for the research.
“A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.”
Antonis C Antoniou, Xianshu Wang, Zachary S Fredericksen, Lesley McGuffog, Robert Tarrell, Olga M Sinilnikova, Sue Healey, Jonathan Morrison, Christiana Kartsonaki, Timothy Lesnick, Maya Ghoussaini, Daniel Barrowdale, EMBRACE, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Diana Eccles, D Gareth Evans, Ros Eeles, Louise Izatt, Carol Chu, Fiona Douglas, Joan Paterson, Dominique Stoppa-Lyonnet, & Fergus J Couch et al.
Additional sources: Mayo Clinic.
Written by: Catharine Paddock, PhD