Defects in the BRCA1 or BRCA2 genes are linked to an increased risk of breast and other cancers. The study, published in Nature Communications, reveals that the genetic background of people carrying these high-risk variants, as well as those linked to colorectal cancer and heart disease, can significantly lower the risk of developing the disease.
'Patients and clinicians often assume that having a high-risk variant makes eventually getting the disease all but inevitable, but an important subset actually go on to live their lives normally,' Dr Akl Fahed, co-first author of the study from Massachusetts General Hospital (MGH), said.
To better understand disease risk in people with single-gene variants, researchers at the Broad Institute, MGH and Harvard Medical School analysed genetic and clinical data from 80,928 participants. The cohort included 61,664 UK BioBank participants, and 19,264 women tested for high-risk breast cancer variants. The team assessed each participant's polygenic score, which takes into account the small contributions from many common gene variants found throughout the genome linked to disease, and then used medical records to determine whether participants developed the disease or not.
The study found that carrying a variant in either BRCA gene increased the likelihood of developing breast cancer, but risk varied considerably across participants. For women without a mutated gene, the average risk was ten percent, but ranged from 3.3-29.6 percent. Women with either BRCA1 or BRCA2 variants had an average risk of 35 percent of developing breast cancer. A risk gradient also emerged; in those with a high-risk variant, the chance of being diagnosed by the age of 75 ranged from 13-76 percent, with risk increasing with a higher polygenic score.
'The changes in risk are striking. For breast cancer, whether a woman's risk is 13 percent or 76 percent may be very important in terms of whether she chooses to get a mastectomy or undergo frequent screening via imaging,' said senior author Dr Amit Khera from MGH.
According to the team, using a 'polygenic risk score' may more accurately determine a person's genetic disease risk, and help explain why some who are genetically predisposed do not develop a disease.
Professor Paul Pharoah, an epidemiologist at the University of Cambridge who was not involved in the study, stressed to the Daily Mail that breast cancer risk in BRCA faulty gene carriers varies widely depending on lifestyle risk factors, as well as polygenic risk. The risk of breast cancer also changes with age, he added, which the authors did not take into account.
Nevertheless, the study could provide a foundation for new approaches for assessing disease risk in the clinic, and more accurately determining the frequency of screenings.