A study carried out in Estonia on healthy relatives of breast and ovarian cancer patients shows around 20% of those tested carried some form of genetic variant that increased their risk of developing cancer.
The study showed that BRCA1/2 cancer-associated variants, currently the most widely recognized and tested cancer predisposition genes overall, accounted for 58.4% of all pathogenic variants uncovered by the investigators, but 41.6% were in non-BRCA genes.
“A carrier rate of 19.7% is remarkably high compared with the general population and strongly supports broader and more systematic genetic testing of relatives in families affected by breast and ovarian cancer,” lead investigator Mikk Tooming, PhD, a researcher at the Institute of Clinical Medicine in Tartu, Estonia, told Inside Precision Medicine.
“The highest yield was observed when a pathogenic variant was already known in the family… However, even among relatives without a previously identified familial variant, 8% carried a pathogenic variant. This is a clinically meaningful detection rate and suggests that genetic testing should not be restricted only to families in which a specific variant has already been identified.”
The current study, published in Frontiers in Genetics, included 3,472 healthy family members of people with breast and ovarian cancer. Of these individuals, 88% were female and 12% male. Most of those tested (79%) were younger than 51 years, which is when cancer screening often starts.
The researchers retrospectively analyzed genetic results from the family members, tested at four hospitals between 2007 and 2023. Testing evolved from targeted Sanger sequencing and microarrays in the early years to broad multigene next generation screening panels covering up to 6,700 genes by 2023.
Overall, around 20% of the tested family members carried a pathogenic or likely pathogenic variant. This went up to 41.8% when a familial variant was already known, versus 8.0% when it was not. BRCA1/2 variants accounted for most variants, but 23 genes were implicated in total, with CHEK2, ATM, BRIP1, and PALB2 also prominent.
Notably, the youngest group tested, those who were 30 years or younger, were more likely to have a cancer risk variant than older groups with a rate of 28%. “Age is highly relevant because many hereditary cancer syndromes begin to confer increased cancer risk well before routine screening starts,” says Tooming. “Identifying carriers early allows surveillance and prevention plans to be implemented at the most appropriate time.”
Despite being under tested, the carrier rate of risk variants in the men tested was high at 34%. Breast and ovarian cancers are thought of as predominantly female conditions. While women may be more impacted by these cancers than men, men can also carry relevant risk variants and these can increase their risk of developing other cancers.
“Both healthcare providers and families may focus testing efforts on women, unintentionally overlooking men,” emphasizes Tooming. “This highlights a significant gap in current practice. Male carriers, particularly those with BRCA2 variants, have elevated risks of prostate cancer, male breast cancer, pancreatic cancer, and several other malignancies. Health systems should actively promote genetic counselling and testing for male relatives when hereditary cancer risk is suspected.”
The researchers support expanded testing but believe that earlier and more personalized genetic risk assessment, for example, in families known to be impacted by cancer, would produce better results than simply lowering the age of cancer screening.
“The data suggest that individuals from families affected by breast and ovarian cancer should undergo earlier evaluation for hereditary cancer risk. When a pathogenic variant is identified, surveillance should be tailored according to the specific gene and associated cancer risk,” says Tooming.
“While our study did not include longitudinal follow-up and therefore cannot directly measure reductions in cancer incidence or mortality, the high proportion of carriers identified before standard screening age strongly suggests that expanded testing has the potential to deliver substantial public health benefits in Estonia and elsewhere.”
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