Estonian study highlights value of early genetic tests to identify hereditary cancer risks

In 2013, Angelina Jolie inspired a wave of testing for pathogenic variants of the gene BRCA1 by announcing that she carried a variant which left her at such high risk of breast cancer, she chose a preventive mastectomy. Many people with similar gene variants won't need risk-reducing surgery, but knowing if you carry a dangerous variant could be lifesaving. Researchers reviewing the genetic testing results of healthy family members of breast and ovarian cancer patients in Estonia found that 19.7% of them carried variants which elevate their cancer risk. This included 34% of men tested.

"Hereditary cancer risk is both more common and more actionable than often assumed," said Dr Mikk Tooming of the Institute of Clinical Medicine in Tartu, Estonia, lead author of the article in Frontiers in Genetics. "People with a family history of breast or ovarian cancer - especially those with multiple affected relatives or early-onset cases - should strongly consider genetic counselling and, where appropriate, genetic testing. Our data show that a substantial proportion of pathogenic variant carriers are identified before the typical screening age, suggesting that relying solely on standard population screening may delay detection of elevated risk.

"Our study also highlights that men should not be overlooked. Male carriers of pathogenic variants, particularly in BRCA2, face increased risks for prostate and other cancers, and may benefit from earlier and more targeted screening." 

Knowledge is power 

To understand how common these genes are in affected families, the scientists collected data on 3,472 people who had undergone testing in Estonia between 2007 and 2023. Most of these people had been referred because their family members had breast or ovarian cancer, and doctors suspected a possible hereditary link.

"Early identification of carriers allows individuals to access tailored risk management strategies," explained Tooming. "These include enhanced surveillance, such as earlier and more frequent breast imaging, and in some cases, consideration of risk-reducing options. For high-risk variants such as BRCA1 and BRCA2, this may involve prophylactic surgery. However, such decisions are highly individual and should always be made in the context of genetic counselling, taking into account personal risk, age, and preferences." 

Of the 3,472 people who received testing, 87.6% were women, and 12.4% were men. The mean age at testing was 41, ten years younger than Estonia's standard cancer screening age, but 78.6% of people tested were even younger. Alarmingly, people under 30 were most likely to test positive for pathogenic variants. However, the detection of dangerous variants in people over 71, when standard screening usually ends, indicates that continued attention is necessary for older patients too. 

19.7% of the participants tested positive for pathogenic variants, a much larger proportion than would be expected in the general population. 23 different variants were identified, but almost 59% of those detected were accounted for by BRCA1 or BRCA2 variants.

Just under a third of the participants had a family member carrying a known variant, and of this group, 41.8% carried a relevant variant themselves. Among the remaining two-thirds, 8% carried pathogenic variants. Male participants were unlikely to get tested if there were no known pathogenic variants in the family, but a third of them tested positive for at least one. 

"The results support earlier genetic risk assessment rather than simply lowering screening age thresholds," said Tooming. "They also strongly support broader and more systematic genetic testing among relatives, particularly when a familial pathogenic variant is identified. The relatively high detection rate we observed, including among individuals without a previously known familial variant, suggests that broader access to multigene panel testing could improve identification of at-risk individuals." 

Known unknowns 

The scientists point out that changes in the quality and accessibility of testing over time could affect their findings. Only three people were tested in 2007, while 731 underwent testing in 2023. An analysis of the data also showed that more pathogenic variants were identified after 2015, when next-generation sequencing became readily available. This means that many patients whose variants would be identified today may have been missed in earlier years. More research is also needed to understand the prevalence of high-risk variants in other populations. 

"Genetic testing and earlier risk assessment in families affected by breast and ovarian cancer can inform healthcare policy and guide the implementation of preventive programs," said Tooming. "In the future, we would like to see population-based screening approaches beyond family-history criteria, strategies to improve male participation in genetic testing, and experimental work aimed at understanding the biological and clinical impact of less common or moderate-risk pathogenic variants."