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Study: Current models overestimate Ashkenazi breast-cancer risk

“Continued research to improve the accuracy of ethnicity-specific breast cancer risk prediction algorithms is required,” the researchers wrote.

A researcher in a medical lab. Credit: Viacheslav Lopatin/Shutterstock.
A researcher in a medical lab. Credit: Viacheslav Lopatin/Shutterstock.

Existing predictive models overstate the risks for Ashkenazi Jewish women of developing breast cancer. That’s according to a paper led by University of Manchester researchers, to be published next month in the journal Genetics in Medicine.

A major component of breast-cancer predictive models is something called a polygenic risk score, but these scores require calibration for different ethnicities.

“Ashkenazi Jewish population is assumed to be of white European origin in some commercially available polygenic risk scores,” the authors write. But there are important differences between the two that, if ignored, could skew models.

So the researchers—including Eleanor Roberts, a doctoral candidate in cancer studies at the University of Manchester, and Dr. Gareth Evans, a renowned cancer genetics scholar, also of Manchester—compared one study that had Ashkenazi and white European subjects with a study of Ashkenazi Jews from northern Israel.

Scholars from Carmel Medical Center and the Technion-Israel Institute of Technology, both in Haifa, were also part of the research team. The group was concerned that current risk assessment tools might misidentify women as higher risk than they truly are.

“We looked at an Ashkenazi group first, because we had the samples available to us through Gareth’s collaborations with Israeli institutions,” Roberts told JNS. “We’d already proved that the score was over-predicting risk.”

Given that there are commercially available polygenic risk scores available in the United States, the researchers thought it was important to study actual risks.

“It is essential that they continue to improve their accuracy, and that people are made aware of the limitations,” Roberts said.

About one in 40 Ashkenazi women has a mutation in a gene called BRCA, which puts that population at a higher risk of developing breast or ovarian cancer in middle age, according to the U.S. Centers for Disease Control and Prevention.

The higher prevalence of certain genetic mutations, such as BRCA 1 mutations and Tay-Sachs disease, in the Ashkenazi population can be attributed to what is called the “founder effect,” notes the National Gaucher Foundation. The effect occurs in populations that originate from a small group of ancestors, often due to persecution or isolation from other social groups. That isolation leads to a concentration of specific genetic variations, which can become more common over generations.

“We found that existing polygenic risk scores, designed mainly for white European populations, were overestimating breast-cancer risk in Ashkenazi Jewish women,” Roberts told JNS.

Unnecessary interventions

“This overestimation could lead to unnecessary interventions such as risk-reducing mastectomy, medications and extra screenings, causing undue stress and anxiety for women,” she added.

The scores employed in risk prediction rely on the analysis of single nucleotide polymorphisms—common genetic variants associated with increased risk of breast cancer. However, the existing scores are largely tailored to the genetic makeup of white European populations.

The forthcoming study recalibrated the scores to more accurately predict risk for Ashkenazi women, marking an advancement in personalized medicine.

“We wanted to validate whether what we did in the Ashkenazi women from the U.K. worked in Ashkenazi women from somewhere else,” Roberts told JNS. “We collaborated with researchers in Israel to ensure the recalibrated scores were effective across different Ashkenazi populations.”

The significance of this study extends beyond its immediate impact on risk prediction for Ashkenazi women, underscoring the growing realization that ethnic diversity must be better considered in health settings, according to Roberts.

“This research challenges the notion that one-size-fits-all genetic risk prediction models can be applied across diverse populations and we hope to continue researching to ensure people of all ethnicities are receiving the best health advice,” she said.

“While polygenic risk scores can provide valuable insights into genetic risk, they are not definitive predictors of disease,” Roberts said. “They offer probabilities based on genetic information and must be considered in conjunction with other factors, including family history, lifestyle and environmental exposures.”

According to Roberts, her and her colleagues’ research seems to be the first study to show that “we can use the existing polygenic risk scores if we recalibrate them so that they can be used across different ethnic groups, and we can be sure that we’re given the right risk.”

The study may pave the way for more precise risk assessments, but the path to clinical application remains complex.

“Polygenic risk scores are still novel, and their suitability for clinical use has not been approved in the U.K.,” Roberts told JNS.

Nicola Smith, senior health information manager at Cancer Research U.K., the country’s top charity for funding cancer research, also urged further investigation.

“This study suggests that existing genetic tests may overestimate breast cancer risk in women with Ashkenazi Jewish backgrounds and that the tests could be adjusted to make them more accurate,” she told JNS. “We need more research to see if adapted tests could help to avoid unnecessary extra testing and worry for people.

Genetic factors play important roles in causing cancer, but Smith stressed the importance of non-genetic factors in raising a person’s cancer risk.

“Most cancers are caused by gene faults that happen during our lifetime; only 5% to 10% of cancers are caused by inherited faulty genes,” she said. “If you think that you may have a strong family history of cancer and have any questions or concerns, talk to your doctor.”

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