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Combining Environmental, Polygenic Risk Factors May Improve Colorectal Cancer Screening


NEW YORK – A new risk score built of both environmental and genomic factors hints at a better way to identify people under 50 years of age who might benefit from earlier colorectal cancer screening.

The risk score was described in a recent study published in the Journal of the National Cancer Institute.

Widespread screening has lowered CRC case numbers among older adults, while the disease's incidence has risen among people under 50, prompting some experts to recommend earlier screening. The scientific and medical community, however, lacks consensus on how early to screen and how targeted early screening should be.

Because CRC is relatively easy to treat when caught early, advocates of early screening argue that the benefits outweigh concerns of unnecessary invasive procedures and their associated costs. The low absolute risk of cancer among younger people, however, suggests that a more targeted approach, such as an individualized risk-based approach, may be better.

"Our research is in response to this public health challenge," Richard Hayes, a professor of population health and environmental medicine at New York University and the study's co-first author, said via email. "Our results point to the possibility of determining at what age to begin screening, given a person's environmental and genetic risk profile."

While oncologists increasingly look to polygenic risk scores, or PRSs, to boost the accuracy of risk predictions in conjunction with other tests, these rarely show strong predictive power as standalone tools. In their study, Hayes and his colleagues analyzed whether adding an environmental risk score, or ERS, to a PRS could improve risk discrimination in early onset CRC cases.

The group analyzed data from 13 population-based studies, comprising 3,486 cases and 3,890 controls. The resulting combined score incorporates 141 single nucleotide polymorphisms and 16 environmental or lifestyle factors.

Environmental factors taken into consideration included BMI, educational attainment, history of type 2 diabetes, smoking status (ever versus never) as well as smoking habits, alcohol consumption, diet, and the use of various drugs, among others.

Although the ERS made a rather modest contribution to the overall score, the combined score outperformed either PRS or ERS individually. Those in the highest ERS quartile showed a 36 percent greater risk of early-onset CRC than those in the lowest quartile, compared to a 3.5-fold higher risk when comparing the highest and lowest PRS quartiles.

An individual's absolute risk of early-onset CRC was considerably smaller. The 10-year absolute risk of CRC for a 40-year-old in the 90th percentile of both ERS and PRS amounted, for instance, to 0.47 percent for men and 0.39 percent for women.

Risk estimates were lower when considering ERS alone, particularly at younger ages. The 10-year ERS-only estimates for 30-year-old men and women in the 90th percentile, for example, reached 0.07 percent and 0.06 percent, respectively.

Jonathan Mosely, a professor of medicine at the Vanderbilt University's Center for Precision Medicine, who was not involved in the study but whose research often involves analyzing the impacts of PRS on disease, isn't surprised by the low predictive power of environmental variables in this case.

"Early onset disease often has a larger genetic component," he said by email.

Hayes commented that the study represents early work and that "some risk factors may have been characterized incompletely."

Nonetheless, past research has suggested that even modest improvements in CRC screening may carry economic benefits.

An international study conducted in 2019, for instance, determined that a PRS meeting a certain statistical threshold called a c-statistic could drive lower testing prices and higher screening participation. The c-statistic measures the probability that a randomly selected individual,­ a patient in this case,­ who experienced CRC had a higher risk score than a patient who had not experienced it. The international study identified a lower threshold of 0.65, while the combined score in Hayes' study achieved a c-statistic of 0.631.

While this may improve as Hayes and his colleagues refine their tool, Mosely cautioned against relying on a modestly performing risk predictor, as this may miss many instances of early-onset disease.

"At present," he wrote, "[this] PRS would not be effective for early detection due to the combination of its modest performance characteristics and the low absolute risk of colon cancer prior to the age of 50."

An improved score, however, could lead to benefits associated with adopting a risk-based screening strategy.

"However," he remarked, "this would be a population-level benefit, which is important for the healthcare system, but not necessarily a gain for precision medicine."

Although Hayes agrees that the research remains at too early a stage to actively pursue the clinical adoption of this tool, much less commercialization, he and his colleagues do plan to move in that direction.

"Evaluation of the approach in large prospective studies, where people are interviewed before disease occurrence," he said, is the next step in that process.