Colorectal cancer, currently one of the leading causes of cancer mortality in Western nations, was one of the first cancer types in which the inherited nature of the disease became evident. Family-based studies on inherited colorectal cancer since the 1960s uncovered a distinctly single-gene pattern of inheritance, exemplified by conditions like the Lynch Syndrome, the most common, yet still rare inherited colorectal cancer syndrome. Decades later, pioneering early research had laid the groundwork for identifying the disease-causing genetic variants and molecular mechanisms in the affected families. Currently, healthcare professionals can utilize this information to assist affected families with genetic screening and early cancer detection.
Beyond rare inherited cancer syndromes, research groups worldwide have more recently begun to understand how common (rather than rare) genetic variants are linked to colorectal cancer. Studying common genetic variants, each with a small effect contributing to the disease, is made possible with genome-wide association studies which compare the genetic makeup of tens of thousands of patients diagnosed with the cancer to those without a diagnosis. While each of these common variants identified in these large studies explain only a very small part of the genetic susceptibility to colorectal cancer, their combined effect can be equally significant as rare mutations in the single-gene conditions. Therefore, one goal of our team’s research conducted at the Institute for Molecular Medicine Finland in Helsinki, Finland, is to determine to what degree this common genetic variation explains why some people are more susceptible to diseases such as colorectal cancer. Currently, these high-risk individuals go undetected in healthcare. One potential benefit of having knowledge of this genetic susceptibility could be to use it to optimize colorectal cancer screening by accounting for genetic risk profiles, similarly as genetic and molecular screening have been championed for decreasing the burden of inherited colorectal cancer syndromes such as the Lynch Syndrome.
In our recent study, we provide insights into these questions using large-scale genetic and health data from Finland included in the FinnGen biobank study, which contains the genetic and health registry data for approximately half a million Finns. In one of the largest studies to date, we developed a genome-wide polygenic risk score (PRS) for colorectal cancer and show that the combined impact of an individual’s genetic risk factors represented in the single score, PRS, can identify those who have a higher inherited risk for the disease. Importantly, the PRS is able to identify individuals who develop the disease sooner. By employing robust epidemiological and statistical approaches to calibrate our estimates with the Finnish population, we were able to study PRSs at larger scale and in more detail compared to most previous studies with smaller datasets which might not be representative of the general population.
With many Western nations currently intensifying colorectal cancer screening due to its increased occurrence in younger adults, basing the required intensity of the screening on factors such as PRS could yield better and more cost-effective screening results. For example, in Finland, routine screening for colorectal cancer with fecal immunochemical testing currently starts at age 60. Based on this screening age, our data show that individuals with a high PRS, as compared to those with a low PRS, could start routine screening up to 18 years apart based on their PRS alone. As an example, women and men at the top 1% of the PRS compared to the average population at age 60 already had equivalent risks at ages 48.9 and 49.3, respectively. Importantly, we found a corresponding result using earlier screening ages employed elsewhere, such as the United States, where colorectal cancer screening with colonoscopy is currently recommended to start at age 45.
Graphical abstract showing the impact of polygenic risk score for colorectal cancer on lifetime risk of the disease. Adapted from Tamlander et al. Br J Cancer (2024).
The PRS was also strongly linked to the occurrence of colorectal adenomas, which are precursor growths for colorectal cancer. This was an important finding, as removing adenomas with screening tests such as colonoscopy is one of the main aims of early prevention of colorectal cancer. Our study further showed that the PRS predicted future 10-year colorectal cancer risk after having no findings in colonoscopy among adults who had undergone colonoscopy. This suggests benefits of more frequent surveillance in patients with a high PRS. Conversely, individuals with a low PRS had a significantly decreased risk of having colorectal cancer after colonoscopy. This suggests that in low-risk individuals, screening could potentially be started later and performed less frequently.
As the costs of genotyping technologies continue to fall, there is growing potential in PRS approaches to not only tailor colorectal cancer screening but also prediction of other prevalent diseases such as cardiovascular disease. Millions of individuals already have their genetic information stored in biobanking projects; for instance, the FinnGen biobank study used in our study currently contains the genomic and health registry data of more than 9% of the entire Finnish population. A notable advantage of PRSs is that genetic data obtained from a single sample can be used over the course of life, without needing any additional blood samples.
To merit their use for tailoring screening, PRS-based approaches still need to undergo further studies, including cost-effectiveness evaluation, to establish the efficacy of risk-based screening. One additional obstacle for the immediate use of existing PRSs is that they have predominantly been tested based on individuals of European ancestry. However, our findings align with previous studies from our team in Helsinki and others on PRSs for breast cancer, another common cancer in which population-level screening is commonly organized. For breast cancer, large-scale clinical trials that assess the effectiveness of similar approaches are currently underway and should also elucidate the potential role of PRS in risk-based colorectal cancer screening.
In summary, our study suggests that PRSs are informative of personal colorectal cancer risk and could be used to identify those individuals whose inherited colorectal cancer risks sharply diverge from those who do not have an increased genetic burden for the disease. Importantly, most colorectal cancer cases occur in individuals without a family history of the disease or other identifiable strong risk factors, and PRSs could therefore aid in assessing risk in such individuals in addition to factors such as age, sex, and family history of colorectal cancer. As the predictive performance of PRSs for colorectal cancer continue to improve with increasing data and improved methodology, our findings speak in favor of further studies to enhance our understanding of the impacts of PRSs for improving screening and prevention of the disease.
References
Tamlander, M., Jermy, B., Seppälä, T.T. et al. Genome-wide polygenic risk scores for colorectal cancer have implications for risk-based screening. Br J Cancer (2024). https://doi.org/10.1038/s41416-023-02536-z
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