TOPLINE

An integrated inherited risk measure was significantly associated with the risk for early-onset colorectal cancer (CRC) among adults younger than 50 years, with the risk substantially higher in the very high-risk group than in the low-risk group.

METHODOLOGY

• An integrated inherited risk measure (GenProbCRC) was developed to quantify inherited susceptibility to CRC independent of age. However, its ability to independently predict early-onset CRC beyond family history and pathogenic variants in Lynch syndrome genes remains unclear.
• Researchers conducted a prospective cohort study to examine the association between GenProbCRC and early-onset CRC.
• They included participants who were younger than 50 years at recruitment and free of CRC at baseline from two independent cohorts: the UK Biobank (n = 102,797) and a US health system-based biobank (n = 7206).
• GenProbCRC integrated a polygenic risk score, family history, and pathogenic variants in Lynch syndrome genes and was used to categorize participants into four prespecified risk groups: low, intermediate, high, and very high risk.
• Participants were followed up from recruitment until the diagnosis of CRC, age 50 years, death, loss to follow-up, or the end of available follow-up.

TAKEAWAY

• In the UK Biobank cohort, 109 participants developed early-onset CRC. The risk for early-onset CRC was nearly sixfold higher in the high-risk group (hazard ratio [HR], 5.95; P < .001) and more than 28-fold higher in the very high-risk group (HR, 28.41; P < .001) than in the low-risk group, whereas no significant difference in risk was observed between the low-risk and intermediate-risk groups.
• By the age of 50 years, the cumulative incidence of early-onset CRC increased progressively across risk groups: 0.08% in the low-risk, 0.11% in the intermediate-risk, 0.46% in the high-risk, and 2.06% in the very high-risk groups (log-rank P < .001).
• Individuals in the high- and very high-risk groups accounted for 61% of early-onset CRC cases despite representing approximately 21% of the population.
• In the US health system-based biobank cohort, 14 incident cases of early-onset CRC were reported. Associations were directionally consistent, although estimates were less precise because of the limited number of early-onset CRC events; similar cumulative incidence patterns to those observed in the UK Biobank cohort were also seen.

IN PRACTICE

"These findings suggest that integrated inherited risk captures a broader segment of elevated-risk individuals beyond traditional monogenic and FH [family history]–based approaches, many of whom would not be identified by FH or monogenic testing alone," the authors wrote.

SOURCE

The study was led by Zhuqing Shi, Program for Genomic Translational Research, Endeavor Health in Evanston, Illinois. It was published online in Gastro Hep Advances.

LIMITATIONS

The number of early-onset CRC events was modest, particularly in the US health system-based biobank, which limited the precision of subgroup analyses. The observational study design left the possibility of residual confounding. Lifestyle risk factors were not completely incorporated into risk stratification.

DISCLOSURES

The study did not receive any specific funding. Endeavor Health has agreements with GenomicMD and GoPath Diagnostics for genetic tests of polygenic risk scores. One author disclosed serving as a scientific advisory board member for GoPath Diagnostics and GenomicMD.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.