Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence

Abstract

Background and aims: Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification. Methods: To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes (APC, MLH1, MSH2, MSH6, PMS2), 2. low (<20%), intermediate (20-80%), or high PRS (>80%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios (OR) and to compute the lifetime incidence, respectively. Results: Depend-ing on the PRS, the CRC lifetime incidence for non-carriers ranges between 6% and 22%, compared to 40% and 74% for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26% for non-carriers and 98% for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve (AUC) in risk prediction (0.704). Conclusion: The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups.

Influence of family history on penetrance of hereditary cancers in a population setting

“… 33 Among pathogenic variant carriers for both HBOC and Lynch syndrome, the probability of disease by age 75 has been estimated to range from 13 to 76% for breast cancer and 11–80% for colon cancer respectively, based on different polygenic background, but again this analysis did not specifically analyse the effect of having a first-degree relative with the disease. 34 Recent work in a smaller subset of UK Biobank has also shown consistent results in colorectal cancer, highlighting the added value of family history in combination with polygenic risk scores. 35 The penetrance of HBOC amongst clinically unselected pathogenic BRCA1/2 variant carriers was previously shown to be significantly different between those with and without a family history (83% versus 60% to age 60 for BRCA1 , and 76% versus 33% to age 80 for BRCA2 ), but the study was limited to just three variants that are relatively common in the Ashkenazi Jewish population of Israel.…”

Influence of family history on penetrance of hereditary cancers in a population setting

“…Among pathogenic variant carriers for both HBOC and Lynch syndrome, the probability of disease by age 75 has been estimated to range from 13-76% for breast cancer and 11-80% for colon cancer respectively, based on different polygenic background, but again this analysis did not specifically analyse the effect of having a first-degree relative with the disease 31 . Recent work in a smaller subset of UK Biobank has also shown consistent results in colorectal cancer, highlighting the added value of family history in combination with polygenic risk scores 32 . The penetrance of HBOC amongst clinically unselected pathogenic BRCA1/2 variant carriers was previously shown to be significantly different between those with and without a family history (83% versus 60% to age 60 for BRCA1, and 76% versus 33% to age 80 for BRCA2), but the study was limited to just three variants that are relatively common in the Ashkenazi Jewish population of Israel 33 .…”