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 and to compute the lifetime incidence, respectively. Results Depending 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 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.

Ability of a polygenic risk score to refine colorectal cancer risk in Lynch syndrome

“…In contrast, studies using individuals from a population-based repository (UKBB) show a different distribution of affected MMR genes, with the vast majority of LS individuals carrying pathogenic variants in the moderate and low penetrance genes MSH6 or PMS2 (Table 4). In a gene-specific analysis, Hassanin et al, found that the modifying effect of the PRS is inversely related to the penetrance of the MMR gene, with the strongest effect in MSH6 and PMS2 carriers 19 , which are clearly underrepresented in the studies of Jenkins et al, 20 and the present. This is in line with hereditary breast cancer, where PRS has proven most relevant as a cancer risk modifier in carriers of pathogenic variants in moderate penetrance genes such as CHEK2, ATM, or PALB2 compared with BRCA1/2 33,34 .…”

“…CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) and Hassanin et al, 19 ) studies is differences in study design and recruitment strategies.…”

“…Initially, a small subset of common CRC-associated SNPs was analysed in selected LS cohorts [29][30][31][32] . More recently, some studies used a more comprehensive set of around 100 CRC-associated SNPs in large population-based or familial CRC cohorts with conflicting results 16,19,20 .…”

“…times more than the UKBB analyses 16,19 . Moreover, the distribution and composition of cases and controls differ between family-registry and population-based studies (Table 4).…”

Transferability of European-derived cardiometabolic polygenic risk scores in the South Asians and their interplay with family history

“…PRS can be a precious tool for risk stratification, particularly in identifying groups of people with extremely high or low genetic risk of developing a specific disease or trait. Moreover, based on our recent work and others, it has become clear that for certain traits high PRS along with rare disease-causing variants can further increase the individuals' risk of developing a disease compared to carriers without a high PRS (4)(5)(6)(7).…”