Age dependency of the polygenic risk score for colorectal cancer

A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age ≥50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC.

Download Full-text

Abstract 881: Benchmarking genome-wide polygenic risk score development techniques in colorectal cancer risk prediction

10.1158/1538-7445.am2021-881 ◽

2021 ◽

Author(s):

Minta Thomas ◽

Lori C Sakoda ◽

Jeffrey K Lee ◽

Mark A Jenkins ◽

Andrea Burnett-Hartman ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Risk ◽

Risk Prediction ◽

Risk Score ◽

Colorectal Cancer Risk ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Genome Wide

Download Full-text

Precision Colorectal Cancer Screening with Polygenic Risk Score

10.1101/2020.08.19.20177931 ◽

2020 ◽

Author(s):

Tonis Tasa ◽

Mikk Puustusmaa ◽

Neeme Tonisson ◽

Berit Kolk ◽

Peeter Padrik

Keyword(s):

Colorectal Cancer ◽

Risk Score ◽

Association Studies ◽

Absolute Risk ◽

Specific Model ◽

Background Information ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

Common Cancer

Colorectal cancer (CRC) is the second most common cancer in women and third most common cancer in men. Genome-wide association studies have identified numerous genetic variants (SNPs) independently associated with CRC. The effects of such SNPs can be combined into a single polygenic risk score (PRS). Stratification of individuals according to PRS could be introduced to primary and secondary prevention. Our aim was to combine risk stratification of a sex-specific PRS model with recommendations for individualized CRC screening. Previously published PRS models for predicting the risk of CRC were collected from the literature. These were validated on the UK Biobank (UKBB) consisting of a total of 458 696 quality-controlled genotypes with 1810 and 1348 prevalent male cases, and 2410 and 1810 incident male and female cases. The best performing sex-specific model was selected based on the AUC in prevalent data and independently validated in the incident dataset. Using Estonian CRC background information, we performed absolute risk simulations and examined the ability of PRS in risk stratifying individual screening recommendations. The best-performing model included 91 SNPs. The C-index of the best performing model in the dataset was 0.613 (SE = 0.007) and hazard ratio (HR) per unit of PRS was 1.53 (1.47 - 1.59) for males. Respective metrics for females were 0.617 (SE = 0.006) and 1.50 (1.44 - 1.58). PRS risk simulations showed that a genetically average 50-year-old female doubles her risk by age 58 (55 in males) and triples it by age 63 (59 in males). In addition, the best performing PRS model was able to identify individuals in one of seven groups proposed by Naber et al. for different coloscopy screening recommendation regimens. We have combined PRS-based recommendations for individual screening attendance. Our approach is easily adaptable to other nationalities by using population-specific background data of other genetically similar populations.

Download Full-text

Novel Common Genetic Susceptibility Loci for Colorectal Cancer

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djy099 ◽

2018 ◽

Vol 111 (2) ◽

pp. 146-157 ◽

Cited By ~ 37

Author(s):

Stephanie L Schmit ◽

Christopher K Edlund ◽

Fredrick R Schumacher ◽

Jian Gong ◽

Tabitha A Harrison ◽

...

Keyword(s):

Colorectal Cancer ◽

Relative Risk ◽

Risk Score ◽

European Ancestry ◽

Polygenic Risk Score ◽

Susceptibility Loci ◽

Polygenic Risk ◽

Control Subjects ◽

Genome Wide ◽

Familial Relative Risk

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Download Full-text