scholarly journals Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3857
Author(s):  
Pilar Mur ◽  
Nuria Bonifaci ◽  
Anna Díez-Villanueva ◽  
Elisabet Munté ◽  
Maria Henar Alonso ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Score ◽  
Early Onset ◽  
Low Risk ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Pathogenic Variants ◽  
Predisposing Genes ◽  
The Mean ◽  
Early Onset 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.

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

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

scholarly journals Polygenic risk score validation using Korean genomes of 265 early-onset acute myocardial infarction patients and 636 healthy controls

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246538
Author(s):  
Youngjune Bhak ◽  
Yeonsu Jeon ◽  
Sungwon Jeon ◽  
Changhan Yoon ◽  
Min Kim ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Prediction ◽  
Risk Score ◽  
Early Onset ◽  
Area Under The Curve ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Repeat Revascularization ◽  
Artery Disease ◽  
Conventional Risk Factors

Background The polygenic risk score (PRS) developed for coronary artery disease (CAD) is known to be effective for classifying patients with CAD and predicting subsequent events. However, the PRS was developed mainly based on the analysis of Caucasian genomes and has not been validated for East Asians. We aimed to evaluate the PRS in the genomes of Korean early-onset AMI patients (n = 265, age ≤50 years) following PCI and controls (n = 636) to examine whether the PRS improves risk prediction beyond conventional risk factors. Results The odds ratio of the PRS was 1.83 (95% confidence interval [CI]: 1.69–1.99) for early-onset AMI patients compared with the controls. For the classification of patients, the area under the curve (AUC) for the combined model with the six conventional risk factors (diabetes mellitus, family history of CAD, hypertension, body mass index, hypercholesterolemia, and current smoking) and PRS was 0.92 (95% CI: 0.90–0.94) while that for the six conventional risk factors was 0.91 (95% CI: 0.85–0.93). Although the AUC for PRS alone was 0.65 (95% CI: 0.61–0.69), adding the PRS to the six conventional risk factors significantly improved the accuracy of the prediction model (P = 0.015). Patients with the upper 50% of PRS showed a higher frequency of repeat revascularization (hazard ratio = 2.19, 95% CI: 1.47–3.26) than the others. Conclusions The PRS using 265 early-onset AMI genomes showed improvement in the identification of patients in the Korean population and showed potential for genomic screening in early life to complement conventional risk prediction.

scholarly journals Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease

2018 ◽  
Vol 62 ◽  
pp. 244.e1-244.e8 ◽  
Author(s):  
Sultan Chaudhury ◽  
Tulsi Patel ◽  
Imelda S. Barber ◽  
Tamar Guetta-Baranes ◽  
Keeley J. Brookes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Score ◽  
Early Onset ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Early Onset Alzheimer’S Disease

scholarly journals Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms

2017 ◽  
Vol 14 (2) ◽  
pp. 205-214 ◽  
Author(s):  
Carlos Cruchaga ◽  
Jorge L. Del-Aguila ◽  
Benjamin Saef ◽  
Kathleen Black ◽  
Maria Victoria Fernandez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Score ◽  
Early Onset ◽  
Late Onset ◽  
Polygenic Risk Score ◽  
Polygenic Risk

scholarly journals Polygenic risk score for schizophrenia is more strongly associated with ancestry than with schizophrenia

2018 ◽  
Author(s):  
David Curtis
Keyword(s):  
Risk Score ◽  
Conflict Of Interest ◽  
Genome Wide Association Study ◽  
Mean Difference ◽  
Polygenic Risk Score ◽  
Psychiatric Genetics ◽  
Polygenic Risk ◽  
Large Numbers ◽  
Genome Wide ◽  
The Mean

AbstractBackgroundThe polygenic risk score (PRS) for schizophrenia, derived from very large numbers of weakly associated genetic markers, has been repeatedly shown to be robustly associated with schizophrenia in independent samples and also with other diseases and traits.AimsTo explore the distribution of the schizophrenia PRS in subjects of different ancestry.MethodThe schizophrenia PRS derived from the large genome-wide association study carried out by the Psychiatric Genetics Consortium was calculated using the downloaded genotypes of HapMap subjects from eleven different ancestral groups. It was also calculated using downloaded genotypes of European schizophrenia cases and controls from the CommonMind Consortium.ResultsThe PRS for schizophrenia varied significantly between ancestral groups (p < 2*10−16) and was much higher in African than European HapMap subjects. The mean difference between these groups was ten times as high as the mean difference between European schizophrenia cases and controls. The distributions of scores for African and European subjects hardly overlapped.ConclusionsThe PRS cannot be regarded as simply a measure of the polygenic contribution to risk of schizophrenia and clearly contains a strong ancestry component. It is possible that this could be controlled for to some extent by incorporating principal components as covariates but doubts remain as to how it should be interpreted. The PRS derived from European subjects cannot be applied to non-Europeans, limiting its potential usefulness and raising issues of inequity. Previous studies which have used the PRS should be re-examined in the light of these findings.Declaration of interestThe author declares he has no conflict of interest.

scholarly journals Precision Colorectal Cancer Screening with Polygenic Risk Score

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.

The BARCODE1 pilot study targeting men with increased genetic risk of developing prostate cancer: Examining the feasibility of a community-based screening program using polygenic risk score to target screening.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 227-227
Author(s):  
Jana Kathlyn McHugh ◽  
Sarah Benafif ◽  
Holly ni Raghallaigh ◽  
Elizabeth Bancroft ◽  
Zsofia Kote-Jarai ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Primary Care ◽  
Dna Extraction ◽  
Risk Score ◽  
Genetic Risk ◽  
Population Screening ◽  
Low Risk ◽  
Polygenic Risk Score ◽  
Genetic Profiling ◽  
Polygenic Risk

227 Background: A significant proportion of Prostate cancer (PrCa) risk is attributable to heritable risk factors of which only a minority are high risk Mendelian traits. A greater proportion of PrCa is due to the combined effect of multiple low risk variants. There have been approximately 170 single nucleotide polymorphisms (SNPs) identified that are associated with PrCa risk in Europeans. Although each of these confer a low to moderate risk of PrCa, the cumulative risk (polygenic risk score, PRS) of increasing numbers of these risk alleles may confer a substantial relative risk. In PrCa genetic profiling, using PRS, could be used to target population screening to those at highest risk. BARCODE1 is the first study to prospectively review the use of a genetic profile in PrCa screening in the general population in the UK. Methods: Our study invited healthy males aged 55-69 to participate through their Primary Care physicians. Collection kits were mailed to retrieve saliva samples. Genotyping was carried out after DNA extraction using a study specific assay and the PRS was calculated for each participant using the sum of weighted alleles for 130 risk loci. Prostate MRI and Biopsy were then offered to men in the top 10% of the genetic risk profile. Results: 1434 men were invited by letter to participate. The uptake was 26%, of whom 87% of men were eligible for inclusion. Following DNA extraction, genotyping, and quality control checks, data were available for 297 men. 25 participants had PRS in the top 10% and were invited for screening; 19 underwent a prostate MRI, and 18 went on to have a systematic (+/- targeted prostate biopsy. There were 7 diagnoses of PrCa (38.9%). The cancers detected were low-risk and are being managed with Active Surveillance (AS). Results of the first year of follow up will be presented and an update of the main study which aims to recruit 5000 men. Conclusions: The BARCODE1 pilot has shown the feasibility of this population-based study, with an overall uptake of 26% and a cancer incidence of nearly 40%. We have identified approximately 70 Primary care providers who have contributed to the transition to the full BARCODE1 study, which will aim to recruit 5,000 men. The BARCODE1 study results will be important in defining the role of PRS genetic profiling in targeted PrCa population screening. Clinical trial information: IRAS257684.

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