Breast and prostate cancer risk: The interplay of polygenic risk, rare pathogenic germline variants, and family history

Hassanin, Emadeldin; Aldisi, Rana; Spier, Isabel; Forstner, Andreas J.; Nöthen, Markus M.; Aretz, Stefan; Krawitz, Peter; Bobbili, Dheeraj Reddy; Maj, Carlo

doi:10.1016/j.gim.2021.11.009

Cited by 29 publications

(26 citation statements)

References 39 publications

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“…As expected, the effect of the PRS seems to be relevant in particular in less penetrant CRC risk genes such as PMS2 where the OR ranges between 0.94 and 5.43 respectively (Supplementary Table S6). This is in line with ndings in moderate breast cancer risk genes such as CHEK2, PALB2 and ATM [43][44][45] and suggests that PRS inclusion in risk strati cation may in particular be relevant to prevent excess of surveillance measures in PV carriers of those genes.…”

Section: Discussionsupporting

confidence: 85%

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

Hassanin

Spier

Bobbili

et al. 2022

Preprint

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Background & 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: 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 (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.

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Section: Discussionsupporting

confidence: 85%

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

Hassanin

Spier

Bobbili

et al. 2022

Preprint

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“…Alternatively, common variants may play a role even in monogenic families, perhaps explaining phenomena such as phenotypic variability and incomplete penetrance. 34 , 35 , 36 , 37 …”

Section: Discussionmentioning

confidence: 99%

Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery

et al. 2022

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“…Furthermore, we focused solely on obesity, a common multifactorial trait that is moderately heritable. While many complex traits have similar feature, we cannot guarantee that our observations can be extrapolated to other outcomes as the genetic architecture, explained variance from common variants, and contribution from rare pathogenic variants may differ ( 36 ).…”

Section: Discussionmentioning

confidence: 95%

The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations

et al. 2022

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Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRScommon) with a rare variant PRS (PRSrare) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m2), obesity (BMI ≥ 30 kg/m2), and extreme obesity (BMI ≥ 40 kg/m2). We built PRSscommon and PRSsrare using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRScommon explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRSrare explained 1.49%, and 2.97% and 3.68%, respectively. The PRSrare was associated with an increased risk of obesity and extreme obesity (ORobesity = 1.37 per SDPRS, Pobesity = 1.7x10-85; ORextremeobesity = 1.55 per SDPRS, Pextremeobesity = 3.8x10-40), which was attenuated, after adjusting for PRScommon (ORobesity = 1.08 per SDPRS, Pobesity = 9.8x10-6; ORextremeobesity= 1.09 per SDPRS, Pextremeobesity = 0.02). When PRSrare and PRScommon are combined, the increase in explained variance attributed to PRSrare was small (incremental Nagelkerke R2 = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRSrare to PRScommon provided little improvement to the prediction of obesity (PRSrare AUC = 0.591; PRScommon AUC = 0.708; PRScombined AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRSrare provides limited improvement over PRScommon in the prediction of obesity risk, based on these large populations.

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Breast and prostate cancer risk: The interplay of polygenic risk, rare pathogenic germline variants, and family history

Cited by 29 publications

References 39 publications

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

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

Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery

The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations

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