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Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence 2022.01.20.22269585
Hassanin, Emadeldin; Spier, Isabel; Bobbili, Dheeraj Reddy et al.
2022
 

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Keywords :
Colocrectal cancer; polygenic risk; family status
Abstract :
[en] 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: 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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Genetics & genetic processes
Oncology
Author, co-author :
Hassanin, Emadeldin
Spier, Isabel
Bobbili, Dheeraj Reddy ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Aldisi, Rana
Klinkhammer, Hannah
David, Friederike
Dueñas, Nuria
Hüneburg, Robert
Perne, Claudia
Brunet, Joan
Capella, Gabriel
Nöthen, Markus M.
Forstner, Andreas J.
Mayr, Andreas
Krawitz, Peter
May, Patrick  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Aretz, Stefan
Maj, Carlo
More authors (8 more) Less
Language :
English
Title :
Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence 2022.01.20.22269585
Publication date :
21 January 2022
Publisher :
Cold Spring Harbor Laboratory Press
Focus Area :
Systems Biomedicine
FnR Project :
FNR11583046 - Epileptogenesis Of Genetic Epilepsies, 2017 (01/04/2018-30/06/2021) - Roland Krause
Name of the research project :
MechEPI
Funders :
FNR - Fonds National de la Recherche [LU]
Available on ORBilu :
since 25 February 2022

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