Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Digestive System Neoplasms; Early Diagnosis; Genetic Association Studies; Genetic Counseling; Genetics; Genetics (clinical); Congenital; Hereditary; and Neonatal Diseases and Abnormalities
Abstract :
[en] [en] BACKGROUND: Polygenic risk scores (PRSs) have been used to stratify colorectal cancer (CRC) risk in the general population, whereas its role in Lynch syndrome (LS), the most common type of hereditary CRC, is still conflicting. We aimed to assess the ability of PRS to refine CRC risk prediction in European-descendant individuals with LS.
METHODS: 1465 individuals with LS (557 MLH1, 517 MSH2/EPCAM, 299 MSH6 and 92 PMS2) and 5656 CRC-free population-based controls from two independent cohorts were included. A 91-SNP PRS was applied. A Cox proportional hazard regression model with 'family' as a random effect and a logistic regression analysis, followed by a meta-analysis combining both cohorts were conducted.
RESULTS: Overall, we did not observe a statistically significant association between PRS and CRC risk in the entire cohort. Nevertheless, PRS was significantly associated with a slightly increased risk of CRC or advanced adenoma (AA), in those with CRC diagnosed <50 years and in individuals with multiple CRCs or AAs diagnosed <60 years.
CONCLUSION: The PRS may slightly influence CRC risk in individuals with LS in particular in more extreme phenotypes such as early-onset disease. However, the study design and recruitment strategy strongly influence the results of PRS studies. A separate analysis by genes and its combination with other genetic and non-genetic risk factors will help refine its role as a risk modifier in LS.
Disciplines :
Oncology
Author, co-author :
Dueñas, Nuria ; Hereditary Cancer Program, Catalan Institute of Oncology - ICO, L'Hospitalet de Llobregat, Spain ; Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain ; Biomedical Research Centre Network for Oncology (CIBERONC), Instituto Salud Carlos III, Madrid, Spain ; European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, Netherlands
Klinkhammer, Hannah ; Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, Bonn, Germany ; Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany
Bonifaci, Nuria; Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain ; Biomedical Research Centre Network for Oncology (CIBERONC), Instituto Salud Carlos III, Madrid, Spain
Spier, Isabel ; European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, Netherlands ; Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany ; National Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany
Mayr, Andreas; Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, Bonn, Germany
HASSANIN, Emadeldin ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core ; Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany
Diez-Villanueva, Anna; Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology - ICO, L'Hospitalet de Llobregat, Spain ; Colorectal Cancer Group (ONCOBELL), Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain ; Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Instituto Salud Carlos III, Madrid, Spain
Moreno, Victor ; Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology - ICO, L'Hospitalet de Llobregat, Spain ; Colorectal Cancer Group (ONCOBELL), Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain ; Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Instituto Salud Carlos III, Madrid, Spain ; Department of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), Universitat de Barcelona, Barcelona, Spain
Pineda, Marta ; Hereditary Cancer Program, Catalan Institute of Oncology - ICO, L'Hospitalet de Llobregat, Spain ; Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain ; Biomedical Research Centre Network for Oncology (CIBERONC), Instituto Salud Carlos III, Madrid, Spain ; European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, Netherlands
Maj, Carlo; Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany
Capellà, Gabriel; Hereditary Cancer Program, Catalan Institute of Oncology - ICO, L'Hospitalet de Llobregat, Spain ; Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain ; Biomedical Research Centre Network for Oncology (CIBERONC), Instituto Salud Carlos III, Madrid, Spain ; European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, Netherlands
Aretz, Stefan ; European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, Netherlands jbrunet@iconcologia.net stefan.aretz@uni-bonn.de ; Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany ; National Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany
Brunet, Joan ; Hereditary Cancer Program, Catalan Institute of Oncology - ICO, L'Hospitalet de Llobregat, Spain jbrunet@iconcologia.net stefan.aretz@uni-bonn.de ; Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain ; Biomedical Research Centre Network for Oncology (CIBERONC), Instituto Salud Carlos III, Madrid, Spain ; European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, Netherlands ; Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Girona, Spain
Instituto de Salud Carlos III Centro de Investigación Biomédica en Red de Cáncer Ministerio de Ciencia e Innovación Ministerio de Economía y Competitividad Fundación Científica Asociación Española Contra el Cáncer Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya
Funding text :
We thank the participating patients and families and all members of the Units of Genetic Counseling and Genetic Diagnostic of the Hereditary Cancer Program of the Catalan Institute of Oncology and the Institute of Human Genetics of the University Hospital Bonn as well as the BufaLynch Association for their support and funding of ICO’s Lynch Syndrome Database. We thank Gemma Aiza for technical support. The authors also acknowledge the Department of Medicine at the Universitat Autònoma de Barcelona and the CERCA Program/Generalitat de Catalunya for institutional support. This research is supported (not financially) by the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS). ERN GENTURIS is funded by the European Union.This research was partially funded by the Spanish Ministry of Economy and Competitiveness and the Spanish Ministry of Science and Innovation, cofunded by FEDER Funds: a Way to Build Europe (grants SAF2015-68016-R and PID2019-111254RB-I00), CIBERONC (CB16/12/00234), the Government of Catalonia (SGR_01112), the Spanish Association Against Cancer Scientific Foundation (grant GCTRA18022MORE) and Spanish Ministry for Economy and Competitivity, Instituto de Salud Carlos III, cofunded by FEDER funds: a Way to Build Europe (FIS PI14-00613). ND was funded by the Instituto de Salud Carlos III and cofunded by the European Social Fund investing in your future (grant CM19/00099), the Catalan-Balearic Society of Oncology (2018 grant of the Catalan-Balearic Society of Oncology), the European Union’s Horizon 2020 research and innovation programme under the EJP RD COFUND-EJP number 825575. AD-V was supported by PERIS contract SLT017/20/000042. The GSA genotyping was performed at the Spanish National Cancer Research Centre, in the Human Genotyping lab, a member of CeGen, PRB3, and is supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF.
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