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Original research
Ability of a polygenic risk score to refine colorectal cancer risk in Lynch syndrome
  1. Nuria Dueñas1,2,3,4,
  2. Hannah Klinkhammer5,6,
  3. Nuria Bonifaci2,3,
  4. Isabel Spier4,7,8,
  5. Andreas Mayr5,
  6. Emadeldin Hassanin6,9,
  7. Anna Diez-Villanueva10,11,12,
  8. Victor Moreno10,11,12,13,
  9. Marta Pineda1,2,3,4,
  10. Carlo Maj6,
  11. Gabriel Capellà1,2,3,4,
  12. Stefan Aretz4,7,8,
  13. Joan Brunet1,2,3,4,14
  1. 1 Hereditary Cancer Program, Catalan Institute of Oncology - ICO, L’Hospitalet de Llobregat, Spain
  2. 2 Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d’Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain
  3. 3 Biomedical Research Centre Network for Oncology (CIBERONC), Instituto Salud Carlos III, Madrid, Spain
  4. 4 European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, Netherlands
  5. 5 Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, Bonn, Germany
  6. 6 Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany
  7. 7 Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany
  8. 8 National Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany
  9. 9 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
  10. 10 Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology - ICO, L'Hospitalet de Llobregat, Spain
  11. 11 Colorectal Cancer Group (ONCOBELL), Institut d’Investigació Biomèdica de Bellvitge - IDIBELL, L’Hospitalet de Llobregat, Spain
  12. 12 Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Instituto Salud Carlos III, Madrid, Spain
  13. 13 Department of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), Universitat de Barcelona, Barcelona, Spain
  14. 14 Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Girona, Spain
  1. Correspondence to Dr Joan Brunet, Hereditary Cancer Program, Catalan Institute of Oncology, Girona 17190, Spain; jbrunet{at}iconcologia.net; Professor Stefan Aretz; stefan.aretz{at}uni-bonn.de

Abstract

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.

  • Digestive System Neoplasms
  • Congenital, Hereditary, and Neonatal Diseases and Abnormalities
  • Early Diagnosis
  • Genetic Association Studies
  • Genetic Counseling

Data availability statement

Data are available upon reasonable request. Data supporting the results were stored in local databases at both centres.

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Data availability statement

Data are available upon reasonable request. Data supporting the results were stored in local databases at both centres.

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Footnotes

  • ND, HK and NB are joint first authors.

  • SA and JB are joint senior authors.

  • Twitter @NDuenas5

  • Contributors NDC: study concept and design, analysis and interpretation of data, drafting of the manuscript and critical revision of the manuscript for important intellectual content. HK, NB and AD-V: study concept and design, statistical analysis, analysis and interpretation of data, drafting of the manuscript and critical revision of the manuscript for important intellectual content. AM, EH and CM: study concept and design, statistical analysis, analysis and interpretation of data and critical revision of the manuscript for important intellectual content. AD-V and VM: study concept and design and critical revision of the manuscript for important intellectual content. IS, MP, GC, SA and JB: study concept and design, Analysis and interpretation of data, critical revision of the manuscript for important intellectual content and study supervision. SA and JB act as guarantor of the study.

  • Funding 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.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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