Article Text
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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- 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.
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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