Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants
Simple Summary A relevant proportion of colorectal cancer patients diagnosed at young age and/or with family history of that type of cancer do not carry germline mutations in know hereditary cancer genes. Moreover, studies aimed to identify additional high-risk colorectal cancer genes were either un...
| Autores: | ; ; ; ; ; ; ; ; ; ; ; ; ; |
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| Tipo de documento: | Artículo |
| Estado: | Published version |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10256/28257 |
| Acceso en línea: | http://hdl.handle.net/10256/28257 |
| Nivel de acceso: | Acceso abierto |
| Palabra clave: | Hereditary colorectal cancer Cancer predisposition Serrated polyposis Polygenic risk score |
| _version_ | 1878733019818229760 |
|---|---|
| author | Mur, Pilar |
| author2 | Bonifaci, Nuria Díez-Villanueva, Anna Munté, Elisabet Alonso Aguado, M.Henar Obón-Santacana, Mireia Aiza, Gemma Navarro, Matilde Piñol Sánchez, Virgínia Brunet i Vidal, Joan Tomlinson, Ian Capellá, Gabriel Moreno Aguado, Víctor Valle, Laura |
| author2_role | author author author author author author author author author author author author author |
| author_browse | Aiza, Gemma Alonso Aguado, M.Henar Bonifaci, Nuria Brunet i Vidal, Joan Capellá, Gabriel Díez-Villanueva, Anna Moreno Aguado, Víctor Munté, Elisabet Mur, Pilar Navarro, Matilde Obón-Santacana, Mireia Piñol Sánchez, Virgínia Tomlinson, Ian Valle, Laura |
| author_facet | Mur, Pilar Bonifaci, Nuria Díez-Villanueva, Anna Munté, Elisabet Alonso Aguado, M.Henar Obón-Santacana, Mireia Aiza, Gemma Navarro, Matilde Piñol Sánchez, Virgínia Brunet i Vidal, Joan Tomlinson, Ian Capellá, Gabriel Moreno Aguado, Víctor Valle, Laura |
| author_role | author |
| collection | Recercat. Dipósit de la Recerca de Catalunya |
| description | Simple Summary A relevant proportion of colorectal cancer patients diagnosed at young age and/or with family history of that type of cancer do not carry germline mutations in know hereditary cancer genes. Moreover, studies aimed to identify additional high-risk colorectal cancer genes were either unsuccessful or identified genes that explain extremely few cases. We aimed to evaluate the role of the accumulation of colorectal cancer low-risk variants in familial and early-onset colorectal cancer patients. We observed that the accumulation of low-risk variants may explain a relevant number of these cases, particularly in the presence of family history of colorectal cancer and of the personal history of multiple colorectal cancers. If validated in other series of patients, the identification of familial/early-onset colorectal cancer patients with accumulation of low-risk variants will translate into personalized clinical management and to the identification of additional at-risk family members. A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age >= 50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_4e7fbccd5a8a985fcff034c594e01d29 |
| institution | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| instname_str | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:recercat.cat:10256/28257 |
| publishDate | 2021 |
| publishDateSort | 2021 |
| publisher | MDPI (Multidisciplinary Digital Publishing Institute) |
| publisherStr | MDPI (Multidisciplinary Digital Publishing Institute) |
| reponame_str | Recercat. Dipósit de la Recerca de Catalunya |
| spelling | Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants Mur, Pilar Bonifaci, Nuria Díez-Villanueva, Anna Munté, Elisabet Alonso Aguado, M.Henar Obón-Santacana, Mireia Aiza, Gemma Navarro, Matilde Piñol Sánchez, Virgínia Brunet i Vidal, Joan Tomlinson, Ian Capellá, Gabriel Moreno Aguado, Víctor Valle, Laura Hereditary colorectal cancer Cancer predisposition Serrated polyposis Polygenic risk score Simple Summary A relevant proportion of colorectal cancer patients diagnosed at young age and/or with family history of that type of cancer do not carry germline mutations in know hereditary cancer genes. Moreover, studies aimed to identify additional high-risk colorectal cancer genes were either unsuccessful or identified genes that explain extremely few cases. We aimed to evaluate the role of the accumulation of colorectal cancer low-risk variants in familial and early-onset colorectal cancer patients. We observed that the accumulation of low-risk variants may explain a relevant number of these cases, particularly in the presence of family history of colorectal cancer and of the personal history of multiple colorectal cancers. If validated in other series of patients, the identification of familial/early-onset colorectal cancer patients with accumulation of low-risk variants will translate into personalized clinical management and to the identification of additional at-risk family members. A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age >= 50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC This research was funded by the Spanish Ministry of Science and Innovation, co-funded by FEDER funds a way to build Europe [SAF2016-80888-R (LV), PID2020-112595RB-I00 (LV), PID2019111254RB-I00 (GC)]; Instituto de Salud Carlos III [CIBERONC CB16/12/00234, Sara Borrell Postdoctoral contract (PM); PI17/00092 (VM)]; the Government of Catalonia [AGAUR 2017SGR1282, CERCA Program for institutional support]; and Fundacion Olga Torres. The genotyping service was carried out at CEGEN-PRB3-ISCIII, which is supported by grant PT17/0019 of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. Sample collection of this study (sporadic CRC and controls) was supported by the Plataforma Biobancos (PT17/0015/0024) and ICOBIOBANC, sponsored by the Catalan Institute of Oncology. This article is based upon work from COST action DYCA17118, supported by COST (European Cooperation in Science and Technology) MDPI (Multidisciplinary Digital Publishing Institute) http://hdl.handle.net/10256/28257 |
| spellingShingle | Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants Mur, Pilar Hereditary colorectal cancer Cancer predisposition Serrated polyposis Polygenic risk score |
| status_str | publishedVersion |
| title | Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants |
| title_full | Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants |
| title_fullStr | Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants |
| title_full_unstemmed | Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants |
| title_short | Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants |
| title_sort | Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants |
| topic | Hereditary colorectal cancer Cancer predisposition Serrated polyposis Polygenic risk score |
| topic_facet | Hereditary colorectal cancer Cancer predisposition Serrated polyposis Polygenic risk score |
| url | http://hdl.handle.net/10256/28257 |