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...

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Autores: 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
Tipo de recurso: artículo
Estado:Versión publicada
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
Access Level:acceso abierto
Palabra clave:Hereditary colorectal cancer
Cancer predisposition
Serrated polyposis
Polygenic risk score
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network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants
title Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants
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
title_short 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_sort Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants
dc.creator.none.fl_str_mv 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 Mur, Pilar
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
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
dc.subject.none.fl_str_mv Hereditary colorectal cancer
Cancer predisposition
Serrated polyposis
Polygenic risk score
topic Hereditary colorectal cancer
Cancer predisposition
Serrated polyposis
Polygenic risk score
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
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
peer reviewed
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10256/28257
url http://hdl.handle.net/10256/28257
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.3390/cancers13153857
info:eu-repo/semantics/altIdentifier/issn/2072-6694
info:eu-repo/semantics/altIdentifier/eissn/2072-6694
dc.rights.none.fl_str_mv Attribution 4.0 International (CC BY 4.0)
http://creativecommons.org/licenses/by/4.0/deed.ca
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution 4.0 International (CC BY 4.0)
http://creativecommons.org/licenses/by/4.0/deed.ca
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI (Multidisciplinary Digital Publishing Institute)
publisher.none.fl_str_mv MDPI (Multidisciplinary Digital Publishing Institute)
dc.source.none.fl_str_mv Cancers, 2021, vol. 13, núm. 15, p. 3857
Articles publicats (IDIBGI)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname: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)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
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repository.mail.fl_str_mv
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spelling Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic VariantsMur, PilarBonifaci, NuriaDíez-Villanueva, AnnaMunté, ElisabetAlonso Aguado, M.HenarObón-Santacana, MireiaAiza, GemmaNavarro, MatildePiñol Sánchez, VirgíniaBrunet i Vidal, JoanTomlinson, IanCapellá, GabrielMoreno Aguado, VíctorValle, LauraHereditary colorectal cancerCancer predispositionSerrated polyposisPolygenic risk scoreSimple 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 CRCThis 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)2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionpeer reviewedapplication/pdfhttp://hdl.handle.net/10256/28257Cancers, 2021, vol. 13, núm. 15, p. 3857Articles publicats (IDIBGI)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/semantics/altIdentifier/doi/10.3390/cancers13153857info:eu-repo/semantics/altIdentifier/issn/2072-6694info:eu-repo/semantics/altIdentifier/eissn/2072-6694Attribution 4.0 International (CC BY 4.0)http://creativecommons.org/licenses/by/4.0/deed.cainfo:eu-repo/semantics/openAccessoai:recercat.cat:10256/282572026-05-29T05:05:01Z
score 15.81155

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