Constitutional epimutations in LTBP4, a component of the TGF-β signaling, and in BRCA1, as potential drivers of early-onset colorectal cancer

Background: Constitutional primary monoallelic promoter methylation of hereditary cancer genes, although rare, may explain early-onset cancers without family history. Also, promoter methylation of a hereditary cancer gene secondary to a genetic alteration in a methylation regulatory region can cause...

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Authors: Terradas, Mariona|||0000-0001-7813-1172, Mur, Pilar, Bousquets-Muñoz, Pablo, Puente, Xose S.|||0000-0001-9525-1483, Nielsen, Maartje|||0000-0002-5351-1870, Lázaro García, Conxi|||0000-0002-7198-5906, Moreno Aguado, Victor Raul|||0000-0002-2818-5487, Valle, Laura|||0000-0003-0371-0844, Morón-Duran, Francisco D., Mengod, Pol, Löffler, Chiara M.L., Helderman, Noah C., Terlouw, Diantha, Sanjuán, Xavier, Viana-Errasti, Julen, Capellá, Gabriel, van Wezel, Tom, Kather, Jakob Nikolas
Format: article
Publication Date:2025
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:dnet:uabarcelona_::b6629ab3cfb6b5aafe7c4262aca1c557
Online Access:https://ddd.uab.cat/record/326944
https://dx.doi.org/urn:doi:10.1186/s13148-025-01924-x
Access Level:Open access
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spelling Constitutional epimutations in LTBP4, a component of the TGF-β signaling, and in BRCA1, as potential drivers of early-onset colorectal cancerTerradas, Mariona|||0000-0001-7813-1172Mur, PilarBousquets-Muñoz, PabloPuente, Xose S.|||0000-0001-9525-1483Nielsen, Maartje|||0000-0002-5351-1870Lázaro García, Conxi|||0000-0002-7198-5906Moreno Aguado, Victor Raul|||0000-0002-2818-5487Valle, Laura|||0000-0003-0371-0844Morón-Duran, Francisco D.Mengod, PolLöffler, Chiara M.L.Helderman, Noah C.Terlouw, DianthaSanjuán, XavierViana-Errasti, JulenCapellá, Gabrielvan Wezel, TomKather, Jakob NikolasBackground: Constitutional primary monoallelic promoter methylation of hereditary cancer genes, although rare, may explain early-onset cancers without family history. Also, promoter methylation of a hereditary cancer gene secondary to a genetic alteration in a methylation regulatory region can cause a hereditary cancer syndrome. This study investigates constitutional promoter methylation as mechanism of inactivation of cancer predisposition genes in genetically unsolved familial and/or early-onset colorectal cancer (CRC) patients. Results: Bisulfite-treated peripheral blood DNA from 46 early-onset/familial CRC patients was analyzed using the Illumina Infinium MethylationEPIC BeadChip. One early-onset CRC patient exhibited constitutional, likely monoallelic, methylation of CpG island 102 in LTBP4, a gene involved in TGF-β signaling. Somatic methylation of this CpG island is common in CRC, and correlates with LTBP4 downregulation. LTBP4 double knockout mice develop colorectal adenomas and carcinomas, supporting the role of this gene in CRC predisposition. No additional cases with constitutional LTBP4 CpG island 102 methylation or enrichment of deleterious LTBP4 variants in CRC patients compared to controls were found. Another early-onset CRC patient exhibited mosaic BRCA1 promoter methylation, typically associated with increased breast and ovarian cancer risk. No somatic second hit in BRCA1 was detected in the patient's tumor, and homologous recombination deficiency-associated features were inconclusive. Conclusions: Our findings suggest that constitutional methylation of LTBP4 CpG island 102 may be associated with increased CRC risk. Identification of additional cases is needed to confirm the existence of a novel CRC predisposition syndrome driven by epigenetic inactivation of LTBP4, potentially also linked to other clinical phenotypes associated with LTBP4 deficiency, such as pulmonary emphysema. Whether constitutional BRCA1 methylation contributes to CRC risk remains to be determined. 22025-01-0120252025-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/326944https://dx.doi.org/urn:doi:10.1186/s13148-025-01924-xreponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2020-112595RB-I00Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 CB16/12/00234Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PMP22/00064Generalitat de Catalunya https://doi.org/10.13039/501100002809 2021SGR01112open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:dnet:uabarcelona_::b6629ab3cfb6b5aafe7c4262aca1c5572026-06-06T12:50:31Z
dc.title.none.fl_str_mv Constitutional epimutations in LTBP4, a component of the TGF-β signaling, and in BRCA1, as potential drivers of early-onset colorectal cancer
title Constitutional epimutations in LTBP4, a component of the TGF-β signaling, and in BRCA1, as potential drivers of early-onset colorectal cancer
spellingShingle Constitutional epimutations in LTBP4, a component of the TGF-β signaling, and in BRCA1, as potential drivers of early-onset colorectal cancer
Terradas, Mariona|||0000-0001-7813-1172
title_short Constitutional epimutations in LTBP4, a component of the TGF-β signaling, and in BRCA1, as potential drivers of early-onset colorectal cancer
title_full Constitutional epimutations in LTBP4, a component of the TGF-β signaling, and in BRCA1, as potential drivers of early-onset colorectal cancer
title_fullStr Constitutional epimutations in LTBP4, a component of the TGF-β signaling, and in BRCA1, as potential drivers of early-onset colorectal cancer
title_full_unstemmed Constitutional epimutations in LTBP4, a component of the TGF-β signaling, and in BRCA1, as potential drivers of early-onset colorectal cancer
title_sort Constitutional epimutations in LTBP4, a component of the TGF-β signaling, and in BRCA1, as potential drivers of early-onset colorectal cancer
dc.creator.none.fl_str_mv Terradas, Mariona|||0000-0001-7813-1172
Mur, Pilar
Bousquets-Muñoz, Pablo
Puente, Xose S.|||0000-0001-9525-1483
Nielsen, Maartje|||0000-0002-5351-1870
Lázaro García, Conxi|||0000-0002-7198-5906
Moreno Aguado, Victor Raul|||0000-0002-2818-5487
Valle, Laura|||0000-0003-0371-0844
Morón-Duran, Francisco D.
Mengod, Pol
Löffler, Chiara M.L.
Helderman, Noah C.
Terlouw, Diantha
Sanjuán, Xavier
Viana-Errasti, Julen
Capellá, Gabriel
van Wezel, Tom
Kather, Jakob Nikolas
author Terradas, Mariona|||0000-0001-7813-1172
author_facet Terradas, Mariona|||0000-0001-7813-1172
Mur, Pilar
Bousquets-Muñoz, Pablo
Puente, Xose S.|||0000-0001-9525-1483
Nielsen, Maartje|||0000-0002-5351-1870
Lázaro García, Conxi|||0000-0002-7198-5906
Moreno Aguado, Victor Raul|||0000-0002-2818-5487
Valle, Laura|||0000-0003-0371-0844
Morón-Duran, Francisco D.
Mengod, Pol
Löffler, Chiara M.L.
Helderman, Noah C.
Terlouw, Diantha
Sanjuán, Xavier
Viana-Errasti, Julen
Capellá, Gabriel
van Wezel, Tom
Kather, Jakob Nikolas
author_role author
author2 Mur, Pilar
Bousquets-Muñoz, Pablo
Puente, Xose S.|||0000-0001-9525-1483
Nielsen, Maartje|||0000-0002-5351-1870
Lázaro García, Conxi|||0000-0002-7198-5906
Moreno Aguado, Victor Raul|||0000-0002-2818-5487
Valle, Laura|||0000-0003-0371-0844
Morón-Duran, Francisco D.
Mengod, Pol
Löffler, Chiara M.L.
Helderman, Noah C.
Terlouw, Diantha
Sanjuán, Xavier
Viana-Errasti, Julen
Capellá, Gabriel
van Wezel, Tom
Kather, Jakob Nikolas
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
description Background: Constitutional primary monoallelic promoter methylation of hereditary cancer genes, although rare, may explain early-onset cancers without family history. Also, promoter methylation of a hereditary cancer gene secondary to a genetic alteration in a methylation regulatory region can cause a hereditary cancer syndrome. This study investigates constitutional promoter methylation as mechanism of inactivation of cancer predisposition genes in genetically unsolved familial and/or early-onset colorectal cancer (CRC) patients. Results: Bisulfite-treated peripheral blood DNA from 46 early-onset/familial CRC patients was analyzed using the Illumina Infinium MethylationEPIC BeadChip. One early-onset CRC patient exhibited constitutional, likely monoallelic, methylation of CpG island 102 in LTBP4, a gene involved in TGF-β signaling. Somatic methylation of this CpG island is common in CRC, and correlates with LTBP4 downregulation. LTBP4 double knockout mice develop colorectal adenomas and carcinomas, supporting the role of this gene in CRC predisposition. No additional cases with constitutional LTBP4 CpG island 102 methylation or enrichment of deleterious LTBP4 variants in CRC patients compared to controls were found. Another early-onset CRC patient exhibited mosaic BRCA1 promoter methylation, typically associated with increased breast and ovarian cancer risk. No somatic second hit in BRCA1 was detected in the patient's tumor, and homologous recombination deficiency-associated features were inconclusive. Conclusions: Our findings suggest that constitutional methylation of LTBP4 CpG island 102 may be associated with increased CRC risk. Identification of additional cases is needed to confirm the existence of a novel CRC predisposition syndrome driven by epigenetic inactivation of LTBP4, potentially also linked to other clinical phenotypes associated with LTBP4 deficiency, such as pulmonary emphysema. Whether constitutional BRCA1 methylation contributes to CRC risk remains to be determined.
publishDate 2025
dc.date.none.fl_str_mv 2
2025-01-01
2025
2025-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/326944
https://dx.doi.org/urn:doi:10.1186/s13148-025-01924-x
url https://ddd.uab.cat/record/326944
https://dx.doi.org/urn:doi:10.1186/s13148-025-01924-x
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2020-112595RB-I00
Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 CB16/12/00234
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PMP22/00064
Generalitat de Catalunya https://doi.org/10.13039/501100002809 2021SGR01112
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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