Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome

The geroncogenesis hypothesis postulates that the decline in metabolic cellular health that occurs naturally with aging drives a “field effect” predisposing normal tissues for cancer development. We propose that mutations in the cancer susceptibility genes BRCA1/2 might trigger “accelerated geroncog...

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Authors: Menendez, J.A., Cuyas, E., Folguera-Blasco, N., Fernandez-Arroyo, S., Joven, J., Alarcon, T.
Format: article
Status:Published version
Publication Date:2016
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2072/377782
Online Access:http://hdl.handle.net/2072/377782
Access Level:Open access
Keyword:Matemàtiques
51
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spelling Accelerated geroncogenesis in hereditary breast-ovarian cancer syndromeMenendez, J.A.Cuyas, E.Folguera-Blasco, N.Fernandez-Arroyo, S.Joven, J.Alarcon, T.Matemàtiques51The geroncogenesis hypothesis postulates that the decline in metabolic cellular health that occurs naturally with aging drives a “field effect” predisposing normal tissues for cancer development. We propose that mutations in the cancer susceptibility genes BRCA1/2 might trigger “accelerated geroncogenesis” in breast and ovarian epithelia. By speeding up the rate at which the metabolic threshold becomes “permissive” with survival and expansion of genomically unstable pre-tumoral epithelial cells, BRCA haploinsufficiency-driven metabolic reprogramming would operate as a bona fide oncogenic event enabling malignant transformation and tumor formation in BRCA carriers. The metabolic facet of BRCA1 one-hit might involve tissue-specific alterations in acetyl-CoA, α-ketoglutarate, NAD+, FAD, or S-adenosylmethionine, critical factors for de/methylation or de/acetylation dynamics in the nuclear epigenome. This in turn might induce faulty epigenetic reprogramming at the “install phase” that directs cell-specific differentiation of breast/ovarian epithelial cells, which can ultimately determine the penetrance of BRCA defects during developmental windows of susceptibility. This model offers a framework to study whether metabolic drugs that prevent or revert metabolic reprogramming induced by BRCA haploinsufficiency might displace the “geroncogenic risk” of BRCA carriers to the age typical for those without the mutation. The identification of the key nodes that directly communicate changes in cellular metabolism to the chromatin in BRCA haploinsufficient cells may allow the epigenetic targeting of genomic instability using exclusively metabolic means. The validation of accelerated geroncogenesis as an inherited “one-hit” metabolic “field effect” might offer new strategies to therapeutically revisit the apparently irreversible genetic-hereditary fate of women with hereditary breast-ovarian cancer syndrome.2016info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion13 p.application/pdfhttp://hdl.handle.net/2072/377782RECERCAT (Dipòsit de la Recerca de Catalunya)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésOncotargetL'accés als continguts d'aquest document queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons:http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2072/3777822026-05-29T05:05:01Z
dc.title.none.fl_str_mv Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome
title Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome
spellingShingle Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome
Menendez, J.A.
Matemàtiques
51
title_short Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome
title_full Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome
title_fullStr Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome
title_full_unstemmed Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome
title_sort Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome
dc.creator.none.fl_str_mv Menendez, J.A.
Cuyas, E.
Folguera-Blasco, N.
Fernandez-Arroyo, S.
Joven, J.
Alarcon, T.
author Menendez, J.A.
author_facet Menendez, J.A.
Cuyas, E.
Folguera-Blasco, N.
Fernandez-Arroyo, S.
Joven, J.
Alarcon, T.
author_role author
author2 Cuyas, E.
Folguera-Blasco, N.
Fernandez-Arroyo, S.
Joven, J.
Alarcon, T.
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Matemàtiques
51
topic Matemàtiques
51
description The geroncogenesis hypothesis postulates that the decline in metabolic cellular health that occurs naturally with aging drives a “field effect” predisposing normal tissues for cancer development. We propose that mutations in the cancer susceptibility genes BRCA1/2 might trigger “accelerated geroncogenesis” in breast and ovarian epithelia. By speeding up the rate at which the metabolic threshold becomes “permissive” with survival and expansion of genomically unstable pre-tumoral epithelial cells, BRCA haploinsufficiency-driven metabolic reprogramming would operate as a bona fide oncogenic event enabling malignant transformation and tumor formation in BRCA carriers. The metabolic facet of BRCA1 one-hit might involve tissue-specific alterations in acetyl-CoA, α-ketoglutarate, NAD+, FAD, or S-adenosylmethionine, critical factors for de/methylation or de/acetylation dynamics in the nuclear epigenome. This in turn might induce faulty epigenetic reprogramming at the “install phase” that directs cell-specific differentiation of breast/ovarian epithelial cells, which can ultimately determine the penetrance of BRCA defects during developmental windows of susceptibility. This model offers a framework to study whether metabolic drugs that prevent or revert metabolic reprogramming induced by BRCA haploinsufficiency might displace the “geroncogenic risk” of BRCA carriers to the age typical for those without the mutation. The identification of the key nodes that directly communicate changes in cellular metabolism to the chromatin in BRCA haploinsufficient cells may allow the epigenetic targeting of genomic instability using exclusively metabolic means. The validation of accelerated geroncogenesis as an inherited “one-hit” metabolic “field effect” might offer new strategies to therapeutically revisit the apparently irreversible genetic-hereditary fate of women with hereditary breast-ovarian cancer syndrome.
publishDate 2016
dc.date.none.fl_str_mv 2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/2072/377782
url http://hdl.handle.net/2072/377782
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Oncotarget
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 13 p.
application/pdf
dc.source.none.fl_str_mv RECERCAT (Dipòsit de la Recerca de Catalunya)
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
repository.name.fl_str_mv
repository.mail.fl_str_mv
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