title: Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome.
abstract: 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.
authors.affiliation: ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain.|Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Salt, Catalonia, Spain.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
authors.affiliation: Computational and Mathematical Biology Research Group, Centre de Recerca Matemàtica (CRM), Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Folguera-Blasco
authors.affiliation: ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain.|Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Salt, Catalonia, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Cuyàs
authors.affiliation: Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Campus of International Excellence Southern Catalonia, Reus, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Fernández-Arroyo
authors.affiliation: Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Campus of International Excellence Southern Catalonia, Reus, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Joven
authors.affiliation: Computational and Mathematical Biology Research Group, Centre de Recerca Matemàtica (CRM), Barcelona, Spain.|Institució Catalana d'Estudis i Recerca Avançats (ICREA), Barcelona, Spain.|Departament de Matemàtiques, Universitat Autònoma de Barcelona, Barcelona, Spain.|Barcelona Graduate School of Mathematics (BGSMath), Barcelona, Spain.
authors.forename: Tomás
authors.initials: T
authors.lastname: Alarcón
mesh_terms: D000368:Aged; D000375:Aging / Q000235:genetics / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D063646:Carcinogenesis; D005260:Female; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006801:Humans; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor
keywords: BRCA1; Gerotarget; cancer; geroncogenesis; metabolism; metformin