FOXO3 on the Road to Longevity: Lessons From SNPs and Chromatin Hubs

Health span is driven by a precise interplay between genes and the environment. Cell response to environmental cues is mediated by signaling cascades and genetic variants that affect gene expression by regulating chromatin plasticity. Indeed, they can promote the interaction of promoters with regulatory elements by forming active chromatin hubs. FOXO3 encodes a transcription factor with a strong impact on aging and age-related phenotypes, as it regulates stress response, therefore affecting lifespan. A significant association has been shown between human longevity and several FOXO3 variants located in intron 2. This haplotype block forms a putative aging chromatin hub in which FOXO3 has a central role, as it modulates the physical connection and activity of neighboring genes involved in age-related processes. Here we describe the role of FOXO3 and its single-nucleotide polymorphisms (SNPs) in healthy aging, with a focus on the enhancer region encompassing the SNP rs2802292, which upregulates FOXO3 expression and can promote the activity of the aging hub in response to different stress stimuli. FOXO3 protective effect on lifespan may be due to the accessibility of this region to transcription factors promoting its expression. This could in part explain the differences in FOXO3 association with longevity between genders, as its activity in females may be modulated by estrogens through estrogen receptor response elements located in the rs2802292-encompassing region. Altogether, the molecular mechanisms described here may help establish whether the rs2802292 SNP can be taken advantage of in predictive medicine and define the potential of targeting FOXO3 for age-related diseases

From genetics to histomolecular characterization: An insight into colorectal carcinogenesis in lynch syndrome

Lynch syndrome is a hereditary cancer‐predisposing syndrome caused by germline defects in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. Carriers of pathogenic mutations in these genes have an increased lifetime risk of developing colorectal cancer (CRC) and other malignancies. Despite intensive surveillance, Lynch patients typically develop CRC after 10 years of follow‐up, regardless of the screening interval. Recently, three different molecular models of colorectal carcinogenesis were identified in Lynch patients based on when MMR deficiency is acquired. In the first pathway, adenoma formation occurs in an MMR‐proficient background, and carcinogenesis is characterized by APC and/or KRAS mutation and IGF2, NEU‐ ROG1, CDK2A, and/or CRABP1 hypermethylation. In the second pathway, deficiency in the MMR pathway is an early event arising in macroscopically normal gut surface before adenoma for-mation. In the third pathway, which is associated with mutations in CTNNB1 and/or TP53, the adenoma step is skipped, with fast and invasive tumor growth occurring in an MMR‐deficient context. Here, we describe the association between molecular and histological features in these three routes of colorectal carcinogenesis in Lynch patients. The findings summarized in this review may guide the use of individualized surveillance guidelines based on a patient’s carcinogenesis subtype

A novel STK11 gene mutation (c.388dupG, p.Glu130Glyfs∗33) in a Peutz-Jeghers family and evidence of higher gastric cancer susceptibility associated with alterations in STK11 region aa 107-170

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Apc splicing mutations leading to in-frame exon 12 or exon 13 skipping are rare events in fap pathogenesis and define the clinical outcome

Familial adenomatous polyposis (FAP) is caused by germline mutations in the tumor suppressor gene APC. To date, nearly 2000 APC mutations have been described in FAP, most of which are predicted to result in truncated protein products. Mutations leading to aberrant APC splicing have rarely been reported. Here, we characterized a novel germline heterozygous splice donor site mutation in APC exon 12 (NM_000038.5: c.1621_1626+7del) leading to exon 12 skipping in an Italian family with the attenuated FAP (AFAP) phenotype. Moreover, we performed a literature meta-analysis of APC splicing mutations. We found that 119 unique APC splicing mutations, including the one described here, have been reported in FAP patients, 69 of which have been characterized at the mRNA level. Among these, only a small proportion (9/69) results in an in-frame protein, with four mutations causing skipping of exon 12 or 13 with loss of armadillo repeat 2 (ARM2) and 3 (ARM3), and five mutations leading to skipping of exon 5, 7, 8, or (partially) 9 with loss of regions not encompassing known functional domains. The APC splicing mutations causing skipping of exon 12 or 13 considered in this study cluster with the AFAP phenotype and reveal a potential molecular mechanism of pathogenesis in FAP disease

A large de novo 9p21.3 deletion in a girl affected by astrocytoma and multiple melanoma.

BACKGROUND: Association of melanoma, neural system tumors and germ line mutations at the 9p21 region in the CDKN2A, CDKN2B and CDKN2BAS genes has been reported in a small number of families worldwide and described as a discrete syndrome in melanoma families registered as a rare disease, the melanoma–astrocytoma syndrome. CASE PRESENTATION: We here studied two young patients developing melanoma after radiotherapy for astrocytoma, both reporting lack of family history for melanoma or neural system tumors at genetic counselling. Patient A is a girl treated for anaplastic astrocytoma at 10 years and for multiple melanomas on the scalp associated to dysplastic nevi two years later. Her monozygotic twin sister carried dysplastic nevi and a slow growing, untreated cerebral lesion. Direct sequencing analysis showed no alterations in melanoma susceptibility genes including CDKN2A, CDK4, MC1R and MITF or in TP53. By microsatellite analysis, multiplex ligation-dependent probe amplification, and array comparative genomic hybridization a deletion including the CDKN2A, CDKN2B and CDKN2BAS gene cluster was detected in both twin sisters, encompassing a large region at 9p21.3 and occurring de novo after the loss of one paternal allele. Patient B is a boy of 7 years when treated for astrocytoma then developing melanoma associated to congenital nevi on the head 10 years later: sequencing and multiplex ligation-dependent probe amplification revealed a normal profile of the CDKN2A/CDKN2B/CDKN2BAS region. Array comparative genomic hybridization confirmed the absence of deletions at 9p21.3 and failed to reveal known pathogenic copy number variations. CONCLUSIONS: By comparison with the other germ line deletions at the CDKN2A, CDKN2B and CDKN2BAS gene cluster reported in melanoma susceptible families, the deletion detected in the two sisters is peculiar for its de novo origin and for its extension, as it represents the largest constitutive deletion at 9p21.3 region identified so far. In addition, the two studied cases add to other evidence indicating association of melanoma with exposure to ionizing radiation and with second neoplasm after childhood cancer. Melanoma should be considered in the monitoring of pigmented lesions in young cancer patients

Targeting SMYD3 to sensitize homologous recombination-proficient tumors to PARP-mediated synthetic lethality

SMYD3 is frequently overexpressed in a wide variety of cancers. Indeed, its inactivation reduces tumor growth in preclinical in vivo animal models. However, extensive characterization in vitro failed to clarify SMYD3 function in cancer cells, although confirming its importance in carcinogenesis. Taking advantage of a SMYD3 mutant variant identified in a high-risk breast cancer family, here we show that SMYD3 phosphorylation by ATM enables the formation of a multiprotein complex including ATM, SMYD3, CHK2, and BRCA2, which is required for the final loading of RAD51 at DNA double-strand break sites and completion of homologous recombination (HR). Remarkably, SMYD3 pharmacological inhibition sensitizes HR-proficient cancer cells to PARP inhibitors, thereby extending the potential of the synthetic lethality approach in human tumors

Innovazioni tecnologiche per le filiere agroalimentari del Tavoliere ed azioni di diffusione nell’ambito del progetto Equal I.S.O.LA.

Il sistema economico produttivo dell’Alto Tavoliere, in provincia di Foggia, caratterizzato da una forte presenza nel settore agroalimentare, ha evidenziato negli ultimi anni l’emergere di una preoccupante contraddizione: redditi bassi per i singoli operatori e grandi potenzialità di crescita per l’intero settore. Il Progetto Equal I.S.O.LA, realizzatosi nel triennio 2005-2008, ha inteso analizzare i principi di una pianificazione strategica del dell’Alto Tavoliere in un sistema ad alta intensità di capitale umano e sociale, in grado di risolvere tale contraddizione. Il capitolo analizza il livello innovativo delle aziende e dell’area e il potenziale creativo degli imprenditori e, quindi, rilevano la loro propensione all’introduzione di innovazioni. Ciò è stato esaminato attraverso i dati ottenuti dall’indagine diretta, condotta per mezzo di questionari. Da ciò è emerso che le attività agricole e agro-industriali costituiscono il fulcro su cui è incardinato il sistema economico dell’Alto Tavoliere. I miglioramenti nelle diverse filiere agro-alimentari hanno riguardato principalmente l’introduzione di tecnologie di prodotto e servizi, scarsi invece, sono stati i miglioramenti relativi alle risorse umane. Non elevata è la propensione alla formazione anche se le previsioni mostrano un aumento. Se da una parte i punti di forza delle filiere nell’Alto Tavoliere sono le favorevoli condizioni pedo-climatiche, la qualità dei prodotti e le produzioni di qualità, i punti di debolezza delle stesse riguardano l’elevata frammentazione delle aziende, i bassi livelli associativi, lo scarso dialogo tra gli attori della filiera e l’insufficiente servizio alle imprese. Pertanto, la capacità di innovare i prodotti nei processi tecnologici ed organizzativi diventa cruciale per la sostenibilità del tessuto produttivo locale. Di conseguenza, la scienza e la tecnologia assumono un ruolo strategico spostando progressivamente l’enfasi dai fattori di produzione a quelli intangibili legati alla conoscenza

L'AGRICOLTURA MULTIFUNZIONALE NELL'ALTO TAVOLIERE.

“L’agricoltura multifunzionale nell’Alto Tavoliere” è da inquadrarsi nell’ambito di due aree di studio, l’agronomico e l’economico, strettamente correlate tra di loro. In relazione alla scienza agronomica essa tratta le problematiche inerenti la sostenibilità delle attività agricole che, come è noto, hanno come obiettivo il perseguimento della diffusione delle Buone Pratiche Agricole, al fine di assicurare la conservazione e la rigenerazione delle risorse produttive ed ambientali di un territorio nella quantità e qualità necessaria per assicurare il futuro sviluppo delle attività umane in genere e di quelle agricole in particolare. Sotto il profilo economico, è noto che, il concetto tradizionale di sviluppo di un territorio, basato solo sull’incremento del reddito pro-capite in termini di tasso di crescita reale, negli ultimi anni ha incluso anche alcune variabili di carattere sociale e ambientale. In particolare, nel territorio preso in considerazione, sono state analizzate: le criticità ambientali in considerazione delle risorse produttive, pedologiche ed idriche; le attività di agricoltura sostenibile, biologica e di agriturismo; i prodotti tipici ed il paesaggio rurale