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THE IMPACT OF ONE-CARBON METABOLISM POLYMORPHIC VARIANTS ON CANCER RISK AND SURVIVAL RATE IN PRIMARY LIVER AND COLON NEOPLASMS ACCORDING TO GLOBAL DNA METHYLATION AND HYDROXYMETHYLATION STATUS: ROLE OF EPIGENETIC MODULATION FROM THE RESULTS OF A CLINICAL STUDY
No full textIl metabolismo delle unità monocarboniose (o mono carbonioso) rappresenta un pathway complesso coinvolto sia nella sintesi dei nucleotidi che nelle reazioni di metilazione biologica inclusa quella del DNA, il principale meccanismo epigenetico negli esseri umani. Uno stato di aberrante metilazione del DNA è una caratteristica comune nel tumore. Numerose varianti polimorfiche di geni all’interno del metabolismo mono-carbonioso sono state correlate al rischio di cancro, ma se il legame tra queste varianti geniche e il rischio/tempo di sopravvivenza legati al cancro possa realizzarsi attraverso un’alterata metilazione del DNA è una ipotesi fino ad ora scarsamente studiata e ancora non chiarita. Oltre alla metilazione, l’idrossimetilazione del DNA è stata recentemente descritta come un nuovo, potenzialmente utile marker epigenetico. I tumori primitivi del fegato, in particolare l’epatocarcinoma (HCC) e il colangiocarcinoma (CC), e il cancro del colon, nonostante l’alta incidenza, sono stati scarsamente caratterizzati dal punto di vista epigenetico. Gli scopi del presente progetto sono stati definire il possibile ruolo della metilazione ed idrossimetilazione del DNA nel tumore ed in particolare: 1. Determinare se le varianti polimorfiche dei geni del metabolismo mono-carbonioso possano influenzare il rischio di tumore primitivo del fegato e di tumore del colon attraverso la metilazione del DNA, definita come livelli di metilcitosina (mCyt) misurata nel DNA delle cellule periferiche mononucleate del sangue (PBMCs). 2. Verificare se lo stato di metilazione del DNA misurato nei PBMCs dei soggetti affetti da HCC, CC e tumore del colon possa correlare con l’andamento clinico e il tempo di sopravvivenza, definendo pertanto un possibile marcatore epigenetico di malattia. 3. Caratterizzare ulteriormente lo status epigenetico di HCC e CC valutando il contenuto globale di mCyt e hmCyt nel DNA del tessuto neoplastico e nel tessuto omologo non neoplastico.
Materiali e metodi: La genotipizzazione di BHMT 716A>G, DHFR 19bp ins/del, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, TCII 776C>G e TS 2rpt-3rpt è stata eseguita in 102 pazienti neoplastici e 363 soggetti liberi da tumore. La metilcitosina e l’idrossimetilcitosina sono state misurate attraverso un metodo LC/MS/MS nel DNA dei PBMCs di tutti i soggetti e nel tessuto neoplastico e nel tessuto omologo non neoplastico di 47 patienti affetti da tumore primitivo del fegato sottoposti a intervento chirurgico.
Risultati:
1. Il genotipo MTHFD1 1958AA era significativamente meno frequente nei soggetti neoplastici rispetto ai controlli (p=0.007) e la sua presenza si associava ad una riduzione del 63% di rischio generale di tumore (OR=0.37, p=0.003) e del 75% di rischio di tumore del colon (OR=0.25, p=0.006). Il genotipo MTHFD1 1958GG era significativamente più frequente tra i pazienti neoplastici (p=0.007) ed era associato ad un più basso livello di metilazione del DNA se comparato ai soggetti portatori dell’allele A (p=0.048).
2. La variante polimorfica RFC1 80AA era associata ad una sopravvivenza significativamente ridotta nei pazienti con tumore primitivo del fegato, rispetto ai portatori dei genotipi GG e GA (p=0.005) in un periodo di follow-up di 60 mesi. Quando i livelli di mCyt sono stati stratificati come alti (> 5.34%) o bassi (≤ 5.34%), in accordo con il valore medio di mCyt, la concomitante presenza del genotipo AA e di bassa mCyt comportava una peggiore prognosi, nel confronto con i soggetti portatori dell’allele G, sia con alti che con bassi valori di mCyt (p<0.0001); non vi erano differenze di sopravvivenza tra i portatori dell’allele G e i soggetti AA con alti livelli di mCyt (p=0.919). Inoltre, un più alto rischio di mortalità era associato con la concomitante presenza del genotipo AA e di bassi livelli di mCyt se comparato ai soggetti portatori dell’allele G (OR=8.35, p=0.001).
3. Livelli di mCyt ≥5.59% nei PBMCs erano associati ad una significativa migliore aspettativa di vita se comparati a valori di mCyt < 5.59% (p=0.034) in un follow-up di 48 mesi nei pazienti affetti da tumore primitivo del fegato. Il contenuto di mCyt nel tessuto neoplastico di HCC era notevolmente più basso che nel tessuto di CC (rispettivamente 3.97% vs 5.26%, p<0.0001). Nell’HCC sono stati osservati livelli di mCyt significativamente ridotti nel tessuto neoplastico rispetto al tessuto non neoplastico (3.97% vs. 4.82% mCyt, p<0.0001), ma questa differenza non era presente nel tessuto epatico dei pazienti affetti da CC. L’idrossimetilazione era significativamente ridotta nel tessuto neoplastico degli HCC vs il tessuto epatico non neoplastico (0.044 vs. 0.128, p<0.0001), così come nel tessuto neoplastico del CC confrontato sia con il tessuto epatico non neoplastico, sia con la colecisti (rispettivamente 0.030 vs. 0.124, p=0.026; 0.030 vs. 0.123, p=0.006).
Conclusioni: i nostri risultati suggeriscono una possibile associazione tra le varianti polimorfiche dei geni del metabolismo mono-carbonioso e la metilazione del DNA. Questa associazione suggerisce che la metilazione del DNA potrebbe rappresentare il legame importante tra varianti geniche polimorfiche e il tumore primitivo del fegato e il tumore del colon, sia in termini di rischio che di aspettativa di vita. Questo riscontro potrebbe collocare la metilazione del DNA nei PBMCs come possibile biomarcatore per questi tipi di tumore. Inoltre, considerato che la metilazione del DNA è un fenomeno potenzialmente reversibile che dipende dal metabolismo mono-carbonioso per il rifornimento di gruppi metilici, si possono immaginare possibili strategie indirizzate ad ottimizzare l’apporto di questi componenti allo scopo di mantenere la metilazione del DNA all’interno di valori adeguati per la prevenzione di malattia. I risultati di questo studio dimostrano, inoltre, che un significativo ridotto grado di metilazione del DNA caratterizza il tessuto neoplastico dell’HCC rispetto al CC, mentre bassi livelli di idrossimetilazione caratterizzano sia il tessuto neoplastico dell’HCC che del CC in confronto al tessuto non neoplastico. Ulteriori conferme dei presenti dati saranno opportune e necessarie per verificare l’utilità e l’affidabilità nella pratica clinica dei biomarcatori genetici-epigenetici come indici prognostici per i pazienti affetti da tumore primitivo del fegato e da tumore del colon.One-carbon metabolism is a complex pathway involved both in nucleotide synthesis and in biological methylation reactions including that of DNA methylation, the main epigenetic mechanism in humans. An aberrant DNA methylation is a common feature in cancer disease. Several polymorphic gene variants within one-carbon metabolism have been related to cancer risk, but whether the link between one-carbon metabolism variants and cancer risk/survival rate may occur through an altered DNA methylation is still poorly investigated and yet unclear. In addition to DNA methylation, hydroxymethylation of DNA has been recently described as a novel, potentially useful epigenetic mark. Primary liver cancers, i.e. hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) as well as colon cancer are highly prevalent but epigenetically poorly characterized, so far.
The main aims of the present project were to define a possible role for DNA methylation in cancer, and specifically: 1. to determine whether polymorphic variants of one- carbon metabolism genes may influence the risk of human primary liver cancers and colon cancer through DNA methylation, defined as methylcytosine (mCyt) levels measured in peripheral blood mononuclear cells (PBMCs) DNA; 2. to verify whether DNA methylation status measured in PBMCs of subjects affected by HCC, CC and colon cancer may correlate with clinical outcomes and survival rate, therefore defining a possible epigenetic marker of disease; 3. to further characterize the epigenetic layout of HCC and CC by evaluating the global DNA mCyt and hydroxymethylcytosine (hmCyt) content in neoplastic and homologous non-neoplastic tissues.
Material and Methods: Genotyping for BHMT 716A>G, DHFR 19bp ins/del, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, TCII 776C>G and TS 2rpt-3rpt was performed in 102 cancer patients and 363 cancer-free subjects. Methylcytosine and hmCyt were measured by an LC/MS/MS method in PBMCs DNA of all subjects and in neoplastic and homologous non-neoplastic tissues of 47 primary liver cancer patients undergoing curative surgery. A follow-up examination was performed on all the patients 48-60 months after the surgical procedure.
Results: 1. The MTHFD1 1958AA genotype was significantly less frequent among cancer patients as compared to controls (p=0.007) and related to 63% reduction of the overall cancer risk (OR=0.37, p=0.003) and 75% of risk for colon cancer (OR=0.25, p=0.006). The MTHFD1 1958GG was significantly more frequent among cancer patients (p=0.007) and associated to lower DNA methylation as compared to MTHFD1 1958 allele A carriers (p=0.048). 2. The RFC1 80AA polymorphic variant was associated in primary liver cancer with a significantly reduced survival rate as compared to GG and GA (p=0.005) at a follow-up period of 60 months. When the mCyt levels were stratified as either high (>5.34%) or low (≤5.34%) according to the mCyt median value, the combination of AA genotype and low mCyt led to a significantly worse survival as compared to the two genotype groups carrying the G allele considered as a whole (p<0.0001); no difference in survival was found between G carriers and AA in association with high mCyt (p=0.919). Moreover, a higher mortality risk was associated with the concomitant presence of the AA genotype and low mCyt, as compared to G carrier subjects (OR=8.35, p=0.001). 3. In primary liver cancer, levels of mCyt ≥5.59% in PBMCs were associated to a significantly higher life expectancy as compared to mCyt<5.59% (p=0.034) at a follow-up period of 48 months. Methylcytosine content in HCC neoplastic tissue was notably lower than in CC tissues (3.97% vs. 5.26% respectively, p<0.0001). Significantly reduced mCyt levels were observed in HCC neoplastic as compared to non-neoplastic tissue (3.97% vs. 4.82% mCyt, p<0.0001) but such difference was not found in liver tissue of patients affected by CC. Hydroxymethylation was significantly decreased in HCC neoplastic vs. non-neoplastic liver tissue (0.044 vs. 0.128, p<0.0001), as well as in CC neoplastic tissue vs. both non-neoplastic liver and gall bladder (0.030 vs. 0.124, p=0.026; 0.030 vs. 0.123, p=0.006, respectively).
Conclusions: Our results suggest a possible association between one-carbon metabolism genes polymorphic variants and DNA methylation. This association suggests that DNA methylation may be the underlying link between polymorphic gene variants and primary liver and colon cancers, both in terms of risk and life expectancy. This finding may situate PBMCs DNA methylation as a possible biomarker for those types of cancer disease. Moreover, since DNA methylation is a reversible phenomenon that relies on one-carbon metabolism for provision of methyl groups, adequate strategies to optimize sources of such compounds to maintain DNA methylation within adequate levels for disease prevention may be considered in the framework to modulate this epigenetic mechanism. The results of this study demonstrate, furthermore, that a significantly lower degree of DNA hypomethylation characterize HCC from CC tissue, whereas DNA hypo-hydroxymethylation characterizes both HCC and CC neoplastic tissues as compared to the non-neoplastic. Further validation of the present novel data is required to assess whether this genetic-epigenetic biomarkers may indeed be a reliable and useful for clinical application as a prognostic tool for patients with primary liver and colon cancers
An unusual case of acute abdominal pain
No full textDifferential diagnosis for abdominal pain should enclose the rare occurrence of venous thromboembolism which may be the clinical expression of a systemic disease including the complication or the unusual first clinical presentation of an inflammatory bowel disease (IBD). Patients with IBD have an elevated risk of venous thromboembolism (VTE) compared with the general population. Mortality among patients with portal-mesenteric vein thrombosis is rather high, while, due to its rare occurrence, studies on splanchnic vein thrombosis are few and there are no univocal data on appropriate duration of oral anticoagulation therapy, long-term prognosis, morbidity and mortality of the disease which remain mostly unknown. The clinical case reported here, describes a life-threatening, rare case of splenic-mesenteric-portal vein thrombosis as the acute manifestation of ulcerative-colitis.
Awareness and early diagnosis of splanchnic thrombosis deserves, therefore, particular attention to ameliorate the final outcome and prognosis of diseas
Cardiovascular epigenetics: from DNA methylation to microRNAs
No full textEpigenetic phenomena define heritable mechanisms that establish and maintain mitotically stable patterns of gene expression regulation that occur without modifying the base sequence of DNA. The major epigenetic features of mammalian cells enclose DNA methylation, post-translational histone modifications and RNA-based mechanisms including those controlled by small non-coding RNAs (miRNAs). Their impact in cardiovascular pathophysiology is now emerging as a major interface between genotype to phenotype variability with strict implications on disease development and progression, opening up to possible novel preventive strategies. Epigenetic mechanisms are potentially reversible and may be influenced by nutritional-environmental factors as well as through gene-environment interactions, all of which have an important role in complex, multifactorial diseases such as those affecting the cardiovascular system. Gene expression regulation through the interplay of DNA methylation and histone modifications is well-established, although the knowledge about the function of epigenetic signatures in cardiovascular disease is still largely unexplored. The study of epigenetic markers is, therefore, an emerging and very promising frontier of science which may help for a deeper understanding of molecular mechanisms underlying the modulation of gene expression in cardiovascular disease-linked biomolecular pathways. This review will focus on up-to-date knowledge pertaining to the role of epigenetics, from DNA methylation to miRNAs, in major cardiovascular diseases such as ischemic heart disease, hypertension, heart failure and stroke
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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