Erratum: Epigenetics of oral and oropharyngeal cancers (Review).

[This corrects the article DOI: 10.3892/br.2018.1136.].

Epigenetics of oral and oropharyngeal cancers.

Oral and oropharyngeal cancers represent the two most common malignancies of the head and neck region. The major risk factors for these cancers include alcohol consumption, tobacco use (via smoking or chewing) and high-risk human papillomavirus infection. The transition from normal epithelium to premalignant tissue and finally carcinoma is in part caused by a summation of genetic and epigenetic modifications. Epigenetic refers to modifications in the way the genome is expressed in cells. The most common examples of epigenetic control of gene expression are DNA methylation, histone modification and regulation by small non-coding RNAs. The aim of the current paper was to review the recent studies on the main epigenetic changes that have been suggested to serve a role in the carcinogenesis process and progression of oral and oropharyngeal cancers. Furthermore, it is discussed how the epigenetic changes may be used as potential predictive biomarkers and how recent findings in the field may impact the personalized cancer therapy approach for these tumors.

Not smoking is associated with lower risk of hypertension: results of the Olivetti Heart Study.

BACKGROUND: Few epidemiological investigations evaluated the role of smoking cessation on blood pressure (BP), and the results are not univocal. Therefore, the aim of this study was to assess the effect of smoking cessation on the risk to develop hypertension (HPT) and on BP values. METHODS: This longitudinal study, with a follow-up period of 8 years, included the participants of the Olivetti Heart Study. Participants were 430 untreated normotensive non-diabetic men with normal renal function, examined twice in 1994-95 and in 2002-04. The sample included current smokers (S, n = 212), former smokers (ES, n = 145) and never smokers (NS, n = 73) at baseline. RESULTS: Basal body mass index (BMI), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly higher in ES than in S (ES vs. S; BMI: 27.0 ± 2.5 vs. 26.1 ± 2.9 kg/m2; P < 0.01; SBP/DBP: 121.2 ± 9.3/80.0 ± 5.8 vs. 19.1 ± 9.9/77.4 ± 6.7 mm Hg; P < 0.05; M ± SD). After 8 years of follow-up, BP changes (Δ) were significantly lower in ES than in S (ΔSBP/DBP: 12.6 ± 13.4/7.9 ± 8.1 vs. 16.0 ± 14.9/10.3 ± 10.1 mm Hg; P < 0.05; M ± SD), also after adjustment for potential confounders. Moreover, at the last examination, the overall HPT prevalence was 33%, with lower values in ES than in S (25 vs. 38%, P = 0.01). After accounting for age, BP and BMI at baseline, and changes in smoking habit over the 8-year period, ES still had significant lower risk of HPT than S (odds ratio 0.30, 95% confidence interval 0.15-0.58; P < 0.01). CONCLUSIONS: In this sample of healthy men, smoking cessation was associated with lower BP increment and minor HPT risk, independently of potential confounders.

Recurrences of meningiomas: predictive value of pathological features and hormonal and growth factors.

OBJECTIVE: Recurrence of apparently completely resected benign meningiomas is a rather frequent event, the mechanisms of which are still unclear. The aim of this study is to define the pathological features, proliferation indexes, growth factors and hormone receptor expression in predicting the meningioma recurrence. METHODS: Two groups of 50 completely resected benign WHO I meningiomas, with and without recurrence respectively, have been reviewed. Tumor location, consistency, vascularity, and histological types have been considered. Immunohistological studies include mitotic index (MI), Ki-67 LI, estrogen and progesterone receptors (ER and PR), Vascular Endothelial Growth Factor (VEGF), Epidermal Growth Factor (EGF), and Bcl-2. All these factors have been correlated with the recurrence. RESULTS: The tumor recurrence was not correlated with the patient age, tumor location, consistency, vascularity and histology. There was not difference in the histological pattern between local and diffuse recurrences. M.I. and Ki-67 LI were significantly correlated with the recurrence (P<0.0001). PR negativity had a strong predictive value of recurrence (P<0.0001), whereas the ER status was not relevant. VEGF and EGF-R were not correlated with the recurrence of meningiomas, whereas the Bcl-2 protein positivity showed a tendency to the significativity (P=0.0294). The negative association between Bcl-2 and PR is an interesting finding of our study. CONCLUSIONS: Higher MI and Ki-67 LI and PR negativity are predictive factors of recurrence of benign (WHO I) completely resected meningiomas, particularly when Bcl-2 positivity is associated.

Prognostic significance of multidrug-resistance protein (MDR-1) in renal clear cell carcinomas: a five year follow-up analysis.

BACKGROUND: A large number of renal cancer patients shows poor or partial response to chemotherapy and the mechanisms have not been still understood. Multi-drug resistance is the principal mechanism by which many cancers develop resistance to chemotherapic drugs. The role of the multi-drug resistant transporter (MDR-1/P-glycoprotein), the gene product of MDR-1, and that one of the so-called multi-drug resistance associated protein (MRP), two energy-dependent efflux pumps, are commonly known to confer drug resistance. We studied MDR-1 expression in selected cases of renal cell carcinoma (RCC), clear cell type, with long-term follow-up, in order to establish its prognostic role and its possible contribution in the choice of post-surgical therapy. METHODS: MDR-1 has been studied by standard LSAB-HRP immunohistochemical technique, in paraffin embedded RCC samples. Protein expression has been compared to clinical and histopathological data and to disease specific survival of RCC patients, by Kaplan-Meier curve and Cox multivariate regression analyses. RESULTS: Two groups of RCCs were obtained by esteeming MDR-1 expression and disease specific survival (obtained with Kaplan-Meier curve and Cox multivariate regression analyses): the first one presents low or absent MDR-1 expression and good survival; the second one is characterized by high MDR-1 expression and significant poor outcome (p < 0.05). Afterwards, we have found disease specific survival, adjusted for stages and independent of therapy: this difference of survival rates was statistically significant (p < 0.05). Stage adjusted disease specific survival rate, according to MDR-1 expression and therapy in patients affected by RCC in early stage (stage I), has revealed that the group of patients with high MDR-1 expression and without adjuvant therapy showed poor survival (p < 0.05). Cox multivariate regression analysis has confirmed that, in our cohort of RCC (clear cell type) patients, the strong association between MDR-1 and worse outcome is independent not only of the adjuvant therapy, but also of the other prognostic parameters (p < 0.05). CONCLUSION: In our opinion, the results of this study well prove the relationship between MDR-1 expression and worse clinical prognosis in RCC, because MDR-1 over-expressing RCCs can be considered a group of tumours with a more aggressive behavior. This finding outlines a possible role of MDR-1 as prognostic factor, dependent and independent of multidrug resistance. These results could be useful to predict cancer evolution and to choose the appropriate treatment: this is another step that can stimulate further promising and interesting investigations on broader study population.

Clinical progression and familial occurrence of cerebral cavernous angiomas: the role of angiogenic and growth factors.

OBJECT: The authors studied the expression of angiogenic and growth factors and various proliferative indices in cavernous angiomas of the brain. The goal was to define whether the often progressive clinical course of both sporadic and familial forms of the lesion is correlated with different expression of these factors. METHODS: Forty-three cavernomas of the brain were investigated with immunohistochemical studies and stained for four growth factors (vascular endothelial growth factor [VEGF], tenascin, transforming growth factor-b [TGFb], and platelet-derived growth factor [PDGF]), and for Ki-67 and bcl-2. The intensity of expression was tested in all cases in the walls of cavernoma vessels, in the perivascular tissue, and in the perilesional brain parenchyma. Among the 43 cavernomas, 32 were stable and sporadic single lesions less than 2 cm in size, whereas 11 were cavernomas larger than 2 cm (up to 6 cm). These larger cavernomas had more aggressive behavior (documented growth in five cases, mass effect in eight, significant hemorrhage in four), familial occurrence (six cases), and/or multiple lesions (five cases). The expression of VEGF, tenascin, and PDGF in cavernomas did not significantly differ in the two groups of patients, whereas TGFb expression was higher in the more aggressive forms of cavernomas. The expression of Ki-67 and bcl-2 was always absent in stable lesions, and it was positive in eight (72.7%) of 11 aggressive lesions. The perilesional brain parenchyma showed a significantly higher expression of TGFb, PDGF, and tenascin in more aggressive cavernomas. CONCLUSIONS: The familial occurrence and more aggressive clinical behavior of cavernous angiomas of the brain are associated with higher expression of Ki-67 and bcl-2 in the cavernoma tissue, as in other proliferative lesions. These features are also associated with higher expression of some growth factors (excluding VEGF) in the perilesional brain parenchyma, suggesting that the neighboring vasculature and glia may be predisposed to and recruited for further growth and progression.

Lack of association between polymorphism in the beta2-adrenergic receptor gene, hypertension, and obesity in the Olivetti heart study.

OBJECTIVE: Several case-control studies have explored the possible association between polymorphism in the beta2 adrenoreceptor gene (beta2AR), hypertension, and obesity--the focus being in particular on the Arg16Gly and Gln27Glu substitutions, which appear to modify the extracellular part of the beta2AR with possible functional modification. However, controversial results have been obtained. DESIGN AND METHODS: The analysis refers to 993 middle-age men characterized for Arg16Gly and Gln27Glu polymorphism of the beta2AR. In this general population sample there were 563 overweight, 160 obese, and 405 hypertensive individuals, of whom 171 were receiving antihypertensive therapy. RESULTS: The genotype frequencies for codon 16 were: GlyGly = 38%; ArGly = 45%; ArgArg = 17%. The frequencies for codon 27 were: GlnGln = 50%; GlnGlu = 39%; GluGlu = 11%. Codon 16 and codon 27 polymorphisms were in linkage disequilibrium. No differences were detected in body mass index and blood pressure across different genotypes. Likewise, no association was detected between either of the two polymorphisms and being overweight (codon 27: chi2 = 0.1, codon 16: chi2 = 1.4), obesity (codon 27: chi2 = 0.1, codon 16: chi2 = 1.7) and hypertension (codon 27: chi2 = 2.7, codon 16: chi2 = 1.9). The odds ratio (with 95% confidence intervals) for overweight, obesity, and hypertension were not different between genotypes. Likewise, no difference in the anthropometric indices of fat distribution, fasting blood glucose, serum insulin, triglycerides, uric acid, and HOMA index could be detected between groups. CONCLUSIONS: In summary, in this large unselected sample of adult white men, genetic variation in the beta2AR was not associated with blood pressure or with overweight, obesity, and fat distribution.