A case-control study on the combined effects of p53 and p73 polymorphisms on head and neck cancer risk in an Italian population

<p>Abstract</p> <p>Background</p> <p>The purpose of this study is to analyze the combined effects of selected <it>p</it>53 and <it>p</it>73 polymorphisms and their interaction with lifestyle habits on squamous cell carcinoma of the head and neck (SCCHN) risk and progression in an Italian population.</p> <p>Methods</p> <p>Two hundred and eighty-three cases and 295 hospital controls were genotyped for <it>p</it>53 polymorphisms on exon 4 (Arg72Pro), intron 3 and 6, and <it>p</it>73 G4C14-to-A4T14. Their association with SCCHN was estimated using a logistic regression analysis, while a multinomial logistic regression approach was applied to calculate the effect of the selected polymorphisms on SCCHN different sites (oral cavity, oropharynx, hypopharynx and larynx). We performed an haplotype analysis of the <it>p</it>53 polymorphisms, and a gene-gene interaction analysis for the combined effects of <it>p</it>73 G4C14-to-A4T14 and <it>p</it>53 polymorphisms.</p> <p>Results</p> <p>We found a significant increased risk of SCCHN among individuals with combined <it>p</it>73 exon 2 G4A and <it>p</it>53 intron 3 variant alleles (OR = 2.22, 95% CI: 1.08–4.56), and a protective effect for those carrying the <it>p</it>53 exon 4-<it>p</it>53 intron 6 diplotype combination (OR = 0.67; 95% CI: 0.47–0.92). From the gene-environment interaction analysis we found that individuals aged < 45 years carrying <it>p</it>73 exon 2 G4A variant allele have a 12.85-increased risk of SCCHN (95% CI: 2.10–78.74) compared with persons of the same age with the homozygous wild type genotype. Improved survival rate was observed among <it>p</it>53 intron 6 variant allele carriers (Hazard Ratio = 0.51 (95% CI: 0.23–1.16).</p> <p>Conclusion</p> <p>Our study provides for the first time evidence that individuals carrying <it>p</it>53 exon 4 and <it>p</it>53 intron 6 variant alleles are significantly protected against SCCHN, and also shows that an additional risk is conferred by the combination of <it>p</it>73 exon 2 G4C14-to-A4T14 and <it>p</it>53 intron 3 variant allele. Larger studies are required to confirm these findings.</p

CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms, smoking, consumption of alcohol and fruit and vegetables and risk of head and neck cancer

Purpose As risk-modiWers of alcohol and tobacco eVects, metabolic genes polymorphisms were investigated as susceptibility candidates for squamous cell carcinoma of the head and neck (SCCHN). Methods A total of 210 cases and 245 hospital controls, age and gender matched, were genotyped for CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms. A measurement of the biological interaction among two risk factors was estimated by the attributable proportion (AP) due to interaction and its 95% conWdence interval (CI). Results SCCHN risk was associated with high-levels of alcohol intake [OR = 3.50 (95%CI: 1.93 6.35) and OR = 6.47 (95%CI: 2.92 14.35) for 19 30 g/day and &gt;30 g/day, respectively], cigarette smoking [OR = 3.47 (95%CI: 1.88 6.41) and OR = 7.65 (95%CI: 4.20 13.90) for 1 25 and &gt;25 packyears of smoking, respectively] and low-fruit and vegetables consumption (OR = 2.45; 95%CI: 1.53 3.92). No diVerences were observed for the genotypes or haplotypes distributions among cases and controls, and no biological interaction emerged from gene gene and gene environment interaction analyses. An attributable proportion (AP) due to biological interaction of 0.65 (95%CI: 0.40 0.90) was detected for heavy drinkers with a low intake of fruit and vegetables, and an AP of 0.40 (95%CI: 0.10 0.72) resulted forever smokers with low fruit and vegetables consumption. Conclusions Even in presence of high alcohol consumption or cigarette smoking, a high intake of fruit and vegetables might prevent the development of around one quarter of SCCHN cases. The lack of interaction between the studied polymorphisms and the environmental exposures suggests that chronic consumption of tobacco and alcohol overwhelm enzyme defences, irrespective of genotype

The interaction of ω2 with the RNA polymerase β′ subunit functions as an activation to repression switch

The ω gene is encoded in broad-host range and low-copy plasmids. It is genetically linked to antibiotic resistance genes of the major human pathogens of phylum Firmicutes. The homodimeric forms of ω (ω) coordinate the plasmid copy number control, faithful partition (ω and δ) and better-than-random segregation (ζεζ) systems. The promoter (P) of the ωεζ operon (P) transiently interacts with ω. Adding δ facilitates the formation of stable ω·P complexes. Here we show that limiting ω interacts with the N-terminal domain of the β′ subunit of the Bacillus subtilis RNA polymerase (RNAP-σ) vegetative holoenzyme. In this way ω recruits RNAP-σ onto P DNA. Partial P occupancy by ω increases the rate at which RNAP-σ complex shifts from its closed (RP) to open (RP) form. This shift increases transcription activation. Adding δ further increases the rate of P transcription initiation, perhaps by stabilizing the ω·P complex. In contrast, full operator occupancy by ω facilitates RP formation, but it blocks RP isomerization and represses P utilization. The stimulation and inhibition of RP formation is the mechanism whereby ω mediates copy number fluctuation and stable plasmid segregation. By this mechanism, ω also indirectly influences the acquisition of antibiotic resistance genes.Funding for open access charge: Dirección General de Investigación-Ministerio de Economía y Competitivida

Sudden cochlear hearing loss as presenting symptom of arachnoid cyst of the cranial posterior fossa

Arachnoid cysts account for almost 1% of neoformations located in the cerebellopontine angle. The aetiopathogenesis is unknown. Arachnoid cysts of the cranial posterior fossa may produce symptoms typical of a tumour such as headache, dizziness, tinnitus and progressive sensorineural hearing loss. Management of these lesions is still controversial; if the arachnoid cyst is symptomatic, surgical treatment is usually recommended. The case is described of an adult female with sudden unilateral cochlear hearing loss as presenting symptom of an arachnoid cyst in the cranial posterior fossa

The pathological diagnosis of neuroendocrine tumors: common questions and tentative answers

Neuroendocrine neoplasms (NEN) develop in many organs, and although they share some pathological and clinical features, significant differences do exist among different tumor types and locations. The correct classification of NENs is based on the recently published WHO classification according to the various locations, and is relevant for the appropriate treatment in each group. The apparently easy diagnostic categorization in well-differentiated NENs, called neuroendocrine tumors, and poorly differentiated NENs, called neuroendocrine carcinomas, is complicated by the existence, among others, of different terminologies, morphological criteria of malignancy, combined exocrine-endocrine tumors, as well as of heterogeneous diagnostic, prognostic, and predictive markers. The present paper is an overview of the most frequently asked questions and an attempt to provide practical answers related to NEN diagnosis in the daily pathology work

Exploring circular MET RNA as a potential biomarker in tumors exhibiting high MET activity

Abstract Background MET-driven acquired resistance is emerging with unanticipated frequency in patients relapsing upon molecular therapy treatments. However, the determination of MET amplification remains challenging using both standard and next-generation sequencing-based methodologies. Liquid biopsy is an effective, non-invasive approach to define cancer genomic profiles, track tumor evolution over time, monitor treatment response and detect molecular resistance in advance. Circular RNAs (circRNAs), a family of RNA molecules that originate from a process of back-splicing, are attracting growing interest as potential novel biomarkers for their stability in body fluids. Methods We identified a circRNA encoded by the MET gene (circMET) and exploited blood-derived cell-free RNA (cfRNA) and matched tumor tissues to identify, stratify and monitor advanced cancer patients molecularly characterized by high MET activity, generally associated with genomic amplification. Results Using publicly available bioinformatic tools, we discovered that the MET locus transcribes several circRNA molecules, but only one candidate, circMET, was particularly abundant. Deeper molecular analysis revealed that circMET levels positively correlated with MET expression and activity, especially in MET-amplified cells. We developed a circMET-detection strategy and, in parallel, we performed standard FISH and IHC analyses in the same specimens to assess whether circMET quantification could identify patients displaying high MET activity. Longitudinal monitoring of circMET levels in the plasma of selected patients revealed the early emergence of MET amplification as a mechanism of acquired resistance to molecular therapies. Conclusions We found that measurement of circMET levels allows identification and tracking of patients characterized by high MET activity. Circulating circMET (ccMET) detection and analysis could be a simple, cost-effective, non-invasive approach to better implement patient stratification based on MET expression, as well as to dynamically monitor over time both therapy response and clonal evolution during treatment