MicroRNAs in Pancreatic Cancer: Involvement in Carcinogenesis and Potential Use for Diagnosis and Prognosis

Pancreatic cancer is one of the most fatal malignancies with increasing incidence and high mortality. Possibilities for early diagnosis are limited and there is currently no efficient therapy. Molecular markers that have been introduced into diagnosis and treatment of other solid tumors remain unreciprocated in this disease. Recent discoveries have shown that certain microRNAs (miRNAs) take part in fundamental molecular processes associated with pancreatic cancer initiation and progression including cell cycle, DNA repair, apoptosis, invasivity, and metastasis. The mechanism involves both positive and negative regulation of expression of protooncogenes and tumor suppressor genes. Various miRNAs are expressed at different levels among normal pancreatic tissue, chronic pancreatitis, and pancreatic cancer and may therefore serve as a tool to differentiate chronic pancreatitis from early stages of cancer. Other miRNAs can indicate the probable course of the disease or determine the survival prognosis. In addition, there is a growing interest directed at the understanding of miRNA-induced molecular mechanisms. The possibility of intervention in the molecular mechanisms of miRNAs regulation could begin a new generation of pancreatic cancer therapies. This review summarizes the recent reports describing functions of miRNAs in cellular processes underlying pancreatic cancerogenesis and their utility in diagnosis, survival prognosis, and therapy

<i>RET</i> Variants and Haplotype Analysis in a Cohort of Czech Patients with Hirschsprung Disease

<div><p>Hirschsprung disease (HSCR) is a congenital aganglionosis of myenteric and submucosal plexuses in variable length of the intestine. This study investigated the influence and a possible modifying function of <i>RET</i> proto-oncogene's single nucleotide polymorphisms (SNPs) and haplotypes in the development and phenotype of the disease in Czech patients. Genotyping of 14 SNPs was performed using TaqMan Genotyping Assays and direct sequencing. The frequencies of SNPs and generated haplotypes were statistically evaluated using chi-square test and the association with the risk of HSCR was estimated by odds ratio. SNP analysis revealed significant differences in frequencies of 11 polymorphic <i>RET</i> variants between 162 HSCR patients and 205 unaffected controls. Particularly variant alleles of rs1864410, rs2435357, rs2506004 (intron 1), rs1800858 (exon 2), rs1800861 (exon 13), and rs2565200 (intron 19) were strongly associated with increased risk of HSCR (p<0.00000) and were over-represented in males vs. females. Conversely, variant alleles of rs1800860, rs1799939 and rs1800863 (exons 7, 11, 15) had a protective role. The haploblock comprising variants in intron 1 and exon 2 was constructed. It represented a high risk of HSCR, however, the influence of other variants was also found after pruning from effect of this haploblock. Clustering patients according to genotype status in haploblock revealed a strong co-segregation with several SNPs and pointed out the differences between long and short form of HSCR. This study involved a large number of SNPs along the entire <i>RET</i> proto-oncogene with demonstration of their risk/protective role also in haplotype and diplotype analysis in the Czech population. The influence of some variant alleles on the aggressiveness of the disease and their role in gender manifestation differences was found. These data contribute to worldwide knowledge of the genetics of HSCR.</p></div

Distribution of haplotypes and diplotypes of 5′ region haploblock in HSCR patients and controls.

<p>* Haplotypes/diplotypes with occurrence <2% in both cohorts are not included.</p

Allelic distribution of single nucleotide polymorphisms of 5′ region haploblock in patients with long-segment and short-segment form of HSCR and in male and female HSCR patients.

<p>Allelic distribution of single nucleotide polymorphisms of 5′ region haploblock in patients with long-segment and short-segment form of HSCR and in male and female HSCR patients.</p

Haplotype blocks generated by the Haploview Programme in cohorts of HSCR patients and control population.

<p>The scheme is shown with confidence bounds. LD values are reported in D′.</p

Allelic distribution of single nucleotide polymorphisms considering allelic distribution of haploblock-haplotypes TTAA and GCCG in HSCR patients and controls.

<p>Allelic distribution of single nucleotide polymorphisms considering allelic distribution of haploblock-haplotypes TTAA and GCCG in HSCR patients and controls.</p

Allelic distribution of single nucleotide polymorphisms considering allelic distribution of haploblock-haplotypes TTAA and GCCG in patients with long-segment and short-segment form of HSCR.

<p>Allelic distribution of single nucleotide polymorphisms considering allelic distribution of haploblock-haplotypes TTAA and GCCG in patients with long-segment and short-segment form of HSCR.</p

A novel RET/PTC variant detected in a pediatric patient with papillary thyroid cancer without ionization history

Molecular tumour pathology - and tumour genetic

Allelic distribution of single nucleotide polymorphisms in HSCR patients and controls.

<p>Allelic distribution of single nucleotide polymorphisms in HSCR patients and controls.</p