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

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

<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

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

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 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 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

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

Thyroid Cancer Detection in a Routine Clinical Setting: Performance of ACR TI-RADS, FNAC, and Molecular Testing in Prospective Cohort Study

The aim of our study was to address the potential for improvements in thyroid cancer detection in routine clinical settings using a clinical examination, the American College of Radiology Thyroid Imaging Reporting and Database System (ACR TI-RADS), and fine-needle aspiration cytology (FNAC) concurrently with molecular diagnostics. A prospective cohort study was performed on 178 patients. DNA from FNA samples was used for next-generation sequencing to identify mutations in the genes BRAF, HRAS, KRAS, NRAS, and TERT. RNA was used for real-time PCR to detect fusion genes. The strongest relevant positive predictors for malignancy were the presence of genetic mutations (p p p < 0.01). Overall, FNAC, ACR TI-RADS, and genetic testing reached a sensitivity of up to 96.1% and a specificity of 88.3%, with a diagnostic odds ratio (DOR) of 183.6. Sensitivity, specificity, and DOR decreased to 75.0%, 88.9%, and 24.0, respectively, for indeterminate (Bethesda III, IV) FNAC results. FNA molecular testing has substantial potential for thyroid malignancy detection and could lead to improvements in our approaches to patients. However, clinical examination, ACR TI-RADS, and FNAC remained relevant factors

NTRK Fusion Genes in Thyroid Carcinomas: Clinicopathological Characteristics and Their Impacts on Prognosis

Chromosomal rearrangements of NTRK genes are oncogenic driver mutations in thyroid cancer (TC). This study aimed to identify NTRK fusion-positive thyroid tumors and to correlate them with clinical and pathological data and determine their prognostic significance. The cohort consisted of 989 different TC samples. Based on the detected mutation, samples were triaged, and those that were positive for a BRAF, HRAS, KRAS, NRAS, RET, RET/PTC or PAX8/PPARγ mutation were excluded from further analyses. NTRK fusion gene testing was performed in 259 cases, including 126 cases using next-generation sequencing. NTRK fusion genes were detected in 57 of 846 (6.7%) papillary thyroid carcinomas and in 2 of 10 (20.0%) poorly differentiated thyroid carcinomas. A total of eight types of NTRK fusions were found, including ETV6/NTRK3, EML4/NTRK3, RBPMS/NTRK3, SQSTM1/NTRK3, TPM3/NTRK1, IRF2BP2/NTRK1, SQSTM1/NTRK1 and TPR/NTRK1.NTRK fusion-positive carcinomas were associated with the follicular growth pattern, chronic lymphocytic thyroiditis and lymph node metastases. NTRK1-rearranged carcinomas showed a higher frequency of multifocality and aggressivity than NTRK3-rearranged carcinomas. Tumor size, presence of metastases, positivity for the NTRK3 or NTRK1 fusion gene and a late mutation event (TERT or TP53 mutation) were determined as factors affecting patient prognosis. NTRK fusion genes are valuable diagnostic and prognostic markers