No abstract

The aim of this study was to evaluate the frequency (as qualitative analysis) and level (as quantitative analysis) of promoter hypermethylation of four genes, P16, TSHR, RASSF1A and RARβ2, and to assess their diagnostic or prognostic values in papillary thyroid tumors. Fifty formalin-fixed paraffin-embedded (FFPE) samples consisting of 25 malignant tumors and 25 non-malignant thyroid tumors were analyzed using COBRA method. Promoter hypermethylation of P16, TESH, RASSF1A and RARB2 genes was noted not only in 10, 7, 19 and 13 cases of malignant tumors, but also it was detected in 7, 11, 23 and 8 cases of benign tumors, respectively, limiting its diagnostic usefulness. The quantitative hypermethylation level was significantly higher in malignant tumors compared to benign tumors for P16 (P<0.004), TSHR (P<0.006) and RASSF1A (P<0.001), but the methylation level of RARβ2 (P<0.31) showed considerable overlap between the two groups. The mean levels of hypermethylation of P16, TSHR and RASSF1A genes were significantly higher in malignant papillary thyroid tumors compared to benign tumors and by choosing the appropriate cutoff for each gene, we could distinguish 9, 9 and 8 PTCs from 25 cases by P16, RASSF1A and TSHR methylation analysis, respectively. According to our results, these three genes, in combination, may be useful as molecular markers. The findings of present study imply that the P16, TSHR and RASSF1A gene promoter hypermethylation may play important roles in the pathogenesis of PTC and can be a potential biomarker for selecting patients with PTC.

Autosomal recessive congenital ichthyosis is a heterogeneous group of disorders associated with mutations in at least nine distinct genes. To ascertain the molecular basis of ichthyosis patients in Iran, a country of approximately 80 million people with a high prevalence of customary consanguineous marriages, we have developed a gene-targeted next generation sequencing array consisting of 38 genes reported in association with ichthyosis phenotypes. In a subset of nine extended consanguineous families, we found homozygous missense mutations in the PNPLA1 gene, six of them being distinct and, to our knowledge, previously unpublished. This gene encodes an enzyme with lipid hydrolase activity, important for development and maintenance of the barrier function of the epidermis. These six mutations, as well as four previously published mutations, reside exclusively within the patatin-like subdomain of PNPLA1 containing the catalytic site. The mutations clustered around the active center of the enzyme or resided at the surface of the protein possibly involved in the protein-protein interactions. Clinical features of the patients showed considerable intra- and interfamilial heterogeneity. Knowledge of the specific mutations allows identification of heterozygous carriers, assisting in genetic counseling, prenatal testing, and preimplantation genetic diagnosis in extended families at risk of recurrence of this disorder, the incidence of which is significantly increased in consanguineous marriages.

Biallelic mutations of the alsin Rho guanine nucleotide exchange factor (ALS2) gene cause a group of overlapping autosomal recessive neurodegenerative disorders including infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS/ALS2), caused by retrograde degeneration of the upper motor neurons of the pyramidal tracts. Here, we describe 11 individuals with IAHSP, aged 2-48 years, with IAHSP from three unrelated consanguineous Iranian families carrying the homozygous c.1640+1G>A founder mutation in ALS2. Three affected siblings from one family exhibit generalized dystonia which has not been previously described in families with IAHSP and has only been reported in three unrelated consanguineous families with JALS/ALS2. We report the oldest individuals with IAHSP to date and provide evidence that these patients survive well into their late 40s with preserved cognition and normal eye movements. Our study delineates the phenotypic spectrum of IAHSP and ALS2-related disorders and provides valuable insights into the natural disease course.

Specific chromosomal abnormalities and gene mutations may serve as diagnostic and prognostic indicators for disease progression and survival. The identification of these anomalies by state-of-the-art molecular (cyto)genetic techniques such as fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), single nucleotide polymorphism (SNP) microarray-based genomic profiling and next-generation sequencing (NGS) can be of paramount help for the clinical management of these patients, including optimal treatment design. The efficacy of novel therapeutics should to be tested according to the presence of these molecular lesions in CLL patients.

The involvement of ATM gene and specifically, the important role of D1853N polymorphism, as a three-hit hypothesis has been previously reported in an Iranian proband affected with brain tumor and this polymorphism could be screened in her relatives as well. The aim of present study was to investigate the involvement of D1853N polymorphism as a predisposition factor in 129 Iranian patients affected with primary breast cancer and 248 sex- and age-matched healthy controls. Mutant allele-specific PCR amplification (MASA) assay was performed to analyze the D1853N polymorphism in the ATM gene. The frequency of D1853N polymorphism in cases, internal and external controls was 31.0% (40/129), 26.9% (28/104) and 12.5% (18/144), respectively. The frequency of D1853N in total control groups, including normal external control and pedigree internal control, was 18.6% (46/248). The odds ratio was calculated with the logistic regression test, with an estimated relative risk of 2.579 (P=0.005). The significant difference was observed between the patient-carriers of this alteration and external controls (P=0.001). The number of controls harboring D1853N polymorphism was higher in internal control compared to external controls, and the difference was statistically significant (P=0.004). The significant difference was observed between the patient-carriers and external controls and could be considered as a predisposing and diagnostic marker in the population and specifically in the cancer-prone pedigrees.

Somatic cells do not have telomerase activity but immortalized cell lines and more than 85 % of the cancer cells show telomerase activation to prevent the telomere from progressive shortening. The activation of this enzyme has been found in a variety of human tumors and tumor-derived cell lines, but only few studies on telomerase activity in human brain tumors have been reported. Here, we evaluated telomerase activity in different grades of human astrocytoma and meningioma brain tumors. In this study, assay for telomerase activity performed on 50 eligible cases consisted of 26 meningioma, 24 astrocytoma according to the standard protocols. In the brain tissues, telomerase activity was positive in 39 (65 %) of 50 patients. One sample t test showed that the telomerase activity in meningioma and astrocytoma tumors was significantly positive entirely (P < 0.001). Also, grade I of meningioma and low grades of astrocytoma (grades I and II) significantly showed telomerase activity. According to our results, we suggest that activation of telomerase is an event that starts mostly at low grades of brain including meningioma and astrocytoma tumors.

Ataxia telangictasia mutated (ATM) is involved in DNA repair pathway and cell-cycle checkpoints. ATM alterations were found in medulloblastomas, gliomas, but not in astrocytoma. The polymorphism D1853N was reported in healthy individuals and medulloblastomas. We could observe this polymorphism, heterozygously, in a proband affected with astrocytoma and traced it through her pedigree. We propose the three-hit hypothesis as a triangle initiators includes D1853N as a first predisposing hit, IVS 38- 63T --> A as a second hit deriving from the first somatic evolution before differentiation and IVS 38- 30 A --> G as a third hit through the development of an astrocytoma. In addition, the D1853N polymorphism was occurred in different allele from IVS 38- 63T --> A and IVS 38- 30 A --> G.