Association of single nucleotide polymorphisms in miR- 499 and miR-196a with susceptibility to breast cancer

Purpose: To investigate the relationship between miR-499 rs3746444 and miR-196a rs11614913 polymorphisms, and susceptibility to breast cancer in an Iranian population.Methods: This case-control study was performed on a population of 200 subjects comprising 100 breast cancer patients (case/observation group) and 100 healthy individuals (control group). Amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was used to genotype these polymorphisms. P-values and odd ratios were determined, and p-values < 0.05 and odd ratios > 1 were considered statistically significant.Results: There were no significant differences between observation and control groups with respect to rs11614913 T/C polymorphism. The rs11614913 T allele was not identified as a risk factor for susceptibility to breast cancer (OR = 0.86, 95 % CI = 0.85 - 1.3, p = 0.46). However, there were significant differences between observation and control groups with respect to rs3746444 T/C polymorphism. It was observed that cytosine-cytosine (CC) (OR = 4.5, 95 % CI = 1.3 - 15.4, p = 0.06), and cytosine-thymine (CT) (OR = 1.9, 95% CI = 1- 3.6, p = 0.04) genotypes had protective influence against susceptibility to breast cancer.Conclusion: These results indicate that CC and CT genotypes are associated with reduced risk of breast cancer. In particular, the presence of C allele is significantly associated with a low risk of breast cancer. These findings may provide useful information for prevention and early diagnosis of breast cancer.Keywords: Breast cancer, Early diagnosis, miR-196a rs11614913, miR-499 rs3746444, Polymorphism, ARMS-PC

Cancer Gene Therapy to Restore P53 Function: A New Way for an Old Aim

Millions of people are living with cancer having specific mutation in p53 gene while every single person is truly unique in genetic basis or clinical manifestation. The gene encodes transcription factor p53, which plays a central role in regulating cell cycle progression, senescence, differentiation, DNA repair and apoptosis in response to DNA damage or other stress signals. P53 activity is up regulated to initiate a cascade of biological events that ultimately results in prevention of tumor development. Mutations in p53 abrogate normal tumor suppressor functions, contributing to the survival and proliferation of abnormal cells. Cancer cells containing mutant p53 are associated with more aggressive disease, increased resistance to chemotherapy and radiation therapy, and poor prognosis. However the majority of p53 mutations are missense and great number of these mutants represent GOF (Gain of Function) effect resulting increased invasion and metastasis in tumors. These mutations confer a dominant-negative activity over the remaining wild-type allele by functionally inactive hetero-oligomers interactions of the mutants with the wild-type protein. Increasing evidence indicates that many p53 mutants also gain new oncogenic properties that are independent from wild-type p53. Several factors including type of p53 mutations in cancers may limit the efficacy and application of p53 gene therapy. As a result, there is a great interest in therapeutic strategies aimed at restoring the function of p53 for the treatment of cancer. Increasing evidence demonstrate that silencing GOF mutations (targeted antisense therapy) reduce the transactivation activity of mutant p53 and induce apoptosis in cells bearing these mutations then provide a potential strategy to inhibit the oncogenic functions of mutant p53 and improve mutant p53-targeted cancer therapies

Whole exome sequencing and homozygosity mapping reveals genetic defects in consanguineous Iranian families with inherited retinal dystrophies

Acknowledgements This research was funded by the Swiss National Science Foundation (Grant #176097 to CR). We would like to express gratitude to the patients and all their family members that participated in this study for their valuable cooperation and participation.Peer reviewedPublisher PD

MicroRNA-124 Overexpression in Associated with Lymph Node Metastasis in Breast Cancer

Breast cancer as a heterogeneous sophisticated disease includes several group with discrete clinical consequences. The disease is the most prevalent malignancy after non-melanoma skin cancers and it is also considered as the second leading cause of death after lung cancer. In fact, breast cancer is account for 23% of all cancer cases and 14% of deaths from cancer. The major cause of breast cancer deaths is actually metastasis of the tumor. As a result, it is prominent to identify the disease mechanism and diagnose molecular tools in order to predict metastasis. The specimens were collected from 30 metastatic and 30 primary tumor tissues of breast cancer patients. After that, RNA extraction was accomplished by means of GeneAll kit and then was stored in -80 degrees. Then, cDNA synthesis was carried out by miscript II RT kit from Qiagenecompany. Finally, sybergreen Real Time PCR of all samples was done for miRNA124, miRNA130a and miRNA 16 as a reference by means of Pre-designed primers of Qiagene Company. The results of molecular expression study showed that the amount of miRNA 124 in metastatic tissues has approximately increased double of primary tumor tissues. It is also revealed that the amount of miRNA has similarly increased by about 1.7 times. According to recent results, it can be possible to regard molecule as a major cause of metastasis process in breast cancer.

Whole exome sequencing in 17 consanguineous Iranian pedigrees expands the mutational spectrum of inherited retinal dystrophies

Funding Information: We would like to thank all of the participating families. We are also grateful to the Swiss Confederation for the award of a PhD fellowship to AUR, to Mashhad University of Medical Sciences for supporting part of the work, in the framework of the PhD thesis of AS, to the Swiss National Science Foundation for grant # 176097 to CR, and to the Fondation Guillaume Gentil for support to ASF.Peer reviewedPublisher PD

Estrogen receptor-α gene codon 10 (T392C) polymorphism in Iranian women with breast cancer: a case study

A case study was conducted to establish a database of polymorphisms in Iranian population in order to compare Western and Iranian (Middle East) distributions and to evaluate ESR1 polymorphism as an indicator of clinical outcome. The ESR1 gene was scanned in Iranian patients newly diagnosed invasive breast tumors, (150 patients) and in healthy individuals (147 healthy control individuals). PCR single-strand conformation polymorphism methodology and direct sequencing were performed. The silent single nucleotide polymorphism (SNPs) was performed, as reported previously in other studies, but at significantly different frequencies, with further increasing predictive accuracy in Iranian population. Data suggest that ESR1 polymorphisms are correlated with various aspects of breast cancer in Iranian ESR1 genotype, as determined during pre-surgical evaluation, might represent a surrogate marker for predicting breast cancer

Broadening the phenotypic and molecular spectrum of FINCA syndrome: Biallelic NHLRC2 variants in 15 novel individuals

FINCA syndrome [MIM: 618278] is an autosomal recessive multisystem disorder characterized by fibrosis, neurodegeneration and cerebral angiomatosis. To date, 13 patients from nine families with biallelic NHLRC2 variants have been published. In all of them, the recurrent missense variant p.(Asp148Tyr) was detected on at least one allele. Common manifestations included lung or muscle fibrosis, respiratory distress, developmental delay, neuromuscular symptoms and seizures often followed by early death due to rapid disease progression.Here, we present 15 individuals from 12 families with an overlapping phenotype associated with nine novel NHLRC2 variants identified by exome analysis. All patients described here presented with moderate to severe global developmental delay and variable disease progression. Seizures, truncal hypotonia and movement disorders were frequently observed. Notably, we also present the first eight cases in which the recurrent p.(Asp148Tyr) variant was not detected in either homozygous or compound heterozygous state.We cloned and expressed all novel and most previously published non-truncating variants in HEK293-cells. From the results of these functional studies, we propose a potential genotype-phenotype correlation, with a greater reduction in protein expression being associated with a more severe phenotype.Taken together, our findings broaden the known phenotypic and molecular spectrum and emphasize that NHLRC2-related disease should be considered in patients presenting with intellectual disability, movement disorders, neuroregression and epilepsy with or without pulmonary involvement

Lunapark deficiency leads to an autosomal recessive neurodevelopmental phenotype with a degenerative course, epilepsy and distinct brain anomalies

LNPK encodes a conserved membrane protein that stabilizes the junctions of the tubular endoplasmic reticulum network playing crucial roles in diverse biological functions. Recently, homozygous variants in LNPK were shown to cause a neurodevelopmental disorder (OMIM#618090) in four patients displaying developmental delay, epilepsy and nonspecific brain malformations including corpus callosum hypoplasia and variable impairment of cerebellum. We sought to delineate the molecular and phenotypic spectrum of LNPK-related disorder. Exome or genome sequencing was carried out in 11 families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified 12 distinct homozygous loss-of-function variants in 16 individuals presenting with moderate to profound developmental delay, cognitive impairment, regression, refractory epilepsy and a recognizable neuroimaging pattern consisting of corpus callosum hypoplasia and signal alterations of the forceps minor ('ear-of-the-lynx' sign), variably associated with substantia nigra signal alterations, mild brain atrophy, short midbrain and cerebellar hypoplasia/atrophy. In summary, we define the core phenotype of LNPK-related disorder and expand the list of neurological disorders presenting with the 'ear-of-the-lynx' sign suggesting a possible common underlying mechanism related to endoplasmic reticulum-phagy dysfunction

Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease

International audienceWe investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi–Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64–25.71) compared with controls (median: 0.93, IQR: 0.57–1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context