DNA repair genes in cancer predisposition: detection of germline pathogenic variants by multigene panel testing

The 5 to 10% diagnosed cancers are linked to an inherited faulty gene. Mutations in distinct DNA repair systems elevate the susceptibility to various cancer types and germline pathogenic (P) variants in DNA damage repair (DDR) genes BRCA1 and BRCA2 explain only 10-20% of these cases. Currently, new DDR genes have been re-lated to of Breast, Ovarian, colorectal and endometrial cancer, but the prevalence of pathogenic variants remains to be explored. The purpose of this study was to investigate the spectrum and the prevalence of pathogenic variants in DDR pathway genes other than BRCA1/2 and to correlate the genotype with the clinical phenotype. A cohort of 416 patients (298 cases were non-BRCA) was analyzed by next-generation sequencing using a multigene panel of the 28 DDR pathways genes related to Breast, Ovarian, colorectal and endometrial cancer. 41 of 416 affected individual were diagnosed with Lynch syndrome. 213 unique variants in 27 of 28 analyzed genes were found, 37 classified as likely pathogenic/ pathogenic and 177 as variants of un-known significance. 10 of 37 LP/P variants were discovered in 10 patients with Lynch syndrome. It was observed a high incidence of deleterious variants in the ATM, MUTYH, CHEK2 and MSH6 gene. These results support the clinical utility of multigene panel to in-crease the detection of P/LP carriers and to identify new actionable pathogenic gene variants useful for preventive and therapeutic approaches

Study of Th1/Th2 balance in peripheral blood mononuclear cells of patients with alopecia areata

Alopecia areata represents an autoimmune pathological process driven primarily by cellular aberrations contained within the immune system, which activates various humoral and cellular elements of the immune response. The aim of this study was to determine the mRNA expression levels of T-bet and GATA-3 as potential inducers of T helper (Th)1 and Th2 differentiation, respectively, as well as Th1(IFN-γ) and Th2(IL-4) cytokine mRNA expression in patients with alopecia areata. Using real-time reverse transcriptase PCR (RT-PCR), the relative amounts of T-bet, GATA-3, IFN-γ, and IL-4 mRNA transcripts were determined in PBMCs from 20 Iranian patients with alopecia areata and compared with those of 20 healthy control subjects. In comparison with the normal group, T-bet and IFN-γ mRNA expression levels were significantly up-regulated in the alopecia areata patients, while GATA-3 and IL-4 mRNA expression levels were down-regulated. Notably, positive correlation (P < 0.05) was found between IFN-γ and T-bet levels in patients and controls. In addition, significant positive correlations existed between GATA-3 and IL-4 (P < 0.05). These results indicate that a Th1/Th2 imbalance exists in alopecia areata, and it may be implicated in the pathogenesis of disease

Heterozygous Pathogenic Nonsense Variant in the ATM Gene in a Family with Unusually High Gastric Cancer Susceptibility

Germline pathogenic variants (PVs) in the Ataxia Telangiectasia mutated (ATM) gene (MIM* 607585) increase the risk for breast, pancreatic, gastric, and prostatic cancer and, to a reduced extent, ovarian and colon cancer and melanoma, with moderate penetrance and variable expressivity. We describe a family presenting early-onset gastric cancer and harboring a heterozygous pathogenic ATM variant. The proband had gastric cancer (age 45) and reported a sister deceased due to diffuse gastric cancer (age 30) and another sister who developed diffuse gastric cancer (age 52) and ovarian serous cancer. Next generation sequencing for cancer susceptibility genes (APC, ATM, BRD1, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL1, SMAD4, STK11, and TP53) was performed. Molecular analysis identified the truncating c.5944C&gt;T, p.(Gln1982*) variant in the ATM (NM_000051.3; NP_000042.3) in the proband. The variant had segregated in the living affected sister and in the unaffected daughter of the deceased affected sister. Familial early-onset gastric cancer is an unusual presentation for ATM-related malignancies. Individual variants may result in different specific risks. Genotype-phenotype correlations are challenging given the low penetrance and variable expressivity. Careful family history assessments are pivotal for prevention planning and are strengthened by the availability of molecular diagnoses

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Mitochondrial ATPase 6,8 Associated with Brain Tumours in Patients Compared to Adjacent Normal Brain Cells

Abstract | Background: Brain cancer is considered one of the most prevalent types of cancer in the world. Primary brain tumours consist of two types. Studies provide some deficiencies in mitochondrial functions that could cause different genetic. Objective: This study aimed to determine the association of ATPase 6,8 alterations of brain tumour cells in comparison with the adjacent healthy tissue cells. Methods: A group of patients was examined, and their disease was identified during precise examinations. These persons were sampled for their affected brain tissues, and these were compared with their adjacent healthy cells. Besides, the populations of 300 healthy controls were selected as the control. The DNA of the brain tumour cells was extracted and analysed using sequencing methods. Result: After the sequence analysis, T8473C, G8584A, A8701G, A8730G and A8860G variants were found—all of them had been reported in other diseases. Also, they were observed in patients with brain tumours, as compared with the adjacent normal tissues. Discussion: The A8860G variant was one of the most prevalent polymorphisms between all these alterations in brain cancer. It seems that the ATPase 6 subunit is more prone to brain cancer. The analysis shows that amongst all the five variants determined in this research, the T8473C, G8584A and A8730G variants—with the p value&lt;0.05—were considered to affect brain tumours

Association of Single Nucleotide Polymorphisms in the VDR and CYP27B1 Genes with Risk of Developing Vitamin D3 Deficiency

This study was carried out to investigate the relationship between common variants in two vitamin D pathway genes (VDR and CYP27B1) and vitamin D3 serum levels. In this study, serum vitamin D metabolite levels were measured in the blood samples of 200 patients with alopecia areata. Then, single nucleotide polymorphisms (SNPs) in VDR and CYP27B1 were analyzed using polymerase chain reaction (PCR)-sequencing. Sixty-three variations were observed in these genes (42 variations in CYP27B1 and 21 variations in VDR). A significant difference in Rs1544410 (odds ratio: 7, P < 0.0005) and rs4646536 (odds ratio: 4.043, P < 0.0005) variants was found between the patients and controls. The study showed the relationship between the two polymorphisms, Rs1544410 (odds ratio: 7, 95% CI, 1–8) and rs4646536 (odds ratio: 4.043, 95% CI, 3–14.038) on the genes VDR and CYP27B1, respectively, with increased risk of developing vitamin D3 insufficiency in the Iranian population. Therefore, SNPs in the VDR and CYP27B1 genes can be considered as prognostic biomarkers of the risk of developing vitamin D3 deficiency

Immunotherapy of Prostate Cancer Patients could Overexpress The Virulence Factor Genes of E.faecalis

Prostate cancer is the most prevalent and second cause of death from cancer in men worldwide. Immunotherapy is a new method for the treatment of several cancers that fights cancer cells by strengthening the immune system through some medications. While immunotherapy is a useful method for cancer treatment; its side effects still are not totally clarified. Numbers of prostate cancer patients which take immunotherapy are experiencing prostate inflammation and prostatitis after treatment period. Enterococcus faecalis is Gram-positive and catalase-negative cocci that are common in the intestines of humans and other animals and cause most enterococcal infections such as intestinal infections, prostatitis, gastroenteritis and endocarditic. Present study aimed to evaluate the mRNA level of virulence genes which are involved in Enterococcus faecalis pathogenesis in prostate cancer patients that treated by immunotherapy. Expression level of gelatinase E (gelE) and Enterococcal surface protein (esp) genes were examined by Real time PCR in three groups of 68 male subjects. Group A normal subjects, group B prostate cancer patients before start treatment and group C prostate cancer patients after six months immunotherapy period. Results were showed significant (P&lt;0.05) over expression of both genes (gelE and esp ) in group C against the group B. According to the results, it is reasonable that immunotherapy may have side effects such as increasing the pathogenicity risk of microflora in patients. Maybe these side effects could cause further infections after ending the immunotherapy of cancer. Antibiotic usage after or at the same time of immunotherapy period could prevent possible infections of microflora including E. faecalis

Mitochondrial Polymorphisms, in The D-Loop Area, Are Associated with Brain Tumors

Objective This study was carried out to evaluate the relationship between mtDNA D-loop variations and the pathogenesis of a brain tumor. Materials and Methods In this experimental study, 25 specimens of brain tumor tissue with their adjacent tissues from patients and 454 blood samples from different ethnic groups of the Iranian population, as the control group, were analysed by the polymerase chain reaction (PCR)-sequencing method. Results Thirty-six variations of the D-loop area were observed in brain tumor tissues as well as the adjacent normal tissues. A significant difference of A750G (P=0.046), T15936C (P=0.013), C15884G (P=0.013), C16069T (P=0.049), T16126C (P=0.006), C16186T (P=0.022), T16189C (P=0.041), C16193T (P=0.045), C16223T (P=0.001), T16224C (P=0.013), C16234T (P=0.013), G16274A (P=0.009), T16311C (P=0.038), C16327T (P=0.045), C16355T (P=0.003), T16362C (P=0.006), G16384A (P=0.042), G16392A (P=0.013), G16394A (P=0.013), and G16477A (P=0.013) variants was found between the patients and the controls. Conclusion The results indicated individuals with C16069T [odds ratio (OR): 2.048], T16126C (OR: 2.226), C16186T (OR: 3.586), G16274A (OR: 4.831), C16355T (OR: 7.322), and T16362C (OR: 6.682) variants with an OR more than one are probably associated with a brain tumor. However, given the multifactorial nature of cancer, more investigation needs to be done to confirm this association

Association of rs12487066, rs12044852, rs10735781, rs3135388, rs6897932, rs1321172, rs10492972, and rs9657904 Polymorphisms with Multiple Sclerosis in Iranian Population

Abstract Objectives: Multiple sclerosis (MS) is a chronic disease of the central nervous system. The pathogenesis of MS is best described by a multifactorial model incorporating interactions between genetic and environmental factors with the role of genetic factors increasingly taken into account. The main goal of this study was to investigate the associations of rs12487066, rs12044852, rs10735781, rs3135388, rs6897932, rs1321172, rs10492972, and rs9657904 polymorphisms with MS in the Iranian population. Methods: A total of 83 patients with MS (82.0% female and 18.0% male; mean age = 35.2±8.6 years) and 100 physically and mentally healthy subjects (81.0% female and 19.0% male; mean age = 40.4±6.4 years) were selected using convenient sampling. A 5 mL blood sample was taken from each case and control patient. We used the tetra-primer ARMS-PCR method to genotype the desired polymorphisms. The associations between polymorphisms and the disease were studied based on codominant, dominant, recessive, and overdominant models. Results: The rs10735781 polymorphism was codominantly (p = 0.029), overdominantly (p = 0.008), and dominantly (p = 0.009) associated with the disease. The rs6897932 was also found to be codominantly (p = 0.012), dominantly (p = 0.019), and recessively (p = 0.011) associated with the disease. Conclusions: We found an association between the rs10735781 and rs6897932 polymorphisms on the EVI5 and IL7RA genes, respectively, with increased MS in the Iranian population. Therefore, single nucleotide polymorphisms in the EVI5 and IL7RA genes can be considered a prognostic marker of MS

Identification of Single Nucleotide Polymorphisms as Markers of Genetic Susceptibility for Alopecia Areata Disease Risk

Abstract | Background: Alopecia areata (AA) is an autoimmune disease, leading to disfiguring hair loss that susceptibility loci and the genetic basis of AA have been largely unknown. Objective: The aim of this study was the scrutiny the susceptible genes of Alopecia areata amongst patients and healthy adult in Iranian populations. Methods: four variants polymorphisms (rs1701704, rs10760706, rs9275572, rs694739) were studied by Tetra Arms PCR, Sequencing methods in 200 Iranian healthy adult blood donors and 200 patients with Alopecia Areata (AA). Results: Results were showed that 4 SNPs had P-values &lt;0.05 for association with Alopecia areata. 3 of 4 SNPs, was demonstrated significant association in analyses 100 AT/AU cases versus 100 AA, which is localised in IKZF4, STX17, PRDX5, HLA-DQB1 (rs1701704, rs10760706, rs694739 and rs9275572 respectively). Conclusions: In this study, 3 of 4 SNP-associated loci were associated significantly with association with the development of Alopecia areata. In another word, the presence of them may be a contributing factor for prognosis of the development of the disease to Totalis and Universalis