The therapeutic potential value of Cancer-testis antigens in immunotherapy of gastric cancer.

Gastric cancer (GC) is the fourth most common cause of mortality and the fifth for incidence, globally. Diagnosis, early prognosis, and therapy remains challenging for this condition, and new tumor-associated antigens are required for its detection and immunotherapy. Cancer-testis antigens (CTAs) are a subfamily of tumor-associated antigens (TAAs) that have been identified as potential biomarkers and targets for cancer immunotherapy. The CTAs-restricted expression pattern in tumor cells and their potential immunogenicity identify them as attractive target candidates in CTA-based diagnosis or prognosis or immunotherapy. To date, numerous studies have reported the dysregulation of CTAs in GC. Several clinical trials have been done to assess CTA-based immunotherapeutic potential in the treatment of GC patients. NY-ESO-1, MAGE, and KK-LC-1 have been used in GC clinical trials. We review recent studies that have investigated the potential of the CTAs in GC regarding the expression, function, aggressive phenotype, prognosis, and immunological responses as well as their possible clinical significance as immunotherapeutic targets with a focus on challenges and future interventions.

A new gene panel as a marker for ESCC poor prognosis; INPP5A, TWIST1, MMP2, and EGFR.

PURPOSE: Esophageal squamous cell carcinoma (ESCC) is categorized among ten common aggressive malignancies, with a higher incidence and mortality rates in the developing than in developed countries. The inositol polyphosphate 5-phosphatase (INPP5A), as an intracellular-calcium mobilizer and modifier enzyme, facilitates cell responses to various stimuli. Epithelial-mesenchymal transition (EMT), a transformation procedure, has a vital role in cancer progression and metastasis when epithelial cells lose their traits in favor of obtaining mesenchymal features. In this study, we analyzed the correlation between the expression of INPP5A and the involved genes in EMT pathway through the progression and development of the ESCCs. MATERIALS AND METHODS: The gene expression analyses of INPP5A, TWIST1, MMP-2, and EGFR were performed using relative comparative real-time PCR in 58 ESCCs patients compared to corresponding margin-normal esophageal tissues. RESULTS: A significant inverse correlation between INPP5A and EGFR/MMP-2 mRNA expression was observed in tumor samples. Underexpression of INPP5A was significantly correlated with overexpression of TWIST1, MMP-2, and EGFR in different invasiveness and aggressiveness pathological features of the ESCCs (P â€‹< â€‹0.05). CONCLUSIONS: The results propose a tumor suppressor role for INPP5A and oncogenic function for concomitant expression of the other genes in ESCC invasion and metastasis. The current study is the first report elucidating the correlation between the downregulation of INPP5A and upregulation of TWIST1, MMP-2, and EGFR in ESCC and introduces this panel of the genes as a marker for poor prognosis of the disease.

Novel mutation in AIRE gene with autoimmune polyendocrine syndrome type 1.

PURPOSE: Autoimmune polyendocrine type 1 (APS-1) is a complex inherited autosomal recessive disorder. Classically, it appears within the first decade of life followed by adrenocortical insufficiency, mucocutaneous candidiasis, Addison's disease, and hypoparathyroidism. The clinical phenotype of APS-1 varies depending upon mutations in the autoimmune regulator gene (AIRE) on chromosome 21q22.3. METHODS: In this study, we performed Sanger sequencing ofAIRE in Iranian patients to identify different variants and probable new mutations corresponding to a clinical diagnosis of APS-1. RESULTS: After analyzing 14AIRE exons, we detected a novel insertion mutation in exon 2 in a patient who presented with severe APS-1, Lys50AsnfsX168. Furthermore, the known mutations in AIRE, including Arg139X, Arg257X, and Leu323SerfsX51, were detected in enrolled patients. DISCUSSION: According to our results, sequencing analysis ofAIRE provides a useful screening method to diagnose patients with incomplete or unusual clinical presentations of APS-1.

Novel DNA variation of GPR54 gene in familial central precocious puberty.

BACKGROUND: Puberty can be considered the end point of a maturation process which is defined by the dynamic interactions of genes and environmental factors during prenatal and postnatal development. Kisspeptin/G protein-coupled receptor-54, is as an essential gatekeeper and regulator of GnRH neurons, and a key factor in initiation of puberty. Loss and gain of functional mutations in the GPR54 gene are associated with hypogonadotropic hypogonadism and precocious puberty, respectively. This study was designed to evaluate variations of GPR54 in familial precocious puberty. METHODS: Genomic DNA was extracted from peripheral whole blood of 25 subjects with familial precocious puberty. Coding exons 1-5 of the GPR54 gene were amplified by polymerase chain reaction (PCR) and the PCR products were purified and sequenced. DNA sequences were compared to the human GenBank GPR54 sequence using Sequencher sequence alignment software. RESULTS: We detected three different Single Nucleotide Polymorphisms (SNPs) in GPR54: rs10407968 (24A > T) in 13 subjects (52%); rs3050132 (1091 T > A) in 16 subjects (64%), and a novel polymorphism (492C > G) in one subject (4%), while three subjects (12%) had no SNPs. No mutations were found in the GPR54 gene. CONCLUSIONS: Regarding the presence of SNPs in 88% of the subjects in this study, it is likely a relationship exists between the SNPs of the GPR54 gene and familial precocious puberty. Further research is needed to investigate this possibility, and potential functional effects of these polymorphisms.

Identification of four novel mutations of the WFS1 gene in Iranian Wolfram syndrome pedigrees.

AIMS: Wolfram syndrome is a rare neurodegenerative disorder with an autosomal recessive pattern of inheritance characterized by various clinical manifestations. The related gene, WFS1, encodes a transmembrane glycoprotein, named wolframin. Genetic analyses demonstrated that mutations in this gene are associated with WS type 1. Our aim in this study was to sequence WFS1 coding region in Iranian Wolfram syndrome pedigrees. METHODS: Genomic DNA was extracted from peripheral blood of 12 WS patients and their healthy parents. Exons 2-8 and the exon-intron junctions of WFS1 were sequenced. DNA sequences were compared to the reference using Sequencher software. RESULTS: Molecular analysis of WFS1 revealed six different mutations. Four novel and two previously reported mutations were identified. One novel mutation, c.1379_1381del, is predicted to produce an aberrant protein. A second novel mutation, c.1384G > T, encodes a truncated protein. Novel mutation, c.1097-1107dup (11 bp), causes a frameshift which results in a premature stop codon. We screened for the novel missense mutation, c.1010C > T, in 100 control alleles. This mutation was not found in any of the healthy controls. CONCLUSION: Our study increased the spectrum of WFS1 mutations and supported the role of WFS1 in susceptibility to WS. We hope that these findings open new horizons to future molecular investigations which may help to prevent and treat this devastating disease.