High-grade mixed neuroendocrine non-neuroendocrine neoplasm of the gastroesophageal junction: A rare case report and review of literature

Mixed neuroendocrine non-neuroendocrine neoplasm (MiNeN) is a recently described entity of the esophagus in the latest (fifth) edition of WHO Classification of Digestive System Tumors. It is often a difficult pathological diagnosis, especially in small preoperative biopsies. We herein report a case of high-grade MiNeN of gastroesophageal junction diagnosed as a squamous cell carcinoma in preoperative biopsy and subsequently as a high-grade MiNeN in esophagogastrectomy specimen comprising areas of mucoepidermoid carcinoma and large-cell neuroendocrine carcinoma (NEC). This report accentuates the importance of deeper multisite preoperative biopsies as the management is completely different in a MiNeN from esophageal squamous cell carcinoma.

ATRX protein is a potential prognostic marker in clear cell renal cell carcinoma

Objective: Cancer cells activate either telomerase or alternative lengthening of telomeres (ALT) to maintain telomere length and achieve immortalization. Alpha thalassemia/mental retardation X-linked (ATRX) is involved in chromatin remodeling. Mutations in ATRX genes are associated with the loss of nuclear expression and correlated with the ALT phenotype. ATRX expression has been evaluated in various cancers, especially sarcoma and neuroendocrine tumors, and its clinical significance has been shown to be diverse, depending on the tumor types. The role and prognostic value of ATRX expression in clear cell renal cell carcinoma (CCRCC) have not been elucidated. Methods: We investigated the messenger RNA (mRNA) expression levels of ATRX using the gene expression profiling interactive analysis (GEPIA) database and evaluated the expression of ATRX using immunohistochemical (IHC) staining in 302 CCRCC cases. Results: Loss of ATRX expression was significantly associated with larger tumor size, higher nuclear grade (NG), lymphovascular invasion (LVI), pathologic T (pT) stage, recurrence/metastasis, and stage. Although ATRX was not an independent prognostic factor, patients with loss of ATRX expression showed poor survival. Conclusion: Our findings suggest that loss of ATRX expression could be a potential biomarker for predicting aggressive tumor behavior and poor clinical outcomes in CCRCC.

Effect of ionizing radiation on apoptosis of lung cancer H460 cells and its mechansim / 吉林大学学报(医学版)

Objective:To explore the effect of ionizing radiation on apoptosis of lung cancer H460 cells after ATRX was silenced by RNAi and its mechanism.Methods:The lentivirus expression vectors targeting ATRX were transfected into the 293T cells,and the lung cancer H460 cells were infected with lentivirus twice,and the ATRX silenced cell model was obtained after puromycin positive screening,then they were named as sh-ATRX1-H460,sh-ATRX2-H460,and sh-ATRX3-H460 cells;the sh-control-H460 cells were regarded as control cells.The cells were divided into sh-control-H460 group and sh-ATRX3-H460 group,accroding to the silencing results and were irradiated by 0,2 and 8 Gy X-rays.The expression levels of ATRX,poly(ADP-ribose) polymerase 1(PARP1),and caspase-3 proteins were measured by Western blotting method;the apoptotic rate was measured by flow cytometry and AnnexinⅤ-FITC/PI kits.Results:The lung cancer cell model of sh-ATRX3-H460 silenced by ATRX was obtained successfully.After 2 and 8 Gy X-ray irradiation,compared with before irradiation,the expression level of ATRX protein in sh-control-H460 group was increased,while there was no expression of ATRX protein in sh-control-H460 group;compared with before irradiation,the apoptotic rates of cells in two groups were increased(P<0.05 or P<0.01);the apoptotic rate in sh-ATRX3-H460 group was significantly higher than that in sh-control-H460 group after 8 Gy X-ray irradiation (P<0.01).The expressions of cleaved PARP1 in the cells in both two groups after 2 Gy and 8 Gy X-ray irradiation were increased and showed similar rule.The expression level of procaspase-3 protein in sh-control-H460 group had little change,and it was increased significantly in sh-ATRX3-H460 group after 8 Gy X-ray irradiation.Conclusion:ATRX silencing can be achived by RNAi,then the silencing could increase the apoptosis induced by irradiation and its mechanism may be related to the PARP1-caspase-3 pathway.

Novel ATRX gene damaging missense mutation c.6740A>C segregates with profound to severe intellectual deficiency without alpha thalassaemia.

Background & objectives: ATRX is a recessive X-linked intellectual deficiency (X-LID) gene causing predominately alpha-thalassaemia with a wide and clinically heterogeneous spectrum of intellectual deficiency syndromes. Although alpha-thalassaemia is commonly present, some patients do not express this sign despite the ATRX gene being altered. Most pathological mutations have been localized in two different major domains, the helicase and the plant homeo-domain (PHD)-like domain. In this study we examined a family of three males having an X-linked mental deficiency and developmental delay, and tried to establish a genetic diagnosis while discussing and comparing the phenotype of our patients to those reported in the literature. Methods: Three related males with intellectual deficiency underwent clinical investigations. We performed a karyotype analysis, CGH-array, linkage study, and X-exome sequencing in the index case to identify the genetic origin of this disorder. The X-inactivation study was carried out in the mother and Sanger sequencing was achieved in all family members to confirm the mutation. Results: A novel ATRX gene missense mutation (p.His2247Pro) was identified in a family of two uncles and their nephew manifesting intellectual deficiency and specific facial features without alpha-thalassaemia. The mutation was confirmed by Sanger sequencing. It segregated with the pathological phenotype. The mother and her two daughters were found to be heterozygous. Interpretation & conclusions: The novel mutation c.6740A>C was identified within the ATRX gene helicase domain and confirmed by Sanger sequencing in the three affected males as well as in the mother and her two daughters. This mutation was predicted to be damaging and deleterious. The novel mutation segregated with the phenotype without alpha-thalassaemia and with non-skewed X chromosome.

Immunohistochemical Analysis of ATRX, IDH1 and p53 in Glioblastoma and Their Correlations with Patient Survival

Glioblastoma (GBM) can be classified into molecular subgroups, on the basis of biomarker expression. Here, we classified our cohort of 163 adult GBMs into molecular subgroups according to the expression of proteins encoded by genes of alpha thalassemia/mental retardation syndrome X-linked (ATRX), isocitrate dehydrogenase (IDH) and TP53. We focused on the survival rate of molecular subgroups, depending on each and various combination of these biomarkers. ATRX, IDH1 and p53 protein expression were evaluated immunohistochemically and Kaplan-Meier analysis were carried out in each group. A total of 15.3% of enrolled GBMs demonstrated loss of ATRX expression (ATRX-), 10.4% expressed an aberrant IDH1 R132H protein (IDH1+), and 48.4% exhibited p53 overexpression (p53+). Survival differences were statistically significant when single protein expression or different combinations of expression of these proteins were analyzed. In conclusion, in the case of single protein expression, the patients with each IDH1+, or ATRX-, or p53- GBMs showed better survival than patients with counterparts protein expressed GBMs. In the case of double protein pairs, the patients with ATRX-/p53-, ATRX-/IDH1+, and IDH1+/p53- GBMs revealed better survival than the patients with GBMs with the remained pairs. In the case of triple protein combinations, the patients with ATRX-/p53-/IDH+ showed statistically significant survival gain than the patients with remained combination of proteins-expression status. Therefore, these three biomarkers, individually and as a combination, can stratify GBMs into prognostically relevant subgroups and have strong prognostic values in adult GBMs.

Expression of ATRX in different central nervous system tumors and the usefulness in differential diagnosis / 实用医学杂志

Objective To investigate the expression of α-thalassemia/mental retardation syndrome X-linked (ATRX) in different central nervous system tumors and the meaningness in differential diagnosis. Methods Expression of ATRX protein was determined by immunohistochemistry in astrocytomas , oligodendrogliomas, glioblastomas, ependymomas and meningiomas. Results Positive expression levels of ATRX in astrocytomas were significantly lower than those in oligodendrogliomas,glioblastomas, ependymomas and meningiomas (all P <0.01). Conclusion The loss of ATRX was mainly occurred in astrocytomas, which could be as a astrocytoma marker in diagnosis.

Research progress on integrated molecular pathological classification of diffuse lower-grade gliomas / 中国肿瘤临床

Diffuse lower-grade glioma is a diversified group of infiltrative brain tumors comprising WHO grades II and III astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. These tumors exhibit a wide range of clinical heterogeneity;thus, histopathological classification does not adequately predict clinical outcomes. In recent years, a number of molecular markers closely related to the clini-cal features and prognosis of gliomas have been discovered. These molecular markers include isocitrate dehydrogenase (IDH) muta-tion, chromosome 1p/19q codeletion, ATRX mutation, TERT promoter mutation, and MGMT promoter methylation. Furthermore, nu-merous studies focusing on the integrated molecular classification of diffuse lower-grade gliomas combined with these molecular markers have been conducted. Results indicate that integrated molecular pathological classification can improve the diagnostic and prognostic accuracy and facilitate therapeutic formulation. This paper reviews the research progress on integrated molecular classifica-tion of diffuse lower-grade gliomas.

ATR-X syndrome in two siblings with a novel mutation (c.6718C>T mutation in exon 31).

ATR-X syndrome is an X-linked mental retardation syndrome characterized by mental retardation, alpha thalassaemia and distinct facial features which include microcephaly, frontal hair upsweep, epicanthic folds, small triangular nose, midface hypoplasia and carp-shaped mouth. Here we report two brothers with clinical features of ATR-X syndrome, in whom a novel missense (C>T) mutation was identified in exon 31 of the ATRX gene.

The First Case of X-linked Alpha-thalassemia/Mental Retardation (ATR-X) Syndrome in Korea

Mutation of the ATRX gene leads to X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome and several other X-linked mental retardation syndromes. We report the first case of ATR-X syndrome documented here in Korea. A 32-month-old boy came in with irritability and fever. He showed dysmorphic features, mental retardation and epilepsy, so ATR-X syndrome was considered. Hemoglobin H inclusions in red blood cells supported the diagnosis and genetic studies confirmed it. Mutation analysis for our patient showed a point mutation of thymine to cytosine on the 9th exon in the ATRX gene, indicating that Trp(C), the 220th amino acid, was replaced by Ser(R). Furthermore, we investigated the same mutation in family members, and his mother and two sisters were found to be carriers.