Clinical features of six patients with Neurodevelopmental disorder with spastic diplegia and visual defects caused by CTNNB1 gene mutation / 中华检验医学杂志

Objective:To investigate the clinical features and characteristics of gene mutation of patients with neurodevelopmental disorder caused by CTNNB1 gene. Method:Genetic mutation analysis of the patients were obtained by using the whole exome sequencing and Sanger sequencing. We reviewed the literatures for the clinical and genetic features of CTNNB1 related neurodevelopmental disorder. Results:Six inpatients, three boys and three girls, who came for speech impairment motor delay were included in this study. The average age for the patients was 17.8±11.1 months. The main clinical manifestations of the patients were craniofacial dysmorphism, microcephaly, hypertonia or spasm, speech impairment motor delay, esotropia and valgus. WES showed that 6 patients carried de novo mutations of CTNNB1 gene, which were c.1057delA, c.1493_1494insA, c.418_424del, c.1985_1988del, c.1420C>T and c.1550T>C. No abnormality was found in the patients′ parents. Conclusions:The clinical manifestation of CTNNB1 related neurodevelopmental disorder involves multiple systems. We found five unreported variants and expanded the variation spectrum of the CTNNB1 gene.

Clinical phenotype and gene mutation analysis of neurodevelopmental disorders caused by CTNNB1 gene mutation / 中华神经科杂志

Objective:To investigate the clinical phenotype and gene mutation in a child with developmental disorders caused by CTNNB1 gene mutation. Methods:Clinical data of a child with CTNNB1 gene mutation who was admitted to Xiamen Hospital of Fudan University Affiliated Pediatric Hospital in May 2017 were collected, whole exome sequencing technology was applied to verify the family lineage of the child, and the pathogenicity of mutation site was analyzed. Results:The patient was a 6 years and 1 month old male, with a clinical phenotype including mental retardation, motor developmental disorders, speech disorders, visual disorders (internal strabismus), microcephaly, and behavioral problems (social withdrawal, overdependence, etc.), as well as panic syndrome (i.e., sudden shrieking in response to auditory and visual stimuli, extensional rigidity of the body, etc., followed by short periods of general extensional rigidity). The whole exome sequencing results showed the presence of a de novo mutation c.283(exon4)C>T in the CTNNB1 gene, and the c.283(exon4)C>T mutation was interpreted as pathogenic (PVS1+PS2+PS1+PM2+PM) according to the American College of Medical Genetics and Genomics variant classification criteria and guidelines. No relevant genetic variants were found in the parental family verification. Conclusion:CTNNB1 gene mutation c.283(exon4)C>T can cause neurodevelopmental disorders, including mental retardation, motor developmental disorders, speech disorders, visual disorders, microcephaly and behavioral abnormalities.

Desmoid-type fibromatosis of the mesentery: a clinicopatho-logical and genetic analysis of 9 cases / 浙江大学学报·医学版

Nine cases of mesenteric desmoid-type fibromatosis were diagnosed and treated in Taizhou Hospital, Wenzhou Medical University between January 2010 and May 2022, including 2 females and 7 males, aged 16 to 59 years. The lesions were in the mesentery of small intestine with 7 cases, ileocecal junction with 1 cases and transverse colon with 1 case. The tumors had an unclear boundary and no envelope, the section was solid, gray and tough. The mean maximum diameter was (10.7±8.5) cm (range 3.5-33.0 cm). Microscopically, fusiform fibroblasts and myofibroblasts were parallel, bunched or staggered, buried in a large amount of extracellular collagen. The cell morphology was relatively consistent, without obvious atypia, and mitosis was rare. Immunohistochemistry showed that the tumor cells were positive for vimentin (9/9), β-catenin (9/9), while smooth muscle actin (5/9) stains were focally positive. Ki-67 proliferation index was 1%-10%. Cytokeratin Pan, S-100, STAT6, CD117, DOG1, CD34, desmin and anaplastic lymphoma kinase stains were negative. Genetic analysis showed that there were 7 cases of c.121G>A(p.Thr41Ala) mutation of CTNNB1 gene, 1 case of c.121G>A(p.Thr41Ala) and 1 case of c.134C>T(p.Ser45Phe) double mutation, and 1 case of wild type. Tumors were surgically resected in all 9 cases. Eight cases had no recurrence or metastasis, 1 case had recurrence 6 months later, and no recurrence or metastasis after additional surgical resection.

The molecular pathogenesis of craniopharyngiomas

ABSTRACT Research from the last 20 years has provided important insights into the molecular pathogenesis of craniopharyngiomas (CPs). Besides the well-known clinical and histological differences between the subtypes of CPs, adamantinomatous (ACP) and papillary (PCP) craniopharyngiomas, other molecular differences have been identified, further elucidating pathways related to the origin and development of such tumors. The present minireview assesses current knowledge on embryogenesis and the genetic, epigenetic, transcriptomic, and signaling pathways involved in the ACP and PCP subtypes, revealing the similarities and differences in their profiles. ACP and PCP subtypes can be identified by the presence of mutations in CTNNB1 and BRAF genes, with prevalence around 60% and 90%, respectively. Therefore, β-catenin accumulates in the nucleus-cytoplasm of cell clusters in ACPs and, in PCPs, cell immunostaining with specific antibody against the V600E-mutated protein can be seen. Distinct patterns of DNA methylation further differentiate ACPs and PCPs. In addition, research on genetic and epigenetic changes and tumor microenvironment specificities have further clarified the development and progression of the disease. No relevant transcriptional differences in ACPs have emerged between children and adults. In conclusion, ACPs and PCPs present diverse genetic signatures and each subtype is associated with specific signaling pathways. A better understanding of the pathways related to the growth of such tumors is paramount for the development of novel targeted therapeutic agents.

Microcystic Stromal Tumor of Testicle: First Case Report and Literature Review / Journal of the Korean Cancer Association, 대한암학회지

Microcystic stromal tumor (MCST) is a rare subtype of sex cord-stromal neoplasm. Tumors from all 31 previously reported cases were located in the ovary. Herein, we present a unique case of a right-side testicular tumor in a 33-year-old Chinese male. The tumor is composed of predominantly lobulated cellular nodules separated by hyalinized fibrous stroma and they expressed CD10, β-catenin (nuclear), and cyclin D1. Molecular analysis identified a point mutation (c.110C>G) in exon 3 of CTNNB1. The histopathological features, immunohistochemistry profiles, and molecular analysis of this tumor were consistent with MCST of the ovary. Therefore, a diagnosis of MCST of the right testicle was determined. To the best of our knowledge, this is the first case of MCST occurring in the testicles. The study may provide new insights to the tumor biology of MCST and a better understanding of this rare entity.

Genetic analysis of ovarian microcystic stromal tumor

Microcystic stromal tumor (MCST) of the ovary is a rare subtype of ovarian tumor first described in 2009. Although high nuclear expression of β-catenin and β-catenin gene (CTNNB1) mutation are related with ovarian MCST, the origin and genetic background of ovarian MCST remain unclear. In this study, two cases of ovarian MCST are presented. Microscopically, the tumors showed a microcystic pattern and regions with lobulated cellular masses with intervening hyalinized, fibrous stroma. Tumor cells of both cases were stained with CD10, vimentin, and Wilms tumor 1. Genetic analysis was performed and β-catenin gene (CTNNB1) mutation in exon 3 was detected in both cases. This is the first report in regards of detecting CTNNB1 mutation in ovarian MCST through the use of pyrosequencing (a novel sequencing technique).

Mecanismos de señalización por β-catenina y su papel en la carcinogénesis / β-catenin signaling mechanisms and its role in carcinogenesis

La alteración de las vías de señalización es un mecanismo común en la oncogénesis de diferentes tipos de tumor. La modificación de una de las proteínas de la vía por mutaciones o por modificaciones genéticas o epigenéticas en el promotor del gen correspondiente podría generar una alteración en la vía, y por tanto condiciones para el crecimiento descontrolado característico del cáncer. La vía de señalización Wnt/β-catenina, donde β-catenina actúa como coactivador, es muy importante en procesos de embriogénesis, organogénesis y homeostasis. La alteración de Wnt/β-catenina por mutaciones o modificaciones epigenéticas de β-catenina o de otras proteínas facilita la acumulación de β-catenina en el núcleo y genera una activación permanente de esta vía de señalización. Este evento desencadena la expresión de genes que codifican proteínas que participan en proliferación celular, diferenciación y mantenimiento de células madre. β-catenina participa también en la adhesión célulacélula, mediando la interacción entre cadherinas y actina. Alteraciones en el complejo β-catenina-cadherina-actina lleva a la pérdida de la adhesión y a una alta capacidad invasiva de las células afectadas, mecanismos asociados con la capacidad de metástasis de las células tumorales. En esta revisión se describe la proteína β-catenina y su papel en la vía Wnt/ β-catenina, así como en la regulación de la expresión génica y en el proceso de adhesión célula-célula, y las alteraciones que pueden desencadenar un proceso oncogénico.

The modification of signaling pathways is a common mechanism in the oncogénesis process of different types of tumor. An alteration in any protein of the pathway by genetic mutations or by epigenetic changes in its gene promoter could cause misregulation of the pathway and therefore lead to uncontrolled cell proliferation. The Wnt/β-catenin signaling pathway is important in several processes, such as embryogenesis, organogenesis and homeostasis. β-catenin protein acts as a co-activator of this pathway, and when it is translocated to the nucleus, it functions as a transcription factor. An imbalance in this pathway by mutations or epigenetic modifications of β-catenin and/or other proteins, favors the accumulation of β-catenin in the nucleus, leading to permanent activation of Wnt/β-catenin signaling pathway. This event triggers the expression of genes encoding proteins involved in cell proliferation, differentiation and maintenance of stem cells. β-catenin is also known to participate in cell-cell adhesion, mediating the interaction between Cadherin and Actin. Alterations in the complex β-catenin-Cadherin-Actin lead to a loss of adhesion and a high invasive capacity of affected cells, mechanisms associated with invasiveness of tumor cells. This review describes the β-catenin protein, and its role in the Wnt/β-catenin signaling pathway, as well as in gene expression regulation and cellcell adhesion, and the alterations that can trigger an oncogenic process.

β-catenin mutation in pediatric malignant tumors / 国际外科学杂志

β-catenin is an important signaling transduetion and adhesion molecules.Mutation of the betacatenin gene,CTNNB1,is a common case in pediatric tumors,which may induce development and metastasis.In hepatoblastoma,48%have CTNNB1 mutation.In Wilms tumor,mutation only occurs in cases with WT1 gene mutation.In neuroblastoma,mutation is also found.

Fusion of the PLAG1 and CTNNB1 genes in pleomorphic adenoma of the salivary glands

The pleomorphic adenoma is the most common neoplasm involving both the major and minor salivary glands. It is a benign, slowgrowing tumor, but local recurrences can occur. The pleomorphic adenoma gene 1 (PLAG1), which is a novel zinc finger gene, is frequently activated by reciprocal chromosomal translocations involving 8q12 in a subset of salivary gland pleomorphic adenomas. This experimental study was preformed to observe the translocation patterns between PLAG1 gene and the three translocation partner genes. We also have analyzed the presence of PLAG1 transcripts by RT-PCR. CTNNB1/PLAG1 gene fusion was observed in three of nine pleomorphic adnomas. However, LIFR/PLAG1 and SII/PLAG1 gene fusions were not detectable. All of three gene fusions was not detectable in one Warthin's tumor and three inflammatory salivary gland tissues. PLAG1 transcripts were expressed in all inflammatory salivary gland tissues and tumors except for three pleomorphic adenomas. Of particular one pleomorphic adenoma showing CTNNB1/P AG1 gene fusion did not express PLAG1 transcipt. Our data indicate that gene fusion involving PLAG1 is a frequent event in pleomorphic adenoma, but correlation between gene fusion involving PLAG1 and PLAG1 transcription is not definite.

Abnormalities of beta-Catenin Gene in Pilomatricomas / 대한피부과학회지

BACKGROUND: beta-Catenin muations were reported to play a causal role in the development of pilomatricomas. In a recent study in Caucasians, 75% of pilomatricomas had beta-Catenin mutations. OBJECTIVE: We investigated the causal role of beta-Catenin gene mutations in pilomatricomas of Koreans. METHODS: This study included 20 formalin-fixed, paraffin-embedded pilomatricomas in Koreans. Basophilic nucleated tumor cells were microdissected and, as normal controls, infiltrating inflammatory lymphocytes were microdissected from the same histologic specimens. Sequencing analysis of exon 3 of the beta-Catenin gene (CTNNB1) was performed. Immunostaining for beta-Catenin and Lef-1 was performed by the avidin-biotin-peroxidase method. RESULTS: Sequencing analysis found missense mutations (S37Y, S37C, S33C, S33F, and S37F) in CTNNB1 in 6 samples (30%) of 20 pilomatricomas. All pilomatricomas revealed intense expression of nuclear Lef-1 and nuclear and cytoplasmic beta-Catenin. CONCLUSION: Frequencies of beta-Catenin mutations were lower in our study compared with the results in Caucasians. The immunohistochemical results suggest the abnormalities in Wnt-wingless pathway resulting in stabilization or constitutive expression of beta-Catenin, but the absence of CTNNB1 mutations in 70% of our cases suggests adenomatous polyposis coli gene inactivation, or the involvement of other components of the Wnt-wingless pathway.