Cribriform-Morular Variant of Papillary Thyroid Carcinoma With Poorly Differentiated Features: A Case Report With Immunohistochemical and Molecular Genetic Analysis.

Cribriform-morular variant of papillary thyroid carcinoma (CMVPTC) is usually an inherited malignancy and may be a presenting indicator of familial adenomatous polyposis syndrome although it may occasionally be sporadic. Known CMVPTC mutations include adenomatous polyposis coli ( APC) and ß-catenin ( CTNNB1) genes. Despite its malignant classification, CMVPTC is considered to be a well-differentiated thyroid tumor with a generally good behavior. In contrast, poorly differentiated thyroid carcinoma is an aggressive tumor. We report a case of CMVPTC with poorly differentiated features in a young female without phenotypic features of familial adenomatous polyposis but with known germline alterations of the APC gene. High throughput sequencing showed germline chromosome 5q deletion encompassing the APC gene in all components with additional unique genetic alterations in the somatic components. A single nucleotide substitution (c.1548+1G>A, NM_000038.5) located one base pair downstream of exon 12 of the APC gene was identified in the CMVPTC component, and a pathogenic frameshift deletion in exon 14 of APC (c.3642del, p.Ser1214Argfs*51, NM_000038.5) was identified in the poorly differentiated thyroid carcinoma component. No other cancer-associated genes were identified by our techniques. Our case represents a rare phenomenon of poorly differentiated features in association with CMVPTC. To our knowledge, ours is the only such report of poorly differentiated features arising in association with an inherited CMVPTC.

Ovarian microcystic stromal tumor with undetermined potential: case study with molecular analysis and literature review.

Ovarian microcystic stromal tumor is a relatively rare tumor type. This tumor is characterized by a unique microcyst structure, and essentially all tumors show benign biological behavior. Here, we report a case with a primary ovarian microcystic stromal tumor that experienced recurrence. Pathological findings showed that the original tumor, relapsed tumor in the ovary, and the recurrent tumor in the iliac fossa presented similar histologic features. The tumor mainly consisted of microcysts, solid cellular regions, and a fibrous stroma. Immunohistochemically, the tumor cells were positive for ß-catenin, CD10, vimentin, and WT-1. Mutational analysis revealed a missense mutation (c.1590C>T; pG530E) in exon 15 of the APC gene and another missense mutation (c.740G>A; pA247V) in exon 1 of the KRAS gene. We also reviewed other published cases to evaluate the prognosis and treatment. This is the first report to describe a microcystic stromal tumor of the ovary presenting with undetermined biological potential.

Pilomatrix carcinoma: More malignant biological behavior than was considered in the past.

Pilomatrix carcinoma is a very rare malignancy, with ~130 cases reported in the literature. In the past, pilomatrix carcinoma was considered to be a low-grade malignant tumor. Currently, however, its significant recurrence and metastatic potential has been well documented. Lymph node and systemic metastases are frequently observed. Wide surgical excision of the primary lesion is the principal modality of treatment, whereas adjuvant radiotherapy may be beneficial in local tumor control. Lymph node metastases may be treated surgically or with radiotherapy. Systemic disease is not responsive to chemotherapy, and is hence associated with a poor prognosis. Since the majority of nodal and systemic metastases present after the initial diagnosis and treatment, follow-up examinations of these patients may be warranted, despite the currently inadequate treatment options. In the present study, a case of pilomatrix carcinoma of the parotid region with early local recurrence only 2 months after complete excision with negative surgical margins is reported. The local recurrence was treated by excision and radiotherapy. The associated literature is also discussed.

Mutational profiling of acral melanomas in Korean populations.

The proportion of acral melanoma (AM) is much higher in Asian populations than in Caucasian populations. Although mutational profiles associated with AM have been discovered in Caucasian populations, knowledge of its genetic alterations in Asian populations is limited. To describe the molecular nature of AM in Korean patients, we performed mutational profiling of AM and matched normal tissues in patients. Fifty-one formalin-fixed paraffin-embedded AM samples and 32 matched pairs from patients' saliva DNA were analysed by next-generation sequencing. Only mutations confirmed via digital droplet PCR or in BRAF, KIT and NRAS, the most frequently altered cancer genes in cutaneous melanoma, were considered as positive. The relationship between mutational status and clinicopathological features were examined. Of the 47 AM patients screened, alteration of BRAF, NRAS and KIT genes was observed in 6.4%, 4.3% and 8.5%, respectively. We also tested matched normal tissues of patients to identify tumor-specific mutations. Examination of the mutational profile in a cohort of 28 primary melanomas and matched normal controls found BRAF mutations in two cases (7.1%), KIT mutations in three cases (10.7%) and CTNNB1 mutations in one case (3.6%). The BRAF, NRAS and KIT mutation status did not correlate with clinicopathological characteristics. Our results show that KIT, NRAS and BRAF hotspot mutations occur at a low frequency in Korean populations. We also observed a case with the CTNNB1 mutation, which raises the possibility that other pathways are associated with AM development.

Spatial Impairment and Memory in Genetic Disorders: Insights from Mouse Models.

Research across the cognitive and brain sciences has begun to elucidate some of the processes that guide navigation and spatial memory. Boundary geometry and featural landmarks are two distinct classes of environmental cues that have dissociable neural correlates in spatial representation and follow different patterns of learning. Consequently, spatial navigation depends both on the type of cue available and on the type of learning provided. We investigated this interaction between spatial representation and memory by administering two different tasks (working memory, reference memory) using two different environmental cues (rectangular geometry, striped landmark) in mouse models of human genetic disorders: Prader-Willi syndrome (PWScrm+/p- mice, n = 12) and Beta-catenin mutation (Thr653Lys-substituted mice, n = 12). This exploratory study provides suggestive evidence that these models exhibit different abilities and impairments in navigating by boundary geometry and featural landmarks, depending on the type of memory task administered. We discuss these data in light of the specific deficits in cognitive and brain function in these human syndromes and their animal model counterparts.

In Vitro Study on Fire Needling and the Expression of Wnt/β-catenin Pathway Genes in Neural Stem Cells in Rats with Spinal Cord Injury / 上海针灸杂志

Objective To investigate the regulating effect of fire needling on Wnt andβ-catenin genes of Wnt/β-catenin pathway in neural stem cells in spinal cord injury.Methods Sixty female SD rats were randomly allocated, including 5 rats to a blank group, 5 rats to a sham operation group, 25 rats to a model group and 25 rats to a fire needling group. The model and fire needling groups of rats were again separately divided into 1 d, 3 d, 7 d, 10 d and 14 d groups. A model was made using modified Allen's method in the model and fire needling groups. The BBB score was recorded and the expressions of Wnt andβ-catenin genes were determined in every group.Results In the model and fire needling groups, the BBB scores were significantly higher at 7 and 10 days than at the previous time point and there was a statistically significant difference (P<0.05). The BBB score at every time point after treatment was significantly higher in the fire needling group than in the model group and there was a statistically significant difference (P<0.05). Wnt3a gene expressions increased in the model and fire needling groups at 7 and 10 days compare with the previous time point (P<0.05). At 7 and 10 days, Wnt3a gene expression was higher in the fire needling group than in the model group and there was a statistically significant difference (P<0.05). The changing tendency ofβ-catenin gene expression levels was basically the same as that of Wnt3a's.Conclusion Fire needling can modulate the expressions of Wnt3a andβ-catenin genes in neural stem cells in spinal cord injury.

In Vitro Study on Fire Needling and the Expression of Wnt/β-catenin Pathway Genes in Neural Stem Cells in Rats with Spinal Cord Injury / 上海针灸杂志

Objective To investigate the regulating effect of fire needling on Wnt andβ-catenin genes of Wnt/β-catenin pathway in neural stem cells in spinal cord injury.Methods Sixty female SD rats were randomly allocated, including 5 rats to a blank group, 5 rats to a sham operation group, 25 rats to a model group and 25 rats to a fire needling group. The model and fire needling groups of rats were again separately divided into 1 d, 3 d, 7 d, 10 d and 14 d groups. A model was made using modified Allen's method in the model and fire needling groups. The BBB score was recorded and the expressions of Wnt andβ-catenin genes were determined in every group.Results In the model and fire needling groups, the BBB scores were significantly higher at 7 and 10 days than at the previous time point and there was a statistically significant difference (P<0.05). The BBB score at every time point after treatment was significantly higher in the fire needling group than in the model group and there was a statistically significant difference (P<0.05). Wnt3a gene expressions increased in the model and fire needling groups at 7 and 10 days compare with the previous time point (P<0.05). At 7 and 10 days, Wnt3a gene expression was higher in the fire needling group than in the model group and there was a statistically significant difference (P<0.05). The changing tendency ofβ-catenin gene expression levels was basically the same as that of Wnt3a's.Conclusion Fire needling can modulate the expressions of Wnt3a andβ-catenin genes in neural stem cells in spinal cord injury.

Knockdown of ß-catenin by siRNA influences proliferation, apoptosis and invasion of the colon cancer cell line SW480.

The aim of the present study was to explore the effect of knocking down the expression of ß-catenin by small interference (si)RNA on the activity of the Wnt/ß-catenin signaling pathway, and the proliferation, apoptosis and invasion abilities of the human colon cancer cell line SW480. For that purpose, double-stranded siRNA targeting ß-catenin (ß-catenin-siRNA) was synthesized and transfected into SW480 cells. Reverse transcription-polymerase chain reaction (RT-PCR) and western blotting were used to detect the messenger (m)RNA and protein levels of ß-catenin in SW480 cells. To detect cell proliferation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed, while cell apoptosis and caspase-3 activity were detected by flow cytometry and caspase-3 activity assay, respectively. Matrigel invasion assay was performed to detect the influence of siRNA-mediated gene silencing on the invasion and metastasis of SW480 cells in vitro. The results of RT-PCR and western blot analysis demonstrated that, compared with the blank control, negative control and liposome groups, ß-catenin-siRNA transfected SW480 cells had significantly decreased mRNA and protein levels of ß-catenin. In addition, following ß-catenin-siRNA transfection, the proliferation of SW480 cells was significantly lower than that of the blank control, negative control and liposome groups, while the apoptosis rate increased in ß-catenin-siRNA transfected cells, compared with the aforementioned groups. Invasion assay showed that, following ß-catenin-siRNA transfection, the number of SW480 cells infiltrating through the Matrigel membrane was significantly lower than that of the blank control, negative control and liposome groups. Following ß-catenin-siRNA transfection, the caspase-3 activity in SW480 cells was lower than that in the blank control, negative control and liposome groups. These results indicate that siRNA-mediated silencing of ß-catenin could inhibit the proliferation and invasion of SW480 cells and induce apoptosis, thus providing novel potential strategies for the clinical treatment of colon cancer, and may serve as a novel target for cancer therapy.

Fibromatosis of the Sigmoid Colon With CTNNB1 (ß-Catenin) Gene Mutation, Arising at the Site of Ileocolic Anastomosis for Resection of Gastrointestinal Stromal Tumor.

We describe a case of intra-abdominal fibromatosis, which occurred in a 44-year-old woman who had a previous history of gastrointestinal stromal tumor (GIST) of the sigmoid mesocolon, which was treated with imatinib and resection. A mass was detected at the site of ileocolic anastomosis of the previous small bowel resection and sigmoid colectomy, nearly 3 years later. Clinically, this was suspected to represent recurrent GIST and was excised, but histology and mutational analysis showed desmoid-type fibromatosis with a mutation in codon 41 of exon 3 of the CTNNB1 (ß-catenin) gene. The occurrence of fibromatosis at the site of excision of GIST is very rare, but its recognition is important as the treatment of the two neoplasms differs significantly. As imaging cannot reliably distinguish between these 2 entities, histological diagnosis is crucial for correct clinical management.

Mutations in TP53, CTNNB1 and PIK3CA genes in hepatocellular carcinoma associated with hepatitis B and hepatitis C virus infections.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Hepatocarcinogenesis is a multistep process mainly associated with persistent infection with hepatitis B (HBV) or C (HCV) viruses and always involving the accumulation of genetic alterations over decades of chronic liver disease. Mutations in TP53 and CTNNB1 genes are considered the cancer drivers for HCC development with variable frequencies depending on the etiology. Here we present a comprehensive review evaluating somatic mutations in TP53 and CTNNB1 genes in HBV- and HCV-related HCCs. Moreover, we report the mutational analysis of TP53 (exons 4-9) and CTNNB1 (exon 3) as well as PIK3CA (exon 9) genes in HCC from Southern Italy. The overall mutation frequency of TP53 and CTNNB1 was 33.3%, while hotspot variations in PIK3CA were completely absent. CTNNB1 mutations were significantly associated with young age (P=0.019) and moderately/poorly differentiated HCV-related HCC (P=0.015). The extended analysis of genetic alterations will help to identify molecular markers for liver cancer prevention, diagnosis and treatment of HBV and HCV-associated liver cancer.

The Association of Beta-catenin Gene Mutations and Human Papillomavirus in Carcinoma of Esophagus in a High-Risk Population of India.

BACKGROUND: Esophageal cancer (EC) is the sixth leading cause of death from cancer. In high-risk regions, squamous cell carcinoma is the most common type of EC, and its etiology remains poorly understood. It shows uneven geographical distribution in its occurrence, reflecting the influence of local environmental conditions, lifestyle and genetic predisposition in the development of the cancer. Kashmir, in the north of India, has been described as a high-risk area for esophageal squamous cell carcinoma (ESCC). In the present investigation an attempt was made to study the role of ß-catenin mutations and human papillomavirus in 62 ESCC patients from Kashmir. METHODS: The hot spot mutation region of ß-catenin exon 3 was evaluated in matched tumor and normal tissues using a combination of PCR-SSCP and direct sequencing. We used two different sets of consensus primers viz., GP5+ and GP6+; PGMY09 and PGMY11 in conjunction with reverse line blot assay to screen for human papillomavirus(HPV). RESULTS: None of the tumors showed the presence of commonly reported mutations in ß-catenin. In view of the fact that HPV has been linked to pathogenesis of EC, we screened all the tumor and control specimens for the presence of HPV and we didn't detect HPV in any of the matched tumor and control specimens in contrast to the positive controls we used. CONCLUSION: In conclusion our results suggest that squamous cell carcinoma of esophagus in Kashmir may arise independent of oncogenic ß-catenin mutations and HPV is unlikely to be an etiologic factor for ESCC in this region.

Effects of Folate Deficiency during Pregnancy of Rats on Expression of Foliate Binding Proteins Gene and WNT Signal Transduction Pathway in Heart of Offspring / 实用儿科临床杂志

Objective To study the expressions of foliate binding protein 1(Folbp1),Wnt and ?-catenin genes on the heart of offspring during the development of embryo,whose mother was deficient of folic acid.Methods Control group involving 18 rats and study group involving 18 rats were choosen from the total 36 adult female SD rats randomly copulate with the male normal rats after feeding different fodder for 2 weeks.The heart of the 13.5,17.5 days embryos and the newborns were obtained.The expressions of Folbp1,Wnt and ?-catenin genes mRNA at the 3 periods were evaluated by RT-PCR.Results The expressions of Folbp1,Wnt and ?-catenin genes mRNA of the study group were significantly weaker than those of the control group in heart of the 13.5,17.5 days embryos and the newborns(all P