Low-density lipoprotein receptor-related protein 6 (LRP6) is a co-receptor of the Wnt signaling pathway, which plays an essential role in various biological activities during embryonic and postnatal development. LRP6 is exceptionally associated with rare diseases and always with autosomal dominant inheritance. Here we report a familial phenotype of high bone mass associated with skeletal anomalies and oligodontia but also persistent left superior vena cava, inguinal hernia, hepatic cysts, abnormal posterior fossa and genital malformations. Molecular analysis revealed a novel heterozygous variant, NM_002336.2: c.724T>C, p.(Trp242Arg), in affected individuals. This variant is located in the first β-propellant motif of LRP6, to which sclerostin (SOST) and dickkopf1 (DKK1), two LRP6 co-receptor inhibitors and various Wnt ligands bind. According to the literature and integrating data from structural analysis, this variant distorts the binding of SOST and DKK1, thus leading to overactivation of Wnt signaling pathways involved in osteoblast differentiation. This novel heterozygous variant in LRP6 underlies the role of LRP6 in skeletal and dental disorders as well as, probably, cardiac, cerebral and genital developments.

UNASSIGNED: An 87-year-old woman presented with a pedunculated nodule of 1.2 × 1.2 × 0.6 cm on her left cheek. Microscopic examination of the lesion revealed bowenoid and rosette-like basaloid components, resembling Bowen disease and neuroendocrine carcinoma, respectively. Immunohistochemically, both components were positive for Wnt signaling pathway molecules-nuclear/cytoplasmic beta-catenin, lymphoid enhancer binding factor 1 (LEF1), and caudal type homeobox 2 (CDX2)-and the adnexal marker SRY-box transcription factor 9 (SOX9). Unlike neuroendocrine tumors and basal cell carcinomas, the basaloid component in the present case was negative for chromogranin A, INSM1, synaptophysin, and p40. Previously reported cases of similar CDX2-positive lesions were diagnosed as squamous cell carcinoma with enteric adenocarcinomatous differentiation and basaloid cutaneous carcinoma with a primitive cytomorphology. However, the lesion in the present case was simultaneously positive for SOX9, indicating adnexal differentiation. In particular, the expression of multiple Wnt signaling pathway molecules indicates follicular differentiation despite the absence of morphological follicular features, such as shadow cells. Moreover, shared immunopositivity for SOX9, CDX2, nuclear/cytoplasmic beta-catenin, and LEF1 by both bowenoid and basaloid components indicated that the bowenoid component did not represent Bowen disease but a part of the adnexal tumor, and that the basaloid component was not a tumor-to-tumor metastasis. After complete excision, no recurrence has been observed for 5 months. The findings of the present case expand the histological spectrum of cutaneous adnexal tumors with follicular immunophenotypic differentiation.

Intranodal palisaded myofibroblastoma (IPM) is a rare stroma-derived spindle-cell neoplasm of the lymph node with myofibroblastic differentiation and CTNNB1 (β-catenin gene) somatic mutations. We present a case of IPM found incidentally in the staging of lung adenocarcinoma. We describe the major histopathological and phenotypic features, including a palisaded bland spindle cell proliferation with myofibroblastic differentiation and Wnt pathway activation by immunohistochemistry, including β-catenin expression. Production of osteoid-like collagen directly from tumor cells was observed. We confirmed p.Gly34Arg CTNNB1 mutation by direct sequencing. We also reviewed the literature for similar cases.

BACKGROUND: Osteoporosis (OP) is the most prevalent metabolic bone disease. Numerous genetic loci are strongly related to OP. AXIN1 is a significant gene that serves an important role in the WNT signaling pathway. The aim of this study was to explore the association between the AXIN1 genetic polymorphism (rs9921222) and OP susceptibility.
METHODS: A total of 101 subjects were enrolled in the study (50 patients with OP and 51 healthy individuals). Genomic DNA was extracted from whole blood using the QIAamp DNA Blood Mini Kit, and the AXIN1 gene polymorphism (rs9921222) was genotyped by TaqMan allelic discrimination assays. A logistic regression analysis was used to assess the association between genotypes and OP risk.
RESULTS: We found that AXIN1 rs9921222 had a significant association with the susceptibility of OP under the homozygote model (TT vs. CC: OR = 16.6, CI = 2.03-136.4, p = 0.009), (CT vs. CC: OR = 6.3, CI = 1.23-31.8, p = 0.027), recessive genetic model (TT vs.TC-CC: OR = 13.6, CI = 1.7-110.4, p = 0.015), and the dominant model (TT-TC vs. CC: OR = 9.7, CI = 2.6-36.3, p < 0.001). Allele T was significantly associated with OP risk (T vs. C: OR = 10.5, CI = 3.5-31.15, p = 0.001). There was a statistically significant difference between genotypes in mean platelet volume (p = 0.004), and platelet distribution width (p = 0.025). In addition, lumbar spine bone density, and femur neck bone density were significantly different between genotypes (p < 0.001).
CONCLUSIONS: AXIN1 rs9921222 was associated with OP susceptibility in the Egyptian population and should be considered a potential determinant risk for OP.

BACKGROUND: Gastric adenocarcinoma of the fundic gland is a rare, well-differentiated variant of gastric adenocarcinoma, which has been proposed as a novel disease entity. As a result of mismatch repair deficiency, microsatellite instability has been frequently observed in various human cancers and widely performed in the area of cancer pathogenesis. Herein, we report a case of gastric adenocarcinoma of fundic gland presented with microsatellite instability phenotype.
METHODS: A 46-year-old man was referred to our hospital for abdominal distension and pain.
METHODS: The patient contained 3 tumor lesions with different degrees of histologic differentiation and microsatellite instability. The lesions were located in the upper third of the stomach. The tumor size was 55 mm. Macroscopically, tumor showed an ulcerative type. In terms of depth of invasion, tumor lesion invaded into subserosa with lymphatic invasion. In addition, this patient did not present GNAS mutation but harbored AXIN2 mutation. By immunohistochemistry, the expression level of β-catenin protein in the nucleus of the carcinoma cells was obviously higher than that in normal nucleus. Compared with microsatellite instability-low lesion, PD-1, PD-L1, and CD8 were positive in the microsatellite instability-high lesions.
METHODS: The patient underwent surgical resection and postoperative chemotherapy.
RESULTS: The patient experienced distant metastasis and died from severe complications after 6 months of treatment.
CONCLUSIONS: These results suggested that the mutation of Wnt component genes associated with Wnt/β-catenin signaling pathway activation may play a role in promoting the occurrence of gastric adenocarcinoma of fundic gland. This is the first report of a gastric adenocarcinoma of fundic gland with microsatellite instability. These findings modify our understanding of the pathophysiology of gastric adenocarcinoma of fundic gland.

Background: The Wnt/β catenin pathway promotes bone mineralization stimulating proliferation, differentiation, and survival of osteoblasts; it also inhibits osteoclast differentiation and osteocyte activity. Sclerostin (SOST) and Dickkopf 1 (DKK1) are Wnt/β catenin pathway inhibitors. Genetic variability in the expression of SOST and DKK1 might be involved in the development of postmenopausal osteoporosis (OP). Aim: To determine whether the SOST rs851056 and DKK1 rs1569198 polymorphisms are associated with OP in Mexican-Mestizo postmenopausal women. Materials and Methods: Two hundred and eighty Mexican-Mestizo postmenopausal women were assessed for their bone mineral density by dual-energy X-ray absorptiometry (DXA). Patients were classified as OP or non-OP. Genomic DNA was extracted from peripheral blood leukocytes. Genetic polymorphisms were analyzed by quantitative polymerase chain reaction using TaqMan probes. Results: The frequency of OP was 40% among the study population. Osteoporotic patients were older (p < 0.001), had a higher frequency of smoking (p = 0.01), and lower body mass index (p < 0.001) compared with the non-osteoporotic patients. The genotypic frequencies of the rs851056 locus of the SOST gene were GG 19%, GC 45%, and CC 35%, whereas the genotypic frequencies of the rs1569198 locus of the DKK1 gene were GG 15%, GA 40%, and AA 44%. In relation to rs851056 locus of the SOST gene, no differences were observed between the OP and non-OP cohorts in the frequencies of the GC polymorphism (48.7% vs. 43.1%). Similarly, analyses of the DKK1 rs1569198 does not demonstrate differences in the GA genotypic frequencies between the OP and non-OP cohorts (42.5% vs. 38.9%). Conclusion: Polymorphisms SOST rs851056 and DKK1 rs1569198 polymorphisms are not associated with OP in Mexican-Mestizo postmenopausal women.

An increasing number of \'-omics\' datasets, generated by labs all across the world, are becoming available. They contain a wealth of data that are largely unexplored. Not every scientist, however, will have access to the required resources and expertise to analyze such data from scratch. Fortunately, a growing number of investigators is dedicating their time and effort to the development of user friendly, online applications that allow researchers to use and investigate these datasets. Here, we will illustrate the usefulness of such an approach. Using regulation of Wnt7b expression as an example, we will highlight a selection of accessible tools and resources that are available to researchers in the area of mammary gland biology. We show how they can be used for in silico analyses of gene regulatory mechanisms, resulting in new hypotheses and providing leads for experimental follow up. We also call out to the mammary gland community to join forces in a coordinated effort to generate and share additional tissue-specific \'-omics\' datasets and thereby expand the in silico toolbox.

We report a case of a patient with concurrent myotonic dystrophy and recurrent pleomorphic adenoma and hypothesize the association between both diseases. A 58-year-old man with classic myotonic dystrophy type 1 was diagnosed with pleomorphic adenoma. Appropriate treatment was commenced. Massive recurrences occurred within 15, 28 and 22 months respectively, after repeated surgical removal. Three case reports on similar occurrences of synchronous myotonic dystrophy and pleomorphic adenoma are discussed and an association between both disease entities is hypothesized. A conceivable association between myotonic dystrophy and pleomorphic adenoma is hypothesized by upregulation of the Wnt/Beta-catenin signaling pathway, initiated by a decreased expression of microRNA, pleomorphic adenoma gene 1 induced Beta-catenin accumulations and alterations in tumor suppressor genes and oncogenes due to RNA processing defects induced by the expanded repeat in the DMPK gene.

BACKGROUND: Ductal carcinoma of the prostate is a histological subtype with a higher mortality than acinar adenocarcinoma. The number of cases is small and there are no treatment guidelines. We believe that this is the first report of ductal carcinoma of the prostate with an adenomatosis polyposis coli (APC) gene mutation in Japan.
METHODS: An 85-year-old man presented with gross hematuria, and a papillary tumor in the prostatic urethra that was diagnosed as ductal carcinoma of the prostate following transurethral resection. Genetic analysis found an APC mutation with loss of heterozygosity. Immunostaining revealed focal nuclear translocation of β-catenin. APC mutations associated with loss of β-catenin degradation in the Wnt signaling pathway and result in over accumulation of β-catenin are thought to increase mortality. In this patient, β-catenin migrated into tumor cell nuclei.
CONCLUSIONS: To the best of our knowledge, this is the first report of ductal carcinoma of the prostate with an APC mutation in Japan. The development of a therapeutic Wnt inhibitor is discussed.

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen\'s disease, is a type of genodermatoses having an autosomal dominant inheritance pattern and is recently considered as a RASopathy. Such patients are very much prone to develop mesenchymal tumors. However, carcinomas are quite rare in NF1 patients. This case study is the first case of oral squamous cell carcinoma (SCC) in tongue of an NF1 patient. A 35-year-old male reported to the Department of Oral Pathology in a tertiary care center with a chief complain of a painful ulcer on tongue for last 1 month. For confirmation of diagnosis of NF1, the \"Diagnostic Criteria for Neurofibromatosis Type 1\" was followed. Biopsied specimen of the tongue lesion was examined under microscope and histopathological features were suggestive of infiltrating SCC. Immunohistochemistry with Pan CK and beta-catenin was positive. RASopathy, WNT-beta-catenin pathway alteration, heat shock factor 1 production, and miRNA activity are investigated to explain the pathogenesis of malignancies in NF1 patients. In this first case of tongue SCC, we have found out the altered WNT-beta-catenin pathway.