Epigenetic control of adamantinomatous craniopharyngiomas.

INTRODUCTION: Studies addressing the methylation pattern in adamantinomatous craniopharyngioma (ACP) are lacking. OBJECTIVE: To identify methylation signatures in ACPs regarding clinical presentation and outcome. METHODS: Clinical and pathology data were collected from 35 ACP patients (54% male; 18.1 years [2-68]). CTNNB1 mutations and methylation profile (MethylationEPIC/Array-Illumina) were analyzed in tumoral DNA. Unsupervised machine learning analysis of this comprehensive methylome sample was achieved using hierarchical clustering and multi-dimensional scaling. Statistical associations between clusters and clinical features were achieved using Fisher's test and global biological process interpretations were aided by Gene Ontology enrichment analyses. RESULTS: Two clusters were revealed consistently by all unsupervised methods (ACP-1: n = 18; ACP-2: n = 17) with strong bootstrap statistical support. ACP-2 was enriched by CTNNB1 mutations (100% vs 56%, P = 0.0006), hypomethylated in CpG Island (CGI), non-CGI sites, and globally (P < 0.001), and associated with greater tumor size (24.1 vs 9.5cm3, P = 0.04). Enrichment analysis highlighted pathways on signaling transduction, transmembrane receptor, development of anatomical structures, cell-adhesion, cytoskeleton organization, and cytokine binding, and also cell-type specific biological processes as regulation of oligodendrocytes, keratinocyte, and epithelial cells differentiation. CONCLUSION: Two clusters of ACP patients were consistently revealed by unsupervised machine learning methods, being one of them significantly hypomethylated, enriched by CTNNB1 mutated ACPs, and associated with increased tumor size. Enrichment analysis reinforced pathways involved in tumor proliferation and in cell-specific tumoral microenvironment.

Incorporating biodiversity responses to land use change scenarios for preventing emerging zoonotic diseases in areas of unknown host-pathogen interactions.

The need to reconcile food production, the safeguarding of nature, and the protection of public health is imperative in a world of continuing global change, particularly in the context of risks of emerging zoonotic disease (EZD). In this paper, we explored potential land use strategies to reduce EZD risks using a landscape approach. We focused on strategies for cases where the dynamics of pathogen transmission among species were poorly known and the ideas of "land-use induced spillover" and "landscape immunity" could be used very broadly. We first modeled three different land-use change scenarios in a region of transition between the Cerrado and the Atlantic Forest biodiversity hotspots. The land-use strategies used to build our scenarios reflected different proportions of native vegetation cover, as a proxy of habitat availability. We then evaluated the effects of the proportion of native vegetation cover on the occupancy probability of a group of mammal species and analyzed how the different land-use scenarios might affect the distribution of species in the landscape and thus the risk of EZD. We demonstrate that these approaches can help identify potential future EZD risks, and can thus be used as decision-making tools by stakeholders, with direct implications for improving both environmental and socio-economic outcomes.

The molecular pathogenesis of craniopharyngiomas.

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, ß-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.

Integrating Methylome and Transcriptome Signatures Expands the Molecular Classification of the Pituitary Tumors.

OBJECTIVE: To explore pituitary tumors by methylome and transcriptome signatures in a heterogeneous ethnic population. METHODS: In this retrospective cross-sectional study, clinicopathological features, methylome, and transcriptome were evaluated in pituitary tumors from 77 patients (61% women, age 12-72 years) followed due to functioning (FPT: GH-secreting n = 18, ACTH-secreting n = 14) and nonfunctioning pituitary tumors (NFPT, n = 45) at Ribeirao Preto Medical School, University of São Paulo. RESULTS: Unsupervised hierarchical clustering analysis (UHCA) of methylome (n = 77) and transcriptome (n = 65 out of 77) revealed 3 clusters each: one enriched by FPT, one by NFPT, and a third by ACTH-secreting and NFPT. Comparison between each omics-derived clusters identified 3568 and 5994 differentially methylated and expressed genes, respectively, which were associated with each other, with tumor clinical presentation, and with 2017 and 2022 WHO classifications. UHCA considering 11 transcripts related to pituitary development/differentiation also supported 3 clusters: POU1F1-driven somatotroph, TBX19-driven corticotroph, and NR5A1-driven gonadotroph adenomas, with rare exceptions (NR5A1 expressed in few GH-secreting and corticotroph silent adenomas; POU1F1 in few ACTH-secreting adenomas; and TBX19 in few NFPTs). CONCLUSION: This large heterogenic ethnic Brazilian cohort confirms that integrated methylome and transcriptome signatures classify FPT and NFPT, which are associated with clinical presentation and tumor invasiveness. Moreover, the cluster NFPT/ACTH-secreting adenomas raises interest regarding tumor heterogeneity, supporting the challenge raised by the 2017 and 2022 WHO definition regarding the discrepancy, in rare cases, between clinical presentation and pituitary lineage markers. Finally, making our data publicly available enables further studies to validate genes/pathways involved in pituitary tumor pathogenesis and prognosis.

Which social, gestational and mental health aspects are associated to maternal-fetal attachment? / Quais aspectos sociais, gestacionais e de saúde mental materna estão associados ao apego materno-fetal?

Abstract Objectives: this study aimed to explore a set of factors associated with lower maternal-fetal attachment (MFA) in pregnant women. Methods: this is a cross-sectional study corresponding to the second wave of a cohort study with a population-based sample of pregnant women in the South of Brazil. The maternal-fetal attachment scale (MFAS) was used to measure MFA. Bivariate analysis was performed using the t-test and ANOVA. The variables that presented p<0.20 were taken for multivariate analysis, through linear regression, in order to control possible confounding factors. Results: a total of 840 pregnant women were included. Pregnant women who had lower MFA means were those who did not live with a partner (B=-3.8 [CI95%=-6.0; -1.7]), those between the first and second trimester of pregnancy (B=-4.3 [CI95%=-5.9; -2.6]), those who did not have support from their mother during pregnancy (B=-2.4 [CI95%=-4.6; -0.2]), and those with depressive symptoms (B=-4.9 [CI95%=-7.4; -2.5]). Conclusions: the results showed that a higher MFA it is associated with an adequate support network during pregnancy, better maternal mental health, and with an advanced pregnancy. Early evaluation of MFA and effort to promote an adequate prenatal bond, focusing on maternal psychological and emotional aspects are strongly suggested.

Resumo Objetivos: explorar um conjunto de fatores associados ao menor apego materno-fetal (AMF) em gestantes. Métodos: trata-se de um estudo transversal, correspondente à segunda fase de um estudo de coorte com uma amostra de base populacional de gestantes no sul do Brasil. Foi utilizada a Escala de Apego Materno-Fetal (EAMF) para medir o AMF. A análise bivariada foi realizada através do teste t e ANOVA. As variáveis que apresentaram p<0,20 foram levadas para análise multivariada, por meio de regressão linear, a fim de controlar possíveis fatores de confusão. Resultados: foram incluídas 840 gestantes. As gestantes que apresentaram menores médias de AMF foram aquelas que não moravam com um companheiro (B=-3,8 [IC95%=-6,0; -1,7]), que estavam entre o primeiro e o segundo trimestre de gestação (B=-4,3 [IC95%=-5,9; -2,6]), que não tiveram o apoio da mãe durante a gestação (B=-2,4 [IC95%=-4,6; -0,2]) e que apresentaram sintomas depressivos (B=-4,9 [IC95%=-7,4; -2,5]). Conclusões: os resultados mostraram que um maior AMF está associado a presença de uma rede de apoio adequada na gravidez, melhor saúde mental materna e a uma gestação avançada. A avaliação precoce do AMF e a promoção de um vínculo pré-natal adequado, com foco nos aspectos psicológicos e emocionais maternos são fortemente sugeridos.

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.

Telomere length and Wnt/ß-catenin pathway in adamantinomatous craniopharyngiomas.

Objectives: To evaluate how telomere length behaves in adamantinomtous craniopharyngioma (aCP) and if it contributes to the pathogenesis of aCPs with and without CTNNB1 mutations. Design: Retrospective cross-sectional study enrolling 42 aCP patients from 2 tertiary institutions. Methods: Clinicopathological features were retrieved from the patient's charts. Fresh frozen tumors were used for RNA and DNA analyses. Telomere length was evaluated by qPCR (T/S ratio). Somatic mutations in TERT promoter (TERTp) and CTNNB1 were detected by Sanger and/or whole-exome sequencing. We performed RNA-Seq to identify differentially expressed genes in aCPs presenting with shorter or longer telomere lengths. Results: Mutations in CTNNB1 were detected in 29 (69%) tumors. There was higher frequency of CTNNB1 mutations in aCPs from patients diagnosed under the age of 15 years (85% vs 15%; P = 0.04) and a trend to recurrent disease (76% vs 24%; P = 0.1). No mutation was detected in the TERTp region. The telomeres were shorter in CTNNB1-mutated aCPs (0.441, IQR: 0.297-0.597vs 0.607, IQR: 0.445-0.778; P = 0.04), but it was neither associated with clinicopathological features nor with recurrence. RNAseq identified a total of 387 differentially expressed genes, generating two clusters, being one enriched for short telomeres and CTNNB1-mutated aCPs. Conclusions: CTNNB1: mutations are more frequent in children and adolescents and appear to associate with progressive disease. CTNNB1-mutated aCPs have shorter telomeres, demonstrating a relationship between the Wnt/ß-catenin pathway and telomere biology in the pathogenesis of aCPs.

Restricted feeding modulates peripheral clocks and nutrient sensing pathways in rats.

OBJECTIVE: Feeding restriction in rats alters the oscillators in suprachiasmatic, paraventricular, and arcuate nuclei, hypothalamic areas involved in food intake. In the present study, using the same animals and experimental protocol, we aimed to analyze if food restriction could reset clock genes (Clock, Bmal1) and genes involved in lipid metabolism (Pgc1a, Pparg, Ucp2) through nutrient-sensing pathways (Sirt1, Ampk, Nampt) in peripheral tissues. METHODS: Rats were grouped according to food access: Control group (CG, food ad libitum), Restricted night-fed (RF-n, food access during 2 h at night), Restricted day-fed (RF-d, food access during 2 h in the daytime), and Day-fed (DF, food access during 12 h in the daytime). After 21 days, rats were decapitated at ZT3 (0900-1000 h), ZT11 (1700-1800 h), or ZT17 (2300-2400 h). Blood, liver, brown (BAT) and peri-epididymal (PAT) adipose tissues were collected. Plasma corticosterone and gene expression were evaluated by radioimmunoassay and qPCR, respectively. RESULTS: In the liver, the expression pattern of Clock and Bmal1 shifted when food access was dissociated from rat nocturnal activity; this phenomenon was attenuated in adipose tissues. Daytime feeding also inverted the profile of energy-sensing and lipid metabolism-related genes in the liver, whereas calorie restriction induced a pre-feeding increased expression of these genes. In adipose tissues, Sirt1 expression was modified by daytime feeding and calorie restriction, with concomitant expression of Pgc1a, Pparg, and Ucp2 but not Ampk and Nampt. CONCLUSION: Feeding restriction reset clock genes and genes involved in lipid metabolism through nutrient-sensing-related genes in rat liver, brown, and peri-epididymal adipose tissues.

Brief cognitive behavioral therapy in pregnant women at risk of postpartum depression: Pre-post therapy study in a city in southern Brazil.

BACKGROUND: Postpartum depression (PPD) affects a high number of women, often the first manifestation of a mood disorder that will occur later in life, bringing serious consequences for the patient and her offspring. Depression today is the leading cause of disability worldwide. The aim of this study was to evaluate the effectiveness of a preventive cognitive behavioral therapy (CBT) for PPD. METHODS: Pre-post therapy study, as part of a population-based cohort study. Pregnant women without a diagnosis of depression participated, who were divided into two groups: risk of depression (CBT) and a control group (without therapy). The preventive therapy consisted of six sessions of CBT, administered weekly. The Outcome Questionnaire (OQ-45) was used in all sessions. The Mini International Neuropsychiatric Interview and Beck Depression Inventory-II were used on three occasions. The final statistical analyses were performed by Poisson regression. RESULTS: The prevalence of PPD in the risk group was 5.5% and in the control group 2.2%, with no difference between the groups (PR 1.66 95% CI 0.44-6.18). The OQ-45 averages gradually reduced during the therapy sessions, indicating therapeutic progress. Schooling was an associated factor, both with the manifestation of PPD and with the greater effectiveness of the therapy. LIMITATIONS: Rate of 40.5% refusal to preventive treatment and absence of a group with similar characteristics in another therapy model. CONCLUSIONS: Brief cognitive behavioral therapy applied by mental health professionals with basic training was effective in preventing the manifestation of PPD.

Generalized and tissue specific glucocorticoid resistance.

Glucocorticoids (GCs) are steroid hormones that influence several physiologic functions and are among the most frequently prescribed drugs worldwide. Resistance to GCs has been observed in the context of the familial generalized GC resistance (Chrousos' syndrome) or tissue specific GC resistance in chronic inflammatory states. In this review, we have summarized the major factors that influence individual glucocorticoid sensitivity/resistance. The fine-tuning of GC action is determined in a tissue-specific fashion that includes the combination of different GC receptor promoters, translation initiation sites, splice isoforms, interacting proteins, post-translational modifications, and alternative mechanisms of signal transduction.

Restricted feeding modulates peripheral clocks and nutrient sensing pathways in rats

ABSTRACT Objective: Feeding restriction in rats alters the oscillators in suprachiasmatic, paraventricular, and arcuate nuclei, hypothalamic areas involved in food intake. In the present study, using the same animals and experimental protocol, we aimed to analyze if food restriction could reset clock genes ( Clock, Bmal1 ) and genes involved in lipid metabolism ( Pgc1a, Pparg, Ucp2 ) through nutrient-sensing pathways ( Sirt1, Ampk, Nampt ) in peripheral tissues. Materials and methods: Rats were grouped according to food access: Control group (CG, food ad libitum ), Restricted night-fed (RF-n, food access during 2 h at night), Restricted day-fed (RF-d, food access during 2 h in the daytime), and Day-fed (DF, food access during 12 h in the daytime). After 21 days, rats were decapitated at ZT3 (0900-1000 h), ZT11 (1700-1800 h), or ZT17 (2300-2400 h). Blood, liver, brown (BAT) and peri-epididymal (PAT) adipose tissues were collected. Plasma corticosterone and gene expression were evaluated by radioimmunoassay and qPCR, respectively. Results: In the liver, the expression pattern of Clock and Bmal1 shifted when food access was dissociated from rat nocturnal activity; this phenomenon was attenuated in adipose tissues. Daytime feeding also inverted the profile of energy-sensing and lipid metabolism-related genes in the liver, whereas calorie restriction induced a pre-feeding increased expression of these genes. In adipose tissues, Sirt1 expression was modified by daytime feeding and calorie restriction, with concomitant expression of Pgc1a , Pparg , and Ucp2 but not Ampk and Nampt . Conclusion: Feeding restriction reset clock genes and genes involved in lipid metabolism through nutrient-sensing-related genes in rat liver, brown, and peri-epididymal adipose tissues.

Peripheral clock system circadian abnormalities in Cushing's disease.

In Cushing's syndrome, the cortisol rhythm is impaired and can be associated with the disruption in the rhythmic expression of clock genes. In this study, we evaluated the expression of CLOCK, BMAL1, CRY1, CRY2, PER1, PER2, PER3 genes in peripheral blood leukocytes of healthy individuals (n = 13) and Cushing's disease (CD) patients (n = 12). Participants underwent salivary cortisol measurement at 0900 h and 2300 h. Peripheral blood samples were obtained at 0900 h, 1300 h, 1700 h, and 2300 h for assessing clock gene expression by qPCR. Gene expression circadian variations were evaluated by the Cosinor method. In healthy controls, a circadian variation in the expression of CLOCK, BMAL1, CRY1, PER2, and PER3 was observed, whereas the expression of PER1 and CRY2 followed no specific pattern. The expression of PER2 and PER3 in healthy leukocytes presented a late afternoon acrophase, similarly to CLOCK, whereas CRY1 showed night acrophase, similarly to BMAL1. In CD patients, the circadian variation in the expression of clock genes was lost, along with the abolition of cortisol circadian rhythm. However, CRY2 exhibited a circadian variation with acrophase during the dark phase in patients. In conclusion, our data suggest that Cushing's disease, which is characterized by hypercortisolism, is associated with abnormalities in the circadian pattern of clock genes. Higher expression of CRY2 at night outlines its putative role in the cortisol circadian rhythm disruption.

USP8 Mutations and Cell Cycle Regulation in Corticotroph Adenomas.

Corticotroph adenomas frequently harbor somatic USP8 mutations. These adenomas also commonly exhibit underexpression of P27, a cell cycle regulator. The present study aimed to determine the influence of USP8 mutations on clinical features of Cushing's disease and to elucidate the relationship between USP8 mutations and P27 underexpression in these tumors. Retrospective study with 32 patients with Cushing's disease was followed at the Ribeirao Preto Medical School University Hospital. We evaluated the patients' clinical data, the USP8 mutation status and the gene expression of cell cycle regulators P27/CDKN1B, CCNE1, CCND1, CDK2, CDK4, and CDK6 in tumor tissue in addition to the protein expression of P27/CDKN1B. We observed somatic mutations in the exon 14 of USP8 in 31.3% of the patients. Larger tumor size was observed in patients harboring USP8 mutations (p=0.04), with similar rates of remission, age of presentation, salivary cortisol at 23:00 h and after 1 mg dexamethasone, ACTH levels, and early postoperative plasma cortisol. We observed no differences regarding the gene or protein expression of the cell cycle regulators according to USP8 mutation status. In this Brazilian series, the observed frequency of USP8 somatic mutations was similar to that reported in European ancestry populations. Although it was reasonable that USP8 mutations could contribute to cell cycle dysregulation and P27 underexpression in corticotroph adenomas, our data did not confirm this hypothesis. It is possible that increased deubiquitinase activity observed in mutated USP8 might influence other pathways related to cell growth and proliferation.

Clinical and epidemiological characteristics of childhood vitiligo: a study of 701 patients from Brazil.

BACKGROUND: Vitiligo is an acquired pigmentary disorder that affects approximately 0.5-2% of the world's population, and 25% of cases begin before 10 years of age. Although prevalent, there are few studies on the characterization of childhood vitiligo. OBJECTIVE: To evaluate the clinical and epidemiological characteristics of childhood vitiligo. METHODS: Transverse study conducted by reviewing data records of patients under the age of 18 in which disease onset occurred before 13 years of age. RESULTS: Predominance of females (62%). The most common subtype was generalized vitiligo (53.8%). The average age of disease onset was 5.9 years. The most affected initial site was head/neck (44.22%). The Koebner phenomenon was present in 38.2%, emotional triggering factors in 67.0% of the patients, halo nevus in 17.4%, and associated autoimmune disease in 6.5% of the patients. Family history of vitiligo was observed in 16.9% of the patients, and stability was reported by 20.1% of patients. The presence of positive family history did not significantly influence the age of onset. We found a significant difference between segmental vitiligo (SV) and nonsegmental vitiligo (NSV) regarding the age of onset, Koebner phenomenon, hypothyroidism, anti-TPO antibodies, family history of psoriasis, and halo nevus. CONCLUSION: Childhood vitiligo has its own characteristics. Vitiligo different subtypes have distinct characteristics. Our study presents a great number of patients, helping to elucidate the peculiarities of childhood vitiligo in the Brazilian population.

People living with HIV/AIDS: body image and its important associations with mental health and BMI.

Patients on antiretroviral therapy face new challenges, such as bodily changes. We conducted a cross-sectional study with people living with HIV/AIDS. We investigate the self-perception of body image and its associations. Most of the patients reported negative self-perception of body image (NSPBI), being mostly women, up to 40 years old and with changes in BMI. NSPBI was associated with depressive symptoms and punctual alterations in the redistribution of body fat: face, abdomen and legs, subjects still little elucidated. Assessing neglected aspects can improve the way these patients see themselves, and come to understand the disease as only a part of their lives.

Corrigendum: Transcriptome Analysis Showed a Differential Signature Between Invasive and Non-invasive Corticotrophinomas.

[This corrects the article DOI: 10.3389/fendo.2017.00055.].

Phenotypic diversity and glucocorticoid sensitivity in patients with familial partial lipodystrophy type 2.

Familial partial lipodystrophy type 2 (FPLD2) is characterized by insulin resistance, adipose atrophy of the extremities and central obesity. Due to the resemblance with Cushing's syndrome, we hypothesized a putative role of glucocorticoid in the pathogenesis of metabolic abnormalities in FPLD2. OBJECTIVE: To evaluate the phenotypic heterogeneity and glucocorticoid sensitivity in FPLD2 patients exhibiting the p.R482W or p.R644C LMNA mutations. DESIGN, PATIENTS AND MEASUREMENTS: Prospective study with FPLD2 patients (n = 24) and controls (n = 24), who underwent anthropometric, body composition, metabolic profile and adipokines/cytokine plasma measurements. Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5 and 1.0 mg of dexamethasone (DEX) given at 23:00 hours. Glucocorticoid receptor (GR) and 11ßHSD isoforms expression were assessed by qPCR. RESULTS: Familial partial lipodystrophy type 2 individuals presented increased waist and neck circumferences, decreased hip circumference, peripheral skinfold thickness and fat mass. Patients presented increased HOMA-IR, triglycerides, TNF-α, IL-1ß, IL-6 and IL-10, and decreased adiponectin and leptin plasma levels. FPLD2 patients showed decreased ability to suppress the HPA axis compared with controls after 0.5 mg DEX. The phenotype was more pronounced in patients harbouring the p.R482W LMNA mutation. GRß overexpression in PBMC was observed in female patients compared with female controls. CONCLUSIONS: Familial partial lipodystrophy type 2 patients exhibited anthropometric, clinical and biochemical phenotypic heterogeneity related to LMNA mutation sites and to gender. LMNA mutations affecting both lamin A and lamin C lead to more severe phenotype. FPLD2 patients also showed blunted HPA axis response to DEX, probably due to the association of increased levels of proinflammatory cytokines with GRß overexpression leading to a more severe phenotype in female.

Impact of the Canonical Wnt Pathway Activation on the Pathogenesis and Prognosis of Adamantinomatous Craniopharyngiomas.

CTNNB1 mutations and abnormal ß-catenin distribution are associated with the pathogenesis of adamantinomatous craniopharyngioma (aCP). We evaluated the expression of the canonical Wnt pathway components in aCPs and its association with CTNNB1 mutations and tumor progression. Tumor samples from 14 aCP patients and normal anterior pituitary samples from eight individuals without pituitary disease were studied. Gene expression of Wnt pathway activator (WNT4), inhibitors (SFRP1, DKK3, AXIN1, and APC), transcriptional activator (TCF7), target genes (MYC, WISP2, and, CDH1), and Wnt modulator (TP53) was evaluated by qPCR. ß-Catenin, MYC, and WISP2 expression was determined by immunohistochemistry (IHC). The transcription levels of all genes studied, except APC, were higher in aCPs as compared to controls and TCF7 mRNA levels correlated with CTNNB1 mutation. CDH1 mRNA was overexpressed in tumor samples of patients with disease progression in comparison to those with stable disease. ß-Catenin was positive and aberrantly distributed in 11 out of 14 tumor samples. Stronger ß-catenin immunostaining associated positively with tumor progression. MYC positive staining was found in 10 out of 14 cases, whereas all aCPs were negative for WISP2. Wnt pathway genes were overexpressed in aCPs harboring CTNNB1 mutations and in patients with progressive disease. Recurrence was associated with stronger staining for ß-catenin. These data suggest that Wnt pathway activation contributes to the pathogenesis and prognosis of aCPs.