TMEM127 suppresses tumor development by promoting RET ubiquitination, positioning, and degradation.

The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell proliferation and tumor burden after TMEM127 loss can be reversed by selective RET inhibitors in vitro and in vivo. Our results define TMEM127 as a component of the ubiquitin system and identify aberrant RET stabilization as a likely mechanism through which TMEM127 loss-of-function mutations cause pheochromocytoma.

Case report: Two sisters with a germline CHEK2 variant and distinct endocrine neoplasias.

Genetic testing has become the standard of care for many disease states. As a result, physicians treating patients who have tumors often rely on germline genetic testing results for making clinical decisions. Cases of two sisters carrying a germline CHEK2 variant are highlighted whereby possible other genetic drivers were discovered on tumor analysis. CHEK2 (also referred to as CHK2) loss of function has been firmly associated with breast cancer development. In this case report, two siblings with a germline CHEK2 mutation also had distinct endocrine tumors. Pituitary adenoma and pancreatic neuroendocrine tumor (PNET) was found in the first sibling and pheochromocytoma (PCC) discovered in the second sibling. Although pituitary adenomas, PNETs, and PCC have been associated with NF1 gene mutations, the second sister with a PCC did have proven germline CHEK2 with a pathogenic somatic NF1 mutation. We highlight the clinical point that unless the tumor is sequenced, the real driver mutation that is causing the patient's tumor may remain unknown.

A RET::GRB2 fusion in pheochromocytoma defies the classic paradigm of RET oncogenic fusions.

The RET kinase receptor is a target of mutations in neural crest tumors, including pheochromocytomas, and of oncogenic fusions in epithelial cancers. We report a RET::GRB2 fusion in a pheochromocytoma in which RET, functioning as the upstream partner, retains its kinase domain but loses critical C-terminal motifs and is fused to GRB2, a physiological RET interacting protein. RET::GRB2 is an oncogenic driver that leads to constitutive, ligand-independent RET signaling; has transforming capability dependent on RET catalytic function; and is sensitive to RET inhibitors. These observations highlight a new driver event in pheochromocytomas potentially amenable for RET-driven therapy.

Insights into Mechanisms of Pheochromocytomas and Paragangliomas Driven by Known or New Genetic Drivers.

Pheochromocytomas and paragangliomas are rare tumors of neural crest origin. Their remarkable genetic diversity and high heritability have enabled discoveries of bona fide cancer driver genes with an impact on diagnosis and clinical management and have consistently shed light on new paradigms in cancer. In this review, we explore unique mechanisms of pheochromocytoma and paraganglioma initiation and management by drawing from recent examples involving rare mutations of hypoxia-related genes VHL, EPAS1 and SDHB, and of a poorly known susceptibility gene, TMEM127. These models expand our ability to predict variant pathogenicity, inform new functional domains, recognize environmental-gene connections, and highlight persistent therapeutic challenges for tumors with aggressive behavior.

Differences in omentin-1 levels in term newborns according to birth weight.

BACKGROUND: Adipokines are produced by adipose tissue and are involved in metabolic processes. Omentin-1 is an adipokine that has been shown in vitro to possibly be involved in insulin sensitivity modulation. The prenatal stage is a crucial period for development of metabolic diseases in the long term, therefore, small (SGA) and large (LGA) for gestational age newborns have an increased risk of type 2 diabetes and metabolic syndrome later in life. AIMS: To evaluate the differences in omentin-1 concentrations in umbilical cord blood from healthy term newborns according to birth weight and explore the association between omentin-1 and anthropometry, glucose, insulin and insulin sensitivity. STUDY DESIGN: This was a secondary analysis of stored umbilical cord blood of term newborns. SUBJECTS: Newborns classified according to birth weight as SGA (n = 30), adequate for gestational age (AGA) (n = 12) and LGA (n = 34). OUTCOME MEASURES: An analysis of omentin-1, glucose and insulin were performed. RESULTS: Differences were found in serum omentin-1 levels (ng/mL) between SGA 328.17 ±â€¯108.04, AGA 253.05 ±â€¯98.25 and LGA 250.91 ±â€¯100.48 (p = 0.009). In the linear regression analysis, the independent variables HOMA-IR, QUICK-I and FGIR were predictors of serum omentin-1 levels (r = 0.175, p = 0.003). CONCLUSIONS: Omentin-1 cord blood levels have a differentiated behavior according to weight for gestational age with LGA newborns having lower levels and SGA newborns higher levels. HOMA-IR, QUICK-I and FGIR weakly predicted omentin-1 in cord blood, suggesting that omentin-1 possibly has an implication in insulin sensitivity since birth.

Are cord blood visfatin concentrations different depending on birth weight category? / Niveles de visfatina en sangre del cordón umbilical, ¿son diferentes según la categoría de peso al nacer?

Background and objective: Increased visceral adipose tissue mass is strongly associated to metabolic disorders. Visfatin is a visceral fat adipocytokine. There is epidemiological evidence of a link between a suboptimal gestational environment and a greater propensity to develop metabolic disease in adult life. The objective of this study was to establish whether visfatin concentrations in umbilical cord blood are different in newborns small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA). Subjects and methods: Term newborns from an university medical center were included in the study. A blood sample was taken from the umbilical cord vein of each baby immediately after birth. Visfatin was measured using an enzyme immunoassay in the study population, consisting of 35 subjects in the SGA group, 58 in the AGA group, and 35 in the LGA group. Results: Cord blood visfatin concentrations were not different in the three groups, with respective values of 2.78 (1.86-4.49) ng/mL, 3.28 (1.98-4.97) ng/mL, and 3.46 (2.48-5.38) ng/mL in the SGA, AGA and LGA groups (p=0.141). Gestational weight gain (GWG) (14.09±6.37kg) was negatively associated to visfatin levels (r=−0.218, p=0.036). GWG is an independent predictor of visfatin concentrations (r2=−0.067, p=0.027). Conclusions: There were no differences in cord blood visfatin concentrations depending on birth weight. GWG is an independent predictor of visfatin levels in the cord blood of term newborns

Antecedentes y objetivo: El aumento de la masa de tejido adiposo visceral está fuertemente asociado con trastornos metabólicos. La visfatina es una adipocitoquina de la grasa visceral. Existe evidencia epidemiológica de un vínculo entre un entorno gestacional subóptimo y una mayor propensión a desarrollar enfermedades metabólicas en la vida adulta. El objetivo de este estudio es determinar si las concentraciones de visfatina en la sangre del cordón umbilical son diferentes entre recién nacidos pequeños para edad gestacional (PEG), apropiados para edad gestacional (AEG) y grandes para edad gestacional (GEG). Materiales y métodos: Se incluyeron los recién nacidos a término de un centro médico universitario. Se tomó una muestra de sangre de la vena del cordón umbilical de cada niño inmediatamente después del nacimiento. La visfatina se midió mediante inmunoensayo enzimático en la población de estudio, que incluyó 35 sujetos en el grupo PEG, 58 en el AEG y 35 en el GEG. Resultados: Las concentraciones de visfatina en sangre del cordón umbilical no fueron diferentes entre los 3 grupos de estudio, 2,78 (1,86-4,49) ng/ml, 3,28 (1,98-4,97) ng/ml, 3,46 (2,48-5,38) ng/ml para el PEG, AEG y GEG, respectivamente (p=0,141). El aumento de peso gestacional (GWG) (14,09±6,37kg) se asoció negativamente con los niveles de visfatina (r=−0,218, p=0,036). El GWG es un predictor independiente de los niveles de visfatina (r2=−0,067, p=0,027). Conclusiones: Los niveles de visfatina en sangre del cordón umbilical no tienen un comportamiento diferenciado según el peso al nacer. El GWG es un predictor independiente de los niveles de visfatina en la sangre del cordón umbilical de recién nacidos a término

Are cord blood visfatin concentrations different depending on birth weight category?

BACKGROUND AND OBJECTIVE: Increased visceral adipose tissue mass is strongly associated to metabolic disorders. Visfatin is a visceral fat adipocytokine. There is epidemiological evidence of a link between a suboptimal gestational environment and a greater propensity to develop metabolic disease in adult life. The objective of this study was to establish whether visfatin concentrations in umbilical cord blood are different in newborns small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA). SUBJECTS AND METHODS: Term newborns from an university medical center were included in the study. A blood sample was taken from the umbilical cord vein of each baby immediately after birth. Visfatin was measured using an enzyme immunoassay in the study population, consisting of 35 subjects in the SGA group, 58 in the AGA group, and 35 in the LGA group. RESULTS: Cord blood visfatin concentrations were not different in the three groups, with respective values of 2.78 (1.86-4.49) ng/mL, 3.28 (1.98-4.97) ng/mL, and 3.46 (2.48-5.38) ng/mL in the SGA, AGA and LGA groups (p=0.141). Gestational weight gain (GWG) (14.09±6.37kg) was negatively associated to visfatin levels (r=-0.218, p=0.036). GWG is an independent predictor of visfatin concentrations (r2=-0.067, p=0.027). CONCLUSIONS: There were no differences in cord blood visfatin concentrations depending on birth weight. GWG is an independent predictor of visfatin levels in the cord blood of term newborns.

Vaspin, a Compensatory Mechanism Against High Glucose Levels Since Birth?

Objective: Hormones produced by fat tissue, adipokines, produced during intrauterine life have recently been implicated in fetal growth. Vaspin is an adipokine expressed in visceral adipose tissue and has insulin-sensitizing effects. Elevated serum vaspin concentrations are associated with alterations in insulin sensitivity. We aimed to determine if vaspin concentrations in cord blood from healthy, term newborns differ among those born small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA). A secondary objective was to determine whether an association existed between vaspin and anthropometric measurements, glucose and insulin levels in the newborn. Methods: The study population included healthy term newborns, 30 subjects in the SGA, 12 in the AGA, and 34 in the LGA group. Anthropometry was documented in all subjects. Blood was taken from the umbilical cord vein from each child for later analysis for vaspin, insulin and glucose concentrations. Results: Cord blood vaspin, insulin and glucose concentrations were not different between the three study groups. A negative correlation between vaspin and glucose concentrations was demonstrated in the whole cohort (r=-0.364, p=0.001). This correlation was also observed in the LGA group (r=-0.482, p=0.004). Glucose concentrations significantly predicted vaspin concentrations (r2=0.132, p=0.001). Conclusion: We found a negative association between glucose and vaspin concentrations in umbilical cord blood. In addition there was a predictive association between blood glucose and resulting vaspin concentration, suggesting that vaspin can be used as a predictor of alterations in the insulin-glucose metabolism from birth.

Adding Multiple Adipokines into the Model do not Improve Weight Gain Prediction by Leptin Levels in Newborns.

OBJECTIVE: Most adipose tissue programming is realized in early life. Also, the postnatal three months, rather than the later phases of infancy, may be more relevant in the development of an adverse cardiometabolic risk profile. The adipokines phenotype, as a predictor of early-life weight gain, has been recently explored in cord blood. To determine whether in addition to leptin levels in cord samples, adiponectin, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), resistin, plasminogen activator inhibitor-1 (PAI-1), and tumor necrosis factor alpha (TNF-α) levels improve weight gain prediction during the first three months of life. METHODS: Adiponectin, IL-6, MCP-1, leptin, resistin, PAI-1, and TNF-α were measured by multiplex immunoassay in a subsample of 86 healthy term newborns. RESULTS: Leptin levels significantly predicted weight gain at 3 months of follow-up (r2=0.09, p=0.006). In the multivariate analysis, including additional adipokines in the model, stepwise or all at once, did not increase the prediction of weight gain after the first three months of life. CONCLUSION: Adding adiponectin, IL-6, MCP-1, resistin, PAI-1, and TNF-α to the prediction model of weight gain in healthy newborns did not prove to be useful. It is probable that their relative contribution to weight gain is not important. Only leptin was relevant as a predictor of weight gain at the 3-month endpoint.

Leptin, IL-6 and TNF-α levels in umbilical cord blood of healthy term newborns in relation to mode of delivery.

In the development of the foetal immune system, cytokines play an important role in its function. Therefore, we sought to determine whether the mode of delivery affects the expression of leptin, IL-6 and TNF-α in umbilical cord blood in healthy term newborns. We collected 125 samples of umbilical cord blood to analyse leptin, IL-6 y TNF-α levels with multiplex immunoassay (MIA). The samples were classified according to mode of delivery: vaginal delivery (VD) and caesarean section (CS). Leptin and IL-6 had higher concentrations in umbilical cord blood in VD than in CS: 42.55 ng/ml (11.92-104.28) versus 35.20 ng/ml (3.26-9326.76), p = 0.039; 9.32 pg/ml (1.13-2020.31) versus 3.81 pg/ml (0.52-834.69) p < 0.001, respectively. Also, a weak correlation between TNF-α and IL-6 was found (r = 0.238, p = 0.007). The most important finding in our study was the differential concentrations of leptin and IL-6 according to mode of delivery.

Measurement of Leptin by RIA Versus MIA in a Population of Healthy Newborns.

BACKGROUND: Assays based on multiplex immunoassay (MIA) technology have demonstrated advantages over enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA). Its acceptance depends on how well it performs in comparison to older techniques. The aim is to compare the results of leptin using RIA versus MIA. METHODS: We analyzed 81 samples of umbilical cord blood of healthy term newborns by RIA and MIA. RESULTS: The concordance correlation coefficient was 0.158 (95% CI 0.10-0.21). Pearson's correlation coefficient was 0.6651 (95% CI 0.52-0.77; P < 0.0001). In the Bland-Altman plot, concordance is acceptable because most of the measurements are within a mean of ±1.96 SD. CONCLUSIONS: As shown by the Bland-Altman plot, there is concordance by both methods, but with a weak correlation.

Association between umbilical cord leptin and weight gain according to feeding type in the early postnatal period, a brief report.

BACKGROUND: Weight gain in infancy depends on in utero nutritional status, with postnatal growth also dependent on feeding practices, culture, food accessibility and parents' education. OBJECTIVE: To evaluate the relationship between umbilical cord blood leptin levels and feeding mode (breast-fed vs. formula) on weight gain at three months of life. MATERIAL AND METHODS: Ninety-nine full-term newborns (male, n = 48; female, n = 51) were included in two groups according to feeding type: breast-fed (n = 49) and formula-fed (n = 50). Leptin was measured in blood obtained from the umbilical cord vein. RESULTS: Umbilical cord leptin levels and weight gain at three months had a significant inverse correlation in formula-fed infants (r = -0.294, P = 0.038). This finding was not reflected in breast-fed infants (r = -0.212, P = 0.144). CONCLUSIONS: In our Mexican breastfeeding cohort, umbilical cord leptin levels were a significant predictor of weight gain in formula-fed infants.

Typical leptin fall is mitigated by breastfeeding in female infants.

BACKGROUND AND AIMS: Programming of the nutritional and hormonal status of offspring occurs mostly during the gestational and breastfeeding periods. Several studies have reported that breastfed children are more protected from developing obesity in adult life; however, the mechanism that explains this phenomenon is not clear. We undertook this study to evaluate if weight, gender or feeding mode (breastfed or formula-fed) affects leptin levels (during the first 3 months after birth) in a cohort of term newborns, the Breastfeeding Cohort. METHODS: A cohort of 99 term newborns divided into four groups according to gender and feeding type: breastfed female, formula-fed female, breastfed male and formula-fed male were studied. Feeding mode was freely chosen by the parents. Blood sampling for glucose, insulin and leptin was performed at birth and after 3 months. RESULTS: No differences were found among the groups for maternal age, marital status, educational and socioeconomic level, maternal occupation, and prenatal care. No statistically significant differences were found for weight, length or body mass index at birth among the four groups. There were differences in leptin with a higher level in girls (0.907 ± 0.332) than boys (0.663 ± 0.351; p <0.001) at birth and at 3 months (0.618 ± 0.225, 0.464 ± 0.195; p <0.0001). A decrease in leptin levels from birth to 3 months was observed in all groups with the exception of breastfed females (0.849 ± 0.352-0.672 ± 0.222, p = NS). CONCLUSIONS: In our study, breastfed females were protected from this fall in serum leptin levels. Our findings support further studies on the long-term effects of breastfeeding.