RESUMO

Resumen La enfermedad inflamatoria intestinal de inicio muy temprano (VEOIBD) es una entidad rara en pediatría. Es conocida su asociación con inmunodeficiencias prima rias de origen monogénico. Presentamos el caso de una paciente con diagnóstico de VEOIBD a quien se le realizó una secuenciación masiva del exoma. El resultado del estudio permitió identificar una variante patogénica en el proto oncogen RET, asociada con enfermedad neoplasia endocrina múltiple tipo 2A. No hay reportes de asociación de variantes en el proto oncogen RET con VEOIBD. No se puede adjudicar la presencia de estas dos entidades clínicas a una única causa genética.

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Abstract Very early onset inflammatory bowel disease (VEOI BD) is a rare entity in pediatrics. Its association with pri mary immunodeficiencies of monogenic origin is known. We present the case of a patient diagnosed with VEOIBD who underwent massive paralleled exome sequencing. The result of the study showed a pathogenic variant in the RET proto-oncogene, associated with multiple endo crine neoplasia type 2A disease. There are no previous reports of association of RET proto-oncogene variants with VEOIBD. The presence of these two clinical entities cannot be attributed to a single genetic cause.

RESUMO

Selpercatinib, a selective RET kinase inhibitor, has demonstrated remarkable efficacy in treating patients with advanced medullary (MTC) and differentiated thyroid cancer with RET alterations. Primary resistance to selpercatinib is a very uncommon situation, and its underlying mechanisms are poorly understood. We report the case of a 42-year-old female with advanced MTC harboring a somatic M918T RET mutation who exhibited a primary resistance to selpercatinib. Despite prompt treatment initiation after the diagnosis of progressive disease, the patient continued experiencing rapid spread of disease, characterized by the appearance of new metastatic lesions and increased tumor burden. Genomic analysis revealed no additional mutations associated with on-target or off-target resistance. This case highlights a rare clinical scenario of primary resistance to selpercatinib in advanced MTC. While secondary resistance mechanisms have been well-documented, primary resistance remains poorly understood. Possible explanations include tumor heterogeneity and activation of alternative signaling pathways that stills need to be elucidated. Emerging therapies targeting resistance mechanisms and next-generation RET inhibitors offer promising avenues for further investigation.

Assuntos

Carcinoma Neuroendócrino , Resistencia a Medicamentos Antineoplásicos , Proteínas Proto-Oncogênicas c-ret , Neoplasias da Glândula Tireoide , Humanos , Feminino , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adulto , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/uso terapêutico

RESUMO

Pheochromocytomas and paragangliomas (PPGL) are neuroendocrine tumors characterized by the excessive production of catecholamines. This study aims to describe the clinical characteristics of PPGL cases in Argentina over recent decades. A multicenter retrospective cross-sectional analysis was carried out using a database comprising both pediatric and adult patients with confirmed PPGL diagnoses based on pathological reports. A cohort of 486 patients with PPGL was recruited. Women represent 58.4% of the patients, with a mean age of 38.3 years old at the time of diagnosis and 15.2% of the patients were under the age of 18. Hypertension, as well as classic signs and symptoms, were present in 80.9% of the patients. The adrenal incidentaloma, as a mode of presentation, increased in the last two decades rising from 3.9% (1953-2000) to 21.8% (2001-2022), p<0.001. Most tumors were located within the adrenal glands, accounting 83.0% of the cases, with bilateral occurrences noted in 20.0%. The median tumor size was 4.8cm. Local recurrence and metastases were observed in 10.9% and 12.2%. Out of 412 patients, 87.0% exhibited urinary excretion elevation of catecholamines and/or their metabolites. Furthermore, 148 patients, representing 30.4% of the study population, displayed a distinct genetic profile indicative of hereditary syndromes. The distribution of hereditary syndromes revealed that MEN2, VHL, and PGL4 constituted the most prevalent syndromes. This population-based study, spanning seven decades, offers valuable insights into the demographic and clinical characteristics of PPGL patients in Argentina.

Assuntos

Neoplasias das Glândulas Suprarrenais , Bases de Dados Factuais , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/patologia , Feocromocitoma/epidemiologia , Argentina , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/patologia , Feminino , Masculino , Estudos Retrospectivos , Adulto , Paraganglioma/patologia , Estudos Transversais , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Criança , Idoso , Recidiva Local de Neoplasia/epidemiologia , Pré-Escolar , Hipertensão/epidemiologia

RESUMO

Very early onset inflammatory bowel disease (VEOIBD) is a rare entity in pediatrics. Its association with primary immunodeficiencies of monogenic origin is known. We present the case of a patient diagnosed with VEOIBD who underwent massive paralleled exome sequencing. The result of the study showed a pathogenic variant in the RET proto-oncogene, associated with multiple endocrine neoplasia type 2A disease. There are no previous reports of association of RET proto-oncogene variants with VEOIBD. The presence of these two clinical entities cannot be attributed to a single genetic cause.

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La enfermedad inflamatoria intestinal de inicio muy temprano (VEOIBD) es una entidad rara en pediatría. Es conocida su asociación con inmunodeficiencias primarias de origen monogénico. Presentamos el caso de una paciente con diagnóstico de VEOIBD a quien se le realizó una secuenciación masiva del exoma. El resultado del estudio permitió identificar una variante patogénica en el proto oncogen RET, asociada con enfermedad neoplasia endocrina múltiple tipo 2A. No hay reportes de asociación de variantes en el proto oncogen RET con VEOIBD. No se puede adjudicar la presencia de estas dos entidades clínicas a una única causa genética.

Assuntos

Doenças Inflamatórias Intestinais , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-ret , Feminino , Humanos , Idade de Início , Sequenciamento do Exoma , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Mutação , Proteínas Proto-Oncogênicas c-ret/genética , Lactente

RESUMO

Context: Genetic analysis of sporadic medullary thyroid carcinoma (MTC) has revealed somatic variants in RET, RAS, and occasionally other genes. However, around 20% of patients with sporadic MTC lack a known genetic driver. Objective: To uncover potential new somatic or germline drivers, we analyze a distinct cohort of patients with sporadic, very early-onset, and aggressive MTC. Methods: Germline and somatic DNA exome sequencing was performed in 19 patients, previously tested negative for germline RET variants. Results: Exome sequencing of 19 germline samples confirmed the absence of RET and identified an NF1 pathogenic variant in 1 patient. Somatic sequencing was successful in 15 tumors revealing RET variants in 80%, predominantly p.Met918Thr, which was associated with disease aggressiveness. In RET-negative tumors, pathogenic variants were found in HRAS and NF1. The NF1 germline and somatic variants were observed in a patient without a prior clinical diagnosis of neurofibromatosis type 1, demonstrating that the loss of heterozygosity of NF1 functions as a potential MTC driver. Somatic copy number alterations analysis revealed chromosomal alterations in 53.3% of tumors, predominantly in RET-positive cases, with losses in chromosomes 9 and 22 being the most prevalent. Conclusion: This study reveals that within a cohort of early-onset nonhereditary MTC, RET remains the major driver gene. In RET-negative tumors, NF1 and RAS are drivers of sporadic MTC. In addition, in young patients without a RET germline mutation, a careful clinical evaluation with a consideration of germline NF1 gene analysis is ideal to exclude Neurofibromatosis type 1 (NF1).

RESUMO

INTRODUCTION: Hirschsprung's disease (HD) is characterized by the absence of ganglion cells in the submucosal and myenteric plexuses of the colon as a result of disorders in the migration and differentiation of enteric neural crest cells during embryogenesis. It is a cross-factor condition, with more than 11 genes identified in its pathogenesis, including the RET proto-onco gene. CASE REPORTS: We present the case of two siblings with total colon HD where a potentially pathogenic variant of the RET gene was found. Their father also had this condition. DISCUSSION: Prenatal diagnosis through genetic testing allows for informed decisions and care planning for the newborn, thus reducing delayed diagnosis and treatment, and minimizing long-term complications. Mutations such as the RET gene variant highlight the importance of the genetic approach in understanding and managing HD.

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INTRODUCCION: La enfermedad de Hirschsprung (EH) se caracteriza por la ausencia de células ganglionares en los plexos submucoso y mientérico del intestino grueso, resultante de deficiencias en la migración y diferenciación de las células de la cresta neural entérica durante la embriogénesis. Es una condición multifactorial, con más de 11 genes identificados en su patogénesis, incluyendo el protooncogén RET. CASO CLINICO: Se presenta el caso de dos hermanos con EH de colon total, cuyo padre también padeció la enfermedad, y en quien se encontró una variante potencialmente patogénica en el gen RET. COMENTARIOS: El diagnóstico prenatal mediante pruebas genéticas permite decisiones informadas y la planificación de cuidados para el neonato afectado, reduciendo demoras en el diagnóstico y tratamiento, y minimizando las complicaciones a largo plazo. La identificación de mutaciones como la variante en el gen RET destaca la importancia del enfoque genético en la comprensión y manejo de la EH.

Assuntos

Doença de Hirschsprung , Feminino , Humanos , Recém-Nascido , Gravidez , Doença de Hirschsprung/diagnóstico , Doença de Hirschsprung/genética , Mutação , Diagnóstico Pré-Natal , Proteínas Proto-Oncogênicas c-ret/genética

RESUMO

Genetic testing for germline RET pathogenic variants, which cause the Multiple Endocrine Neoplasia Type 2 (MEN2) syndrome, has become crucial in managing patients with medullary thyroid carcinoma (MTC). Classically, RET heterozygous missense pathogenic variants are transmitted in a Mendelian autosomal dominant pattern, of which germline/gonadal mosaicism has never been reported. We report the novel occurrence of a MEN2A patient's family in which the siblings inherited three different RET 634 genotypes: wild type (p.Cys634), p.Cys634Gly or p.Cys634Arg heterozygous pathogenic variants. We hypothesized that germline/gonadal mosaicism, derived from an inherited + early somatic mutation in the mother or a double de novo mutation during maternal embryogenesis, led to this rare event in the RET gene. Exome analysis of the proband's deceased mother's paraffin-embedded thyroid tissue confirmed the three nucleotides in the same 634 codon position. For the first time, we describe germline/gonadal mosaicism in RET, generating a second pathogenic amino acid change in the same codon causing MEN2A. Our finding shows that RET parental mosaicism, confirmed by somatic exome sequencing, might explain discrepant genotype cases in siblings with inherited cancers.

Assuntos

Mutação em Linhagem Germinativa , Mosaicismo , Neoplasia Endócrina Múltipla Tipo 2a , Linhagem , Proteínas Proto-Oncogênicas c-ret , Humanos , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Proteínas Proto-Oncogênicas c-ret/genética , Mutação em Linhagem Germinativa/genética , Feminino , Masculino , Adulto , Substituição de Aminoácidos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Genótipo , Sequenciamento do Exoma

RESUMO

RET fusions occur in 1-2% of non-small cell lung cancer. Selpercatinib and pralsetinib are selective RET inhibitors with significant improvement of outcome in patients with tumor harboring RET fusion; however, resistance mechanisms appear frequently, mainly driven by MAPK pathway bypass, secondary RET mutations, or in 5% via MET amplification. Co-inhibition of RET and MET is a compelling strategy for overcoming MET-dependent resistance to RET inhibitors and potentially other inhibitors. To our knowledge, this is the first report of a novel ISOC1-RET fusion lung cancer with a durable complete response to selpercatinib, with resistance via MET amplification, which was overcome by the successful combination of selpercatinib and capmatinib.

RESUMO

Pheochromocytoma and paragangliomas (PPGLs) are rare neuroendocrine tumors carrying 25-40% pathogenic germline gene variants (PGVs). We evaluated clinical, laboratory, and germline molecular profile of 115 patients with pathologic (14 patients were relatives from 8 different families recruited for genetic survey) confirmed PPGL followed in our institution. Patients with classic MEN2A/MEN2B phenotypes and at-risk relatives underwent direct analysis of RET proto-oncogene, and the remaining had samples submitted to complete next-generation sequencing aiming 23 PPGL-related genes: ATM, ATR, CDKN2A, EGLN1, FH, HRAS, KIF1B, KMT2D, MAX, MDH2, MERTK, MET, NF1, PIK3CA, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, and VHL. We also developed a clinical judgment score (CJS) to determine the probability of patients having a potentially hereditary disease. The resulting genetic landscape showed that 67 patients (58.3%) had variants in at least one gene: 34 (50.7%) had exclusively pathogenic or likely pathogenic variants, 13 (19.4%) had pathogenic or likely pathogenic variants and variant of undetermined significance (VUS), and 20 (29.8%) carried only VUS. PGVs were found in RET (n = 18; 38.3%), VHL (n = 10; 21.3%), SDHB and NF1 (n = 8; 17% each), and MAX, SDHD, TMEM127, and TP53 (n = 1; 2.1% each). Direct genetic testing disclosed 91.3% sensitivity, 81.2% specificity, and 76.4% and 93.3% positive predictive value (PPV) and negative predictive values (NPV), respectively. The CJS to identify patients who would not benefit from genetic testing had 75% sensitivity, 96.4% specificity, and 60% and 98.2% PPV and NPV, respectively. In summary, the landscape of PPGL germline gene variants from 115 Brazilian patients resulted in slightly higher prevalent pathogenic and likely pathogenic variants, especially in the RET gene. We suggest a CJS to identify PPGL patients who would not require initial genetic evaluation, improving test specificity and reducing costs.

RESUMO

Abstract Introduction During pregnancy, women are at an increased risk of developing iron-deficiency anemia. Objective The objective of this study was to assess the diagnostic performance of the reticulocyte hemoglobin equivalent (RET-He) in the early detection of iron-deficiency anemia in a group of pregnant women and to establish a reference range for this parameter in a group of control individuals. Method: A total of 60 patients and 130 control subjects were included in the study. Blood samples collected from the subjects were submitted to a complete blood count and a serum ferritin test and the data were analyzed by comparing the groups and ROC curves. Results The reference range found for the RET-He was between 29.75pg and 38.24pg, with a median of 35pg. The receiver operating characteristic (ROC) curve analysis for the ferritin parameter showed an area under the curve of 0.732 for the RET-He, 0.586 for hemoglobin, 0.551 for the mean corpuscular hemoglobin concentration and 0.482 for the mean corpuscular volume. Conclusion Early diagnosis of iron deficiency anemia in pregnancy is essential to prevent damage to both maternal and fetal health. The RET-He presents an excellent potential as an auxiliary tool for the diagnosis of iron deficiency in pregnant women.

Assuntos

Humanos , Feminino , Gravidez , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Gravidez , Deficiências de Ferro , Reticulócitos , Hemoglobinas , Anemia Ferropriva , Hematologia

RESUMO

INTRODUCTION: During pregnancy, women are at an increased risk of developing iron-deficiency anemia. OBJECTIVE: The objective of this study was to assess the diagnostic performance of the reticulocyte hemoglobin equivalent (RET-He) in the early detection of iron-deficiency anemia in a group of pregnant women and to establish a reference range for this parameter in a group of control individuals. METHOD: A total of 60 patients and 130 control subjects were included in the study. Blood samples collected from the subjects were submitted to a complete blood count and a serum ferritin test and the data were analyzed by comparing the groups and ROC curves. RESULTS: The reference range found for the RET-He was between 29.75pg and 38.24pg, with a median of 35pg. The receiver operating characteristic (ROC) curve analysis for the ferritin parameter showed an area under the curve of 0.732 for the RET-He, 0.586 for hemoglobin, 0.551 for the mean corpuscular hemoglobin concentration and 0.482 for the mean corpuscular volume. CONCLUSION: Early diagnosis of iron deficiency anemia in pregnancy is essential to prevent damage to both maternal and fetal health. The RET-He presents an excellent potential as an auxiliary tool for the diagnosis of iron deficiency in pregnant women.

RESUMO

Scientist-teacher partnerships are highly beneficial to K-12 STEM education. While much is known about the benefits for teachers in these partnerships, the corresponding benefits for scientists are less well known. With emphasis on the scientists' perspective, here we describe our NSF RET (Research Experiences for Teachers) project consisting of five successive cohorts from 2012 to 2016. Coincident with a "once-in-a-century" expansion of the Panama Canal, the science research focused on the paleontology, evolutionary biology, and geology of this region to better understand the ancient Neotropical biota related to the Great American Biotic Interchange (GABI). In the field, scientists and teachers worked together collecting fossils and geological samples. Back in the K-12 classrooms, lesson plans related to their experiences were implemented and the teachers hosted scientist role-model visits. More than 30 scientists and 44 teachers participated in this Panama "GABI RET" project. Using a new validated survey developed during this project and focus groups, we explored the impact of this project, and in particular the perceived benefits accrued by the scientists. Our study confirmed that scientists felt they improved their communication skills, had a better appreciation for the K-12 teaching professions, greatly enjoyed working with the teachers, considered them colleagues, and many wanted to continue K-12 outreach as part of their careers. Overall, scientists perceived that they greatly benefited from these partnerships. In addition to describing their activities, they had numerous recommendations for similar partnerships in the future. For example, these include: (1) having more teachers participate in multiple cohorts, (2) continued opportunities for teachers to be involved in professional meetings, (3) ongoing webinars and face-to-face engagement, and (4) more diversity of racial and ethnic backgrounds, subjects taught, and regions represented. Although this case study was focused on the GABI RET, our results also potentially inform other projects that involve scientists' education and outreach activities. Supplementary Information: The online version contains supplementary material available at 10.1186/s12052-022-00177-z.

RESUMO

Precision medicine is a reality in some diseases; it supports the development of accurate and specific diagnostic methods, new drugs and molecules. Our research team in Mexico, made up of clinical and biomedical researchers, has been performing free RET gene mutational diagnosis for medullary thyroid cancer and multiple endocrine neoplasia (MEN) 2 and 3 for 20 years. RET pathogenic variants in the Mexican population are consistent with reported data: most common mutations are 634/NEM2 and 918/NEM3. Currently, new nanobiotechnology methods are being developed for this type of determination in order to obtain faster, simpler, more sensitive and specific results applicable in all types of laboratories.

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La medicina de precisión en algunas enfermedades es una realidad; respalda el desarrollo de métodos diagnósticos certeros y específicos, de nuevas drogas y moléculas. Nuestro equipo de investigación en México, conformado por investigadores clínicos y biomédicos, desde hace 20 años realiza de forma gratuita el diagnóstico mutacional del gen RET y su relación con el cáncer medular de tiroides y la neoplasia endocrina múltiple (NEM) 2 y 3. Las variantes patogénicas de RET en la población mexicana coinciden con los datos reportados: la mayoría con 634/NEM2 y 918/NEM3. Actualmente se están desarrollando nuevos métodos de nanobiotecnología para este tipo de determinaciones, de tal forma que puedan obtenerse resultados más rápidos, simples, sensibles y específicos aplicables en todo tipo de laboratorio.

Assuntos

Carcinoma Medular , Neoplasia Endócrina Múltipla Tipo 2a , Neoplasias da Glândula Tireoide , Carcinoma Medular/genética , Humanos , México , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Medicina de Precisão , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/patologia

RESUMO

Resumen La medicina de precisión en algunas enfermedades es una realidad; respalda el desarrollo de métodos diagnósticos certeros y específicos, de nuevas drogas y moléculas. Nuestro equipo de investigación en México, conformado por investigadores clínicos y biomédicos, desde hace 20 años realiza de forma gratuita el diagnóstico mutacional del gen RET y su relación con el cáncer medular de tiroides y la neoplasia endocrina múltiple (NEM) 2 y 3. Las variantes patogénicas de RET en la población mexicana coinciden con los datos reportados: la mayoría con 634/NEM2 y 918/NEM3. Actualmente se están desarrollando nuevos métodos de nanobiotecnología para este tipo de determinaciones, de tal forma que puedan obtenerse resultados más rápidos, simples, sensibles y específicos aplicables en todo tipo de laboratorio.

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Abstract Precision medicine is a reality in some diseases; it supports the development of accurate and specific diagnostic methods, new drugs and molecules. Our research team in Mexico, made up of clinical and biomedical researchers, has been performing free RET gene mutational diagnosis for medullary thyroid cancer and multiple endocrine neoplasia (MEN) 2 and 3 for 20 years. RET pathogenic variants in the Mexican population are consistent with reported data: most common mutations are 634/NEM2 and 918/NEM3. Currently, new nanobiotechnology methods are being developed for this type of determination in order to obtain faster, simpler, more sensitive and specific results applicable in all types of laboratories.

RESUMO

PURPOSE: Breast cancer (BC) is considered a heterogeneous disease composed of distinct subtypes with diverse clinical outcomes. Luminal subtype tumors have the best prognosis, and patients benefit from endocrine therapy. However, resistance to endocrine therapies in BC is an obstacle to successful treatment, and novel biomarkers are needed to understand and overcome this mechanism. The RET, BCAR1, and BCAR3 genes may be associated with BC progression and endocrine resistance. METHODS: Aiming to evaluate the expression profile and prognostic value of RET, BCAR1, and BCAR3, we performed immunohistochemistry on tissue microarrays (TMAs) containing a cohort of 361 Luminal subtype BC. RESULTS: Low expression levels of these three proteins were predominantly observed. BCAR1 expression was correlated with nuclear grade (p = 0.057), and BCAR3 expression was correlated with lymph node status (p = 0.011) and response to hormonal therapy (p = 0.021). Further, low expression of either BCAR1 or BCAR3 was significantly associated with poor prognosis (p = 0.005; p = 0.042). Pairwise analysis showed that patients with tumors with low BCAR1/low BCAR3 expression had a poorer overall survival (p = 0.013), and the low BCAR3 expression had the worst prognosis with RET high expression stratifying these patients into two different groups. Regarding the response to hormonal therapy, non-responder patients presented lower expression of RET in comparison to the responder group (p = 0.035). Additionally, the low BCAR1 expression patients had poorer outcomes than BCAR1 high (p = 0.015). CONCLUSION: Our findings suggest RET, BCAR1, and BCAR3 as potential candidate markers for endocrine therapy resistance in Luminal BC.

Assuntos

Neoplasias da Mama , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Proteína Substrato Associada a Crk , Feminino , Fatores de Troca do Nucleotídeo Guanina , Humanos , Imuno-Histoquímica , Prognóstico , Proteínas Proto-Oncogênicas c-ret

RESUMO

RET is a receptor tyrosine kinase with oncogenic potential in the mammary epithelium. Several receptors with oncogenic activity in the breast are known to participate in specific developmental stages. We found that RET is differentially expressed during mouse mammary gland development: RET is present in lactation and its expression dramatically decreases in involution, the period during which the lactating gland returns to a quiescent state after weaning. Based on epidemiological and pre-clinical findings, involution has been described as tumor promoting. Using the Ret/MTB doxycycline-inducible mouse transgenic system, we show that sustained expression of RET in the mammary epithelium during the post-lactation transition to involution is accompanied by alterations in tissue remodeling and an enhancement of cancer potential. Following constitutive Ret expression, we observed a significant increase in neoplastic lesions in the post-involuting versus the virgin mammary gland. Furthermore, we show that abnormal RET overexpression during lactation promotes factors that prime involution, including premature activation of Stat3 signaling and, using RNA sequencing, an acute-phase inflammatory signature. Our results demonstrate that RET overexpression negatively affects the normal post-lactation transition.

Assuntos

Glândulas Mamárias Humanas , Neoplasias , Animais , Feminino , Humanos , Lactação/fisiologia , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Glândulas Mamárias Humanas/metabolismo , Camundongos , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Fator de Transcrição STAT3/metabolismo

Assuntos

Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/fisiopatologia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-ret , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Feminino , Humanos , Neoplasias Meníngeas , Pessoa de Meia-Idade

RESUMO

Negative feedback loops represent a regulatory mechanism that guarantees that signaling thresholds are compatible with a physiological response. Previously, we established that Lrig1 acts through this mechanism to inhibit Ret activity. However, it is unclear whether other Lrig family members play similar roles. Here, we show that Lrig1 and Lrig3 are co-expressed in Ret-positive mouse dorsal root ganglion (DRG) neurons. Lrig3, like Lrig1, interacts with Ret and inhibits GDNF/Ret signaling. Treatment of DRG neurons with GDNF ligands induces a significant increase in the expression of Lrig1 and Lrig3. Our findings show that, whereas a single deletion of either Lrig1 or Lrig3 fails to promote Ret-mediated axonal growth, haploinsufficiency of Lrig1 in Lrig3 mutants significantly potentiates Ret signaling and axonal growth of DRG neurons in response to GDNF ligands. We observe that Lrig1 and Lrig3 act redundantly to ensure proper cutaneous innervation of nonpeptidergic axons and behavioral sensitivity to cold, which correlates with a significant increase in the expression of the cold-responsive channel TrpA1. Together, our findings provide insights into the in vivo functions through which Lrig genes control morphology, connectivity and function in sensory neurons.

Assuntos

Axônios/metabolismo , Epiderme/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais/genética , Animais , Animais Recém-Nascidos , Linhagem Celular Transformada , Gânglios Espinais/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Células HEK293 , Humanos , Ligantes , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Neurônios Motores/metabolismo , Proteínas do Tecido Nervoso/genética , Crescimento Neuronal/genética , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transfecção

RESUMO

OBJECTIVE: In pheochromocytomas, accelerated catecholamine production can cause secondary diabetes. The gene responsible for multiple endocrine neoplasia type 2 (MEN2)-related pheochromocytomas is the RET proto-oncogene. The objective of this report is to describe a unique case of surgical remission of misdiagnosed type 2 diabetes mellitus (T2DM) in a woman with bilateral pheochromocytoma and RET proto-oncogene mutation. METHODS: Clinical examination, urinary metanephrine level, triple-phase abdominal computed tomography (CT) with adrenal protocol, positron emission tomography with 18F-fluorodeoxyglucose integrated with CT, surgical pathology, and genetic testing were performed. RESULTS: A 46-year-old woman with a 5-year history of apparent T2DM complicated by neuropathy, without a contributory family history, presented with occasional headaches, weight loss, and abdominal pain. A 24-hour urinary metanephrine of 5 mg (reference range, 0.05-1 mg) was found. Abdominal CT showed bilateral adrenal masses with <60% washout. Positron emission tomography with 18F-fluorodeoxyglucose integrated with CT showed a left solid-cystic lesion with low metabolic activity and a right nodular lesion with a higher metabolic activity, which was conclusive of bilateral pheochromocytoma. The remission of diabetes was achieved 1 year after a bilateral adrenalectomy. In addition, a multinodular goiter was found, and a fine-needle aspiration biopsy confirmed that it was a medullary thyroid carcinoma. A heterozygous pathogenic variant of the RET proto-oncogene was found and MEN2A was confirmed. CONCLUSION: This is the first report of a patient with a RET proto-oncogene mutation experiencing remission of diabetes after surgical resection of bilateral pheochromocytomas. Timely recognition and treatment of the underlying condition are important to potentially achieve diabetes remission and prevent its long-term complications.