New update to the guidelines on testing predictive biomarkers in non-small-cell lung cancer: a National Consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology

Non-small cell lung cancer (NSCLC) presents the greatest number of identified therapeutic targets, some of which have therapeutic utility. Currently, detecting EGFR, BRAF, KRAS and MET mutations, ALK, ROS1, NTRK and RET translocations, and PD-L1 expression in these patients is considered essential. The use of next-generation sequencing facilitates precise molecular diagnosis and allows the detection of other emerging mutations, such as the HER2 mutation and predictive biomarkers for immunotherapy responses. In this consensus, a group of experts in the diagnosis and treatment of NSCLC selected by the Spanish Society of Pathology and the Spanish Society of Medical Oncology have evaluated currently available information and propose a series of recommendations to optimize the detection and use of biomarkers in daily clinical practice (AU)

The prognostic and predictive values of differential expression of exosomal receptor tyrosine kinases and associated with the PI3K/AKT/mTOR signaling in breast cancer patients undergoing neoadjuvant chemotherapy

Purpose Cancer cell-derived exosomes are the mediator of the tumor microenvironment and the molecular content of exosomes presents a promising prognostic or predictive marker in tumor progression and the treatment response of cancer patients. The aim of this study was to identify the expression levels of receptor tyrosine kinases (RTKs) and AKT1 and mTOR before and after neoadjuvant chemotherapy (NACT) in the exosomes of BC patients compared with healthy females. Methods After isolating exosomes in the serum of 25 BC patients and characterization by flow cytometry, the mRNA levels of FGFR2, FGFR3, PDGFRB, AKT1 and mTOR in the exosomes were analyzed by RT-PCR. Results Our preliminary findings showed that FGFR2, PDGFRB, AKT1 and mTOR levels were significantly upregulated in BC patients before NACT compared with the healthy group (p < 0.05). Furthermore, the mRNA levels PDGFRB and AKT1 were significantly down-regulated after NACT compared with control. PDGFRB expression level could predict pathological non-response and significantly correlated with tumor size after NACT. Conclusion Therefore, especially FGFR2, PDGFRB and AKT1 could be a therapeutic target as a prognostic marker, whereas PDGFRB may be a promising predictive indicator of therapy response in BC patients. However, the prognostic or predictive role of RTKs and PI3K/AKT/mTOR signaling in the exosomes should be further investigated in a large patient population (AU)

IFN-γ affects pancreatic cancer properties by MACC1-AS1/MACC1 axis via AKT/mTOR signaling pathway

BackgroundMetastasis-related in colon cancer 1 (MACC1) is highly expressed in a variety of solid tumours, but its role in pancreatic cancer (PC) remains unknown. Interferon gamma (IFN-γ) affecting MACC1 expression was explored as the potential mechanism following its intervention.MethodsExpressions of MACC1 treated with IFN-γ gradient were confirmed by quantitative real-time PCR (qRT-PCR) and western blot (WB). Proliferation, migration, and invasion abilities of PC cells treated with IFN-γ were analysed by CCK8, EDU, colony formation, Transwell (with or without matrix gel) and wound-healing assays. Expression of antisense long non-coding RNA of MACC1, MACC1-AS1, and proteins of AKT/mTOR pathway, (pho-)AKT, and (pho-)mTOR was also assessed by qRT-PCR and WB. SiRNA kit and lentiviral fluid were conducted for transient expression of MACC1 and stable expression of MACC1-AS1, respectively. Rescue assays of cells overexpressing MACC1-AS1 and of cells silencing MACC1 were performed and cellular properties and proteins were assessed by the above-mentioned assays as well.ResultsIFN-γ inhibited MACC1 expression in a time- and dose-dependent manner; 100 ng/mL IFN-γ generally caused downregulation of most significant (p ≤ 0.05). In vitro experiments revealed that IFN-γ decreased cellular proliferation, migration, and invasion abilities and downregulated the expression of pho-AKT and pho-mTOR (p ≤ 0.05). Conversely, overexpression of MACC1-AS1 upregulated pho-AKT and pho-mTOR proteins, and reversed cellular properties (p ≤ 0.05). Rescue assays alleviated the above changes of pho-AKT/ mTOR and cellular properties.ConclusionIFN-γ affected PC properties by MACC1-AS1/MACC1 axis via AKT/mTOR signaling pathway, which provides novel insight for candidate targets for treating PC.

Ubiquitin-specific protease 8 inhibits lipopolysaccharide-triggered pyroptosis of human bronchial epithelial cells by regulating PI3K/AKT and NF-kB pathways

Asthma, characterized by dysfunction of airway epithelial cells, is regarded as a chronic inflammatory disorder in the airway. Ubiquitin-specific protease 8 (USP8) belongs to ubiquitin proteasome system and mediates the stability of E3 ligases. The anti-inflammatory effect of USP8 has been widely investigated in distinct diseases, while the role of USP8 in asthma remains elusive. Firstly, human bronchial epithelial cells (BEAS-2B) were treated with lipopolysaccharide, which reduced the cell viability of BEAS-2B and induced the secretion of lactate dehydrogenase (LDH). Moreover, the expression of USP8 was downregulated in BEAS-2B post lipopolysaccharide treatment. Secondly, overexpression of USP8 enhanced cell viability of lipopolysaccharide-treated BEAS-2B, and reduced the LDH secretion. USP8 overexpression also attenuated lipopolysaccharide-induced upregulation of TNF-α, IL-6, and IL-1β in BEAS-2B. Thirdly, lipopolysaccharide treatment promoted the expression of NLRP3 (NLR Family Pyrin Domain Containing 3), N-terminal domain of gasdermin D (GSDMD-N), caspase-1, IL-1β, and IL-18 in BEAS-2B, which was inhibited by USP8 overexpression. Lastly, USP8 overexpression decreased the phosphorylation of NF-κB, while it increased the phosphorylation of PI3K and AKT in lipopolysaccharide-treated BEAS-2B. In conclusion, USP8 inhibited lipopolysaccharide-triggered inflammation and pyroptosis in human bronchial epithelial cells by activating PI3K/AKT signaling and inhibiting NF-κB signaling pathway (AU)

Hypoxia-mediated down-regulation of miRNAs’ biogenesis promotes tumor immune escape in bladder cancer

Background The study examines the function of hypoxia-mediated down-regulation of microRNAs (miRNAs) (mir-30c, mir-135a, and mir-27a) in the process of bladder cancer immune escape. Methods Quantitative Real-time PCR (qRT-PCR) was carried out to determine gene expression levels of Drosha and Dicer under hypoxia treatment, while western blotting and flow cytometry were used to determine protein expression. Seven reported miRNAs were identified via qRT-PCR assay. Flow cytometry detection of CD3/CD4/CD8-positive expression and statistics. Enzyme-linked immunosorbent assay (ELISA) detected cellular immune factors content. Cell apoptosis was checked via flow cytometry assay. Luciferase report assay and western blot assays were both used to verify the relationship between miRNAs and Casitas B-lineage lymphoma proto-oncogene b (Cbl-b). The animal model was established and Hematoxylin–eosin (HE) staining, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and immunohistochemistry (IHC) assays were separately used to verify the conclusions. Results The CD3 + /CD4 + expression was increased in the hypoxia group, while CD3 + /CD8 + expression, the cellular immune factors content Interleukin-2 (IL-2) and Tumor Necrosis Factor-α (TNFα) along with the cell apoptosis were suppressed. The protein expression of Cbl-b was found to be up-regulated in the hypoxia group. After constructing the overexpression/ knockdown of Cbl-b in peripheral blood mononuclear cell (PBMC), Cbl-b has been found to promote tumor immune escape in bladder cancer. Furthermore, Cbl-b had been identified as the co-targets of mir-30c, mir-135a, and mir-27a and down-regulation of miRNA biogenesis promotes Cbl-b expression and deactivating T cells in vitro/in vivo. Conclusion Hypoxia-mediated down-regulation of miRNAs’ biogenesis promotes tumor immune escape in bladder cancer, which could bring much more advance to the medical research on tumors (AU)

Long intergenic non-coding RNA-p21 is associated with poor prognosis in chronic lymphocytic leukemia

Long non-coding RNAs (LncRNAs) are RNA transcripts longer than 200 nucleotides. They are new players in transcriptional regulation and cancer research. LincRNA-p21 is a p53-regulated lncRNA involved in the p53 transcriptional network. It has an important role in regulating cellular proliferation and apoptosis. Chronic lymphocytic leukemia is derived by a typical defect in apoptosis and characterized by clonal proliferation and accumulation of mature B cells. The aim of the present study was to assess the expression pattern of the lincRNA-p21 and investigate its potential role as a new prognostic marker in CLL. Methods The study was conducted on 80 newly diagnosed CLL patients and 80 age- and sex-matched controls. The analysis of LincRNA-p21 and the p53 downstream proapoptotic target genes (MDM2, PUMA, BAX, and NOXA) was performed by real-time PCR. The cytogenetic abrasions and expression of ZAP70 and CD38 were detected by FISH and Flow cytometry, respectively. Results LincRNA-p21 was significantly downregulated in CLL patients compared to controls. The downstream proapoptotic targets were significantly downregulated in CLL patients and positively correlated with lincRNA-p21. Low expression of lincRNA-p21 was associated with poor prognostic markers (advanced stages of CLL, del 17p13, ZAP70, and CD38 expression), failure of complete remission, shorter progression free survival, and overall survival. Low lincRNA-p21 expression was independently prognostic for shorter time to treatment. Conclusion Low expression of lincRNA-p21 demarcates a more aggressive form of CLL with poor prognosis. Therefore, it could be considered as a new prognostic marker to predict disease outcome in CLL (AU)

Mutación del gen BRAF V600E en el cáncer papilar de tiroides y su efecto en la terapia con yodo radiactivo (131I) posquirúrgica: ¿deberíamos modificar nuestra estrategia terapéutica? / BRAF V600E mutation in papillary thyroid cancer and its effect on postoperative radioiodine (131I) therapy: Should we modify our therapeutic strategy?

INTRODUCCIÓN: La mutación BRAF V600E en el cáncer papilar de tiroides (CPT) parece asociarse a una resistencia al 131I. Nuestro principal objetivo fue cuantificar la respuesta al 131I tras la cirugía tanto en pacientes que presentaban la mutación (BRAF+) como en los que no presentaban el gen mutado (BRAF-). MÉTODO: Estudio prospectivo de los CPT intervenidos y tratados con 131I desde septiembre de 2015 hasta enero de 2017. VARIABLES: edad, género, estadio tumoral, histológicas, tiroglobulina antes de 131I, a las 48h y a los 6 meses; dosis absorbida y % de actividad a los 2 y a los 7días y tiempo de eliminación. RESULTADOS: Cuarenta y un pacientes y 67 restos tiroideos. El 61% eran BRAF+. En los estadios III y IV, el 80% eran BRAF+. En el vaciamiento ganglionar terapéutico, el 100% eran BRAF+. El número de ganglios fue superior en BRAF+: 3,4 vs 1,2 (p = 0,01). La variante clásica fue predominante en BRAF+ (91,7% vs 8,3%; p = 0,03). El 85,7% vs 14,3% de los BRAF+ tuvieron reacción desmoplásica (p = 0,02). Los BRAF+ presentaban menor dosis absorbida respecto a la actividad administrada (5,4 vs 20Gy/MBq; p = 0,02); menor % de actividad respecto a la unidad de masa a los 2 (0,046 vs 0,103%/g; p = 0,02) y a los 7 días (0,006 vs 0,034%/g, p = 0,04). CONCLUSIONES: La mutación del gen BRAF V600E se relaciona con una mayor resistencia al tratamiento posquirúrgico con 131I desde el inicio de la enfermedad

INTRODUCTION: The BRAF V600E mutation in papillary thyroid cancer (PTC) has been associated with resistance to 131I. Our aim was to quantify the response to 131I after surgery in patients who had the mutation (BRAF+) and those who did not have the mutated gene (BRAF-). METHOD: A prospective cohort study was designed, from September 2015 to February 2016, which included patients with PTC receiving therapy after surgical treatment. Variables were described for age, gender, histology, tumor stage, thyroglobulin values before, 48 h after and 6months after 131I; absorbed dose and % activity on days 2 and 7 and elimination time. RESULTS: 41 patients giving in total 67 thyroid remnants were included. 61% were BRAF+. In stagesiii and IV, 80% were BRAF+. In lateral resection, 100% were BRAF+. The number of nodes was higher in BRAF+: 3.4 vs 1.2 (P = .01). The classic variant was predominant in BRAF+ (91.7% vs 8.3%, P = .03). 85.7% vs 14.3% of BRAF+ had desmoplastic reaction (P = .02). The BRAF+ had a lower absorbed dose than the administered activity (5.4Gy/MBq vs 20Gy/MBq, P = .02); lower% activity with respect to the unit of mass at 2 (0.046%/g vs 0.103%/g, P = .02) and at 7days (0.006%/gr vs 0.034%/gr, P = .04) CONCLUSIONS: The mutation of the BRAF V600E gene is related with greater resistance to postoperative treatment with 131I since the onset of the disease

Biological function and mechanism of miR-33a in prostate cancer survival and metastasis: via downregulating Engrailed-2

Objective. Recent studies have identified Engrailed-2 (EN-2), a homeobox-containing transcription factor, as a candidate oncogene in prostate cancer (PC). Therapeutic targeting on EN-2, however, is limited because the mechanism underlying EN-2 overexpression in prostatic cancer cells is unknown. This study was to investigate the potential regulatory role of miR-33a on EN-2 expression and explore this signaling axis in ability of prostate cancer survival and metastasis. Methods. The relative expression of miR-33a and EN-2 in paired prostate cancer tissue and adjacent normal tissue as well as in prostate cancer cell lines, PC3 and DU145, was determined using quantitative real-time PCR or western blot, respectively. Cells survival, migration and invasion were evaluated by assays of MTT, TUNEL and Boyden chamber assays, respectively. Direct regulation of EN-2 by miR-33a was examined by luciferase reporter assay. Results. The data showed that miR-33a was upregulated and EN-2 was downregulated in both prostate cancer tissue and prostate cancer cells. miR-33a overexpression suppresses prostate cancer cell survival and metastasis. miR-33a can directly act on EN-2 expression by binding to 3′UTR of its mRNA. Also, miR-33a negatively regulated EN-2 mRNA and protein expression. In pcDNA-EN-2 and miR-33a mimic co-transfected PC3 and DU145 cells, EN-2 overexpression reverses the anti-cell survival and metastasis actions of miR-33a overexpression. The pivotal role of miR-33a in inhibiting prostate tumor growth was confirmed in xenograft models of prostate cancer. Conclusion. Our data suggest that the functional interaction of miR-33a and EN-2 is involved in tumorigenesis of prostate cancer. Also in this process EN-2 serves as a negative responder for miR-33a (AU)

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MEN 2A con doble mutación en gen RET: carcinoma medular de tiroides secretor de ACTH / MEN 2A with double mutation in RET gene: ectopic ACTH production in medullary thyroid carcinoma

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Actualización en mastocitosis. Parte 1: fisiopatología, clínica y diagnóstico / Update on Mastocytosis (Part 1): Pathophysiology, Clinical Features, and Diagnosis

Las mastocitosis constituyen un grupo heterogéneo de enfermedades caracterizadas por la proliferación clonal de mastocitos en distintos órganos, siendo la localización cutánea la más frecuente. Es «una enfermedad rara o poco frecuente», y afecta a todos los grupos de edad, si bien suele aparecer en la primera década de la vida o entre la segunda y la quinta década de la vida, con una distribución similar por sexos. En los últimos años se han realizado grandes avances en el conocimiento fisiopatogénico del trastorno: las mutaciones somáticas del gen c-kit y la presencia de alteraciones inmunofenotípicas en los mastocitos son elementos importantes en la fisiopatogenia de las mastocitosis. Las manifestaciones clínicas son variadas y las lesiones cutáneas son la clave diagnóstica en la mayoría de los pacientes

Mastocytosis is a term used to describe a heterogeneous group of disorders characterized by clonal proliferation of mast cells in various organs. The organ most often affected is the skin. Mastocytosis is a relatively rare disorder that affects both sexes equally. It can occur at any age, although it tends to appear in the first decade of life, or later, between the second and fifth decades. Our understanding of the pathophysiology of mastocytosis has improved greatly in recent years, with the discovery that somatic c-kit mutations and aberrant immunophenotypic features have an important role. The clinical manifestations of mastocytosis are diverse, and skin lesions are the key to diagnosis in most patient

Mutual interaction between BCL6 and miRNAs contributing to the pathogenesis of various cancers

MicroRNA (miRNA), a class of non-proteincoding RNAs, plays a critical role in many cellular processes, such as invasion, proliferation and migration, and also function in disease pathology. The transcription factor and proto-oncogene B cell CLL/lymphoma 6 (BCL6) is aberrantly expressed in various cancers. An increasing body of evidence has demonstrated that miRNAs and BCL6 can target one another and mutually adjust their expression which are of great importance in the pathogenesis of various cancers. In this report, we summarize the mutual interaction between miRNAs and BCL6, which have been studied in cancers, highlighting their mechanisms and potential therapeutic targets in cancers (AU)

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Demografía, características clínicas y genéticas de pacientes con carcinoma medular de tiroides en los últimos 16 años en Castilla-La Mancha / Demographic, clinical, and genetic characteristics of patients with medullary thyroid cancer in the past 16 years in Castilla-La Mancha

OBJETIVO: El carcinoma medular de tiroides es un tumor de baja prevalencia cuyo pronóstico es peor que el del cáncer diferenciado de tiroides debido su mayor agresividad. El objetivo de este trabajo es describir las características demográficas, clínicas y genéticas de los pacientes atendidos en el área sanitaria de la Comunidad de Castilla-La Mancha durante 16 años. PACIENTES Y MÉTODOS: Los datos se recogieron mediante revisión de historias clínicas. RESULTADOS: Se revisaron las historias clínicas de 58 pacientes con una edad media al diagnóstico de 51 años (intervalo de 6 a 82 años) y un 63,8% de mujeres. La prevalencia fue de 2,84 casos por 100.000 habitantes, con una gran variabilidad entre áreas (de 0 a 5,4 casos por 100.000 habitantes). Los casos familiares representaron el 34,5% del total, siendo la mutación más frecuente la C634Y. El motivo más frecuente de diagnóstico fue la palpación de un bultoma cervical (70,6%); se solicitó ecografía al diagnóstico en 56 de 58 casos, y la calcitonina en 8 de 58 casos. La multicentricidad del tumor fue descrita en el 59 y 50% de los casos de síndrome de neoplasia endocrina múltiple tipo 2A y 2B, respectivamente, y en ningún caso esporádico. El 52% de los pacientes presentaba un estadio avanzado al diagnóstico (III o IV). La mediana de seguimiento fue de 36 meses (rango intercuartílico 14-210), con la pérdida de 11 pacientes durante el seguimiento. CONCLUSIONES: El diagnóstico de carcinoma medular de tiroides en Castilla-La Mancha se basa en la ecografía cervical, pero no en la calcitonina. Existe una alta prevalencia de este carcinoma, tanto familiar como esporádico, y una importante variabilidad en el tipo de mutación del protooncogén rearranged during transfection comparadas con las del resto de la población española

OBJECTIVE: Medullary thyroid cancer is a rare tumor that is more aggressive and has a worse prognosis than differentiated thyroid cancer. The purpose of this study was to report the demographic, clinical, and genetic characteristics of patients seen in the health care system of the community of Castilla-La Mancha over a 16-year period. PATIENTS AND METHODS: Data were collected through a review of patients' medical records. RESULTS: The medical records of 58 patients (mean age at diagnosis, 51 years; range, 6-82 years; 63.8% women) were reviewed. Prevalence rate was 2.84 cases per 100,000 inhabitants, with a high variability between areas (range, 0-5.4 cases per 100,000 inhabitants). Familial cases accounted for 34.5% of all medullary thyroid cancers, and the most common mutation was C634Y. The condition was most commonly diagnosed following palpation of a cervical lump (70.6%). At diagnosis, 56 of 58 patients underwent ultrasound and 8 of 58 patients were tested for serum calcitonin. Tumor multicentricity was reported in 59 and 50% of patients with multiple endocrine neoplasia syndrome type 2A and 2B, respectively, and in no sporadic cases. Fifty-two percent of patients had an advanced stage (III or IV) at diagnosis. Median follow-up was 36 months (interquartile range, 14-210); 11 patients were lost to follow-up. CONCLUSIONS: In Castilla-La Mancha, medullary thyroid cancer is diagnosed by cervical ultrasound, rather than calcitonin assay. There is a high prevalence of both familial and sporadic medullary thyroid cancer, and a significant variability in the type of proto-oncogen rearranged during transfection mutation as compared to the rest of the Spanish population

A new era in the treatment of melanoma: from biology to clinical practice

Melanoma is the deadliest cutaneous malignancy and its incidence continues to grow. Until 2011, the treatment options for metastatic melanoma were scarce and without any overall survival benefit. The emergence of new targeted therapies for BRAF mutant melanoma (vemurafenib) and immunotherapy (ipilimumab) has changed the standard of care for this disease. The objective of the present review is to summarise the biological background of the new therapeutic approaches in melanoma, focusing on apoptosis resistance, immune modulation and angiogenesis, and the direct translation into clinical practice (AU)

Futuro de los marcadores moleculares en cáncer: hacia un tratamiento personalizado / The future of molecular markers in cancer: towards a tailored treatment

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Genética del carcinoma medular de tiroides / Genetics of medullary thyroid carcinoma

El carcinoma medular de tiroides (CMT) puede presentarse en forma esporádica o familiar, en cuyo caso se integra en la neoplasia endocrina múltiple tipo 2 (NEM 2). La NEM 2 se origina como consecuencia de mutaciones germinales en el gen RET. Este gen incluye 21 exones y codifica el receptor RET, un receptor de membrana citoplasmática con actividad tirosinacinasa. La peculiaridad de esta alteración reside en la posibilidad de establecer una relación genotipo-fenotipo. Las distintas mutaciones en los codones del gen RET dan lugar a diversos cuadros clínicos, etiquetados clásicamente como NEM 2A, NEM 2B y CMTF (CMT familiar). En los últimos años se ha añadido una nueva clasificación en función de la agresividad del comportamiento tumoral, en la que se distinguen 3 niveles de riesgo. En la presente revisión exponemos las características fisiológicas y patológicas del gen RET, la relación genotipo-fenotipo tanto clásica como por grados de agresividad, los elementos posiblemente modificadores en esa relación (polimorfismos de un único nucleótido), la actitud a adoptar ante el CMT y el tratamiento recomendado según las características genéticas (AU)

Medullary thyroid carcinoma (MTC) can be sporadic or hereditary. The hereditary form of MTC is classified as multiple endocrine neoplasia type 2 (MEN 2). MEN 2 syndromes are caused by germinal mutations in the RET proto-oncogene. The RET gene includes 21 exons and encodes a plasma membrane-bound tyrosine kinase enzyme, the RET receptor. The peculiarity of this disease lies in the possibility of establishing genotype-phenotype correlations. Distinct RET codon mutations give rise to the different MEN 2 syndromes, traditionally classified as MEN 2A, MEN 2B and familial MTC. In the last few years, a new classification has been suggested, based on biologic tumoral aggressiveness, in which RET mutations are stratified into three levels of risk. In this review, we explain the physiological and pathological features of the RET gene, genotype-phenotype correlations (both traditional and the new risk classification), the elements that may modify this relationship (such as single nucleotide polymorphisms), suggested clinical decision-making in MTC and genetically-based treatment (AU)

Molecular biology of gastric cancer

Despite its decreasing incidence overall, gastric cancer is still a challenging disease. Therapy is based mainly upon surgical resection when the tumour remains localised in the stomach. Conventional chemotherapy may play a role in treating micrometastatic disease and is effective as palliative therapy for recurrent or advanced disease. However, the knowledge of molecular pathways implicated in gastric cancer pathogenesis is still in its infancy and the contribution of molecular biology to the development of new targeted therapies in gastric cancer is far behind other more common cancers such as breast, colon or lung. This review will focus first on the difference of two well defined types of gastric cancer: intestinal and diffuse. A discussion of the cell of origin of gastric cancer with some intriguing data implicating bone marrow derived cells will follow, and a comprehensive review of different genetic alterations detected in gastric cancer, underlining those that may have clinical, therapeutic or prognostic implications (AU)

Carcinogénesis pulmonar / Pulmonary carcinogenesis

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Tiroidectomía profiláctica en pacientes pediátricos con riesgo de carcinoma medular tiroideo / Prophylactic thyroidectomy in children at risk for medullary thyroid carcinoma

El carcinoma medular de tiroides (CMT) es una rara neoplasiaen la infancia. En la actualidad el estudio molecular del proto-oncogén RET, relacionado con los síndromes de neoplasia endocrina múltiple (MEN II) y carcinoma medular familiar de tiroides (CMFT)permiten identificar pacientes con riesgo de padecer carcinoma medularde tiroides en edades precoces, antes de que se manifieste la enfermedad clínicamente. Niños con antecedentes familiares de MEN II o CMFT fueron estudiados bioquímica (test de pentagastrina) y genéticamente con el fin dedeterminar el riesgo de padecer CMT y evaluar la posibilidad de realizar tiroidectomía profiláctica (AU)

The medullary thyroid carcinoma (MTC) is a rare neoplasiaoccurring during childhood. At present time the molecular examinationof the proto-oncogen RET, related to syndromes of multipleendocrine neoplasia (MEN II) and familial medullary thyroid carcinoma(FMTC) to allows identify patients with risk of suffering of medullarythyroid carcinoma in early ages, before the disease becomes clinicallypronunced. Children with familial antecedents of MEN II orFMTC were biochemically (pentagastrin-stimulated) and geneticallystudied with the purpose of determining the risk of developing a MTCand in order to assess the possibilities of making a prophylactic thyroidectomyThe medullary thyroid carcinoma (MTC) is a rare neoplasia occurring during childhood. At present time the molecular examinationof the proto-oncogen RET, related to syndromes of multiple endocrine neoplasia (MEN II) and familial medullary thyroid carcinoma(FMTC) to allows identify patients with risk of suffering of medullary thyroid carcinoma in early ages, before the disease becomes clinically pronunced. Children with familial antecedents of MEN II orFMTC were biochemically (pentagastrin-stimulated) and genetically studied with the purpose of determining the risk of developing a MTCand in order to assess the possibilities of making a prophylactic thyroidectomy (AU)

Neoplasia endocrina múltiple: estudio genético / Multiple endocrine neoplasia: genetic approach

Las neoplasias endocrinas múltiples (MEN) son síndromes de herencia autosómica dominante caracterizados por la asociación de lesiones en distintas glándulas presentes en varios miembros de una misma familia. Las principales características de MEN tipo 1 incluyen hiperparatiroidismo primario, tumores pancreáticos y adenomas hipofisarios; con menos frecuencia pueden aparecer adenomas suprarrenales, tumores tímicos y bronquiales, lipomas y varias lesiones cutáneas. Los síndromes tipo 2 (MEN 2A y 2B, y carcinoma medular de tiroides familiar) se caracterizan por alta penetrancia de carcinoma medular de tiroides y difieren en su expresión variable de feocromocitoma, hiperparatiroidismo y otros rasgos clínicos. El gen supresor de tumores MEN1 codifica para una proteína nuclear, la menina, que interactúa con diferentes factores de transcripción. Los síndromes MEN 2 se producen por mutaciones en línea germinal en el protooncogén RET, que codifica para un receptor tirosincinasa. El estudio genético de mutaciones en estos 2 genes permite la identificación de individuos con predisposición a la enfermedad, el diagnóstico temprano y el adecuado tratamiento clínico y terapéutico (AU)

Multiple endocrine neoplasias (MEN) are inherited autosomal dominant syndromes characterized by the association of distinct glandular lesions in several members of the same kindred. The main clinical features of MEN1 include primary hyperparathyroidism, pancreatic islet cell tumors and pituitary adenomas; less common features are adrenal adenomas, thymic and bronchial carcinoid tumors, lipomas and various cutaneous lesions. The MEN2 syndromes (MEN2A, MEN2B and familial medullary thyroid carcinomas) are characterized by a high penetrance of medullary thyroid carcinoma and differ in their variable expression of pheochromocytoma, hyperparathyroidism and other clinical features. The MEN1 tumor suppressor gene encodes a nuclear protein, menin, which interacts with distinct transcription factors. The MEN2 syndromes are caused by germ-line which encodes a tyrosine kinase transmembrane receptor. Genetic testing for mutmutations of the RET proto-oncogene, ations in these two genes allows identification of individuals predisposed to the disease, and their early diagnosis, and appropriate clinical and therapeutic management (AU)

Mecanismos de activación de proto-oncogenes. Papel de la sobreexpresión génica en cáncer de mama / Proto-oncogenes activation mechanisms. Role of gene overexpression in breast cancer

Los proto-oncogenes desempeñan un papel clave en la regulación de la proliferación y diferenciación celular, junto con genes supresores, genes de reparación del ADN y genes reguladores de la apoptosis, fundamentalmente. La acumulación de sucesivas alteraciones cualitativas y/o cuantitativas de estos genes constituye la base del desarrollo del cáncer. La sobreexpresión de proto-oncogenes constituye un importante mecanismo de activación oncogénica al representar una ganancia de función y, por tanto, la estimulación de la proliferación o la supervivencia celular. La sobreexpresión génica puede estar asociada a cambios genéticos, tales como la translocación cromosómica o la amplificación génica, o a cambios epigenéticos, consistentes principalmente en alteraciones de los patrones de metilación del ADN y acetilación de las histonas. Dicha alteración es frecuente en cáncer de mama y se asocia a factores de mal pronóstico y resistencia al tratamiento. (AU)