Advances in Melanoma: From Genetic Insights to Therapeutic Innovations.

Advances in melanoma research have unveiled critical insights into its genetic and molecular landscape, leading to significant therapeutic innovations. This review explores the intricate interplay between genetic alterations, such as mutations in BRAF, NRAS, and KIT, and melanoma pathogenesis. The MAPK and PI3K/Akt/mTOR signaling pathways are highlighted for their roles in tumor growth and resistance mechanisms. Additionally, this review delves into the impact of epigenetic modifications, including DNA methylation and histone changes, on melanoma progression. The tumor microenvironment, characterized by immune cells, stromal cells, and soluble factors, plays a pivotal role in modulating tumor behavior and treatment responses. Emerging technologies like single-cell sequencing, CRISPR-Cas9, and AI-driven diagnostics are transforming melanoma research, offering precise and personalized approaches to treatment. Immunotherapy, particularly immune checkpoint inhibitors and personalized mRNA vaccines, has revolutionized melanoma therapy by enhancing the body's immune response. Despite these advances, resistance mechanisms remain a challenge, underscoring the need for combined therapies and ongoing research to achieve durable therapeutic responses. This comprehensive overview aims to highlight the current state of melanoma research and the transformative impacts of these advancements on clinical practice.

Hereditary angioedema classification: Expanding knowledge by genotyping and endotyping.

Hereditary angioedema (HAE) encompasses a group of diseases characterized by recurrent, genetically mediated angioedema associated with increased vascular permeability primarily due to bradykinin. The disease poses diagnostic challenges, leading to underdiagnosis and delayed therapy. Severe manifestations include laryngeal and intestinal angioedema, contributing to significant morbidity and mortality. If left undiagnosed, the estimated mortality rate of the disease ranges from 25% to 40% due to asphyxiation caused by laryngeal angioedema. There is a pressing need to enhance awareness of hereditary angioedema and its warning signs. The acronym "H4AE" may facilitate the memorization of these signs. This study comprehensively reviews clinical, laboratory, and physiopathological features of documented HAE subtypes. The study advocates for an improved HAE classification based on endotypes, building on the knowledge of angioedema pathophysiology. The proposed endotype classification of HAE offers a clear and applicable framework, encouraging advancements in disease understanding and classification.

CARD9 mutations in patients with fungal infections: An update from the last 5 years.

BACKGROUND: Autosomal recessive deficiency in the caspase recruitment domain-containing protein 9 (CARD9) is a congenital immunological condition that leads to susceptibility to mucocutaneous and invasive fungal infections. There is growing incidence of fungal infections in patients with CARD9 deficiency, a phenomenon that is increasingly recognised. OBJECTIVES: This study aimed to assess the frequency, geographic distribution and nature of mutations in patients with CARD9 deficiency, based on published papers in the literature until March 2023. METHODS: We swiftly conducted a study to pinpoint every documented instance of fungal infections arising from CARD9 deficiency. We selected case reports from the databases of PubMed, Embase, Scopus and Google Scholar spanning the period from October 2009 to March 2023. RESULTS: We analysed 90 cases of fungal infections and identified 32 mutations in the CARD9 gene. Notably, the homozygous (HMZ) p.Q295X (c.883C > T) mutation was associated with an increased risk of candidiasis. In contrast, the HMZ p.Q289X (c.865C > T) mutation is linked to a higher risk of dermatophytosis. We observed differences in the geographical distribution of these mutations. The primary mutations found in African patients differ from those in Asian patients. Specifically, Asian patients exhibit a broader spectrum of CARD9 mutations than African patients. CONCLUSIONS: The diversity of mutations observed in the 90 cases revealed 32 distinct variations, emphasising the unique genetic alterations in the CARD9 gene associated with specific geographical areas and the corresponding prevalence of fungal infections.

The Molecular Pathology of Odontogenic Tumors: Expanding the Spectrum of MAPK Pathway Driven Tumors.

Odontogenic tumors comprise a heterogeneous group of lesions that arise from the odontogenic apparatus and their remnants. Although the etiopathogenesis of most odontogenic tumors remains unclear, there have been some advances, recently, in the understanding of the genetic basis of specific odontogenic tumors. The mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) pathway is intimately involved in the regulation of important cellular functions, and it is commonly deregulated in several human neoplasms. Molecular analysis performed by different techniques, including direct sequencing, next-generation sequencing, and allele-specific qPCR, have uncovered mutations in genes related to the oncogenic MAPK/ERK signaling pathway in odontogenic tumors. Genetic mutations in this pathway genes have been reported in epithelial and mixed odontogenic tumors, in addition to odontogenic carcinomas and sarcomas. Notably, B-Raf proto-oncogene serine/threonine kinase (BRAF) and KRAS proto-oncogene GTPase (KRAS) pathogenic mutations have been reported in a high proportion of ameloblastomas and adenomatoid odontogenic tumors, respectively. In line with the reports about other neoplasms that harbor a malignant counterpart, the frequency of BRAF p.V600E mutation is higher in ameloblastoma (64% in conventional, 81% in unicystic, and 63% in peripheral) than in ameloblastic carcinoma (35%). The objective of this study was to review MAPK/ERK genetic mutations in benign and malignant odontogenic tumors. Additionally, such genetic alterations were discussed in the context of tumorigenesis, clinical behavior, classification, and future perspectives regarding therapeutic approaches.

[Invasive candidiasis: A view to central nervous system infection]. / Candidiasis invasora: un enfoque a la infección en el sistema nervioso central.

Candidemia is the most frequent invasive mycosis in hospitalized patients worldwide. Fungal infection in central nervous system is a life-threatening complication which aggravates patients' prognosis. This article summarizes relevant aspects on the clinical characteristics of this pathology, mechanisms of fungus invasion, local immune response to Candida albicans and the impact of genetic defects on innate immune receptors that increase susceptibility to the acquisition of this form of mycosis.

Mutations in renal cell carcinoma.

Renal cell carcinoma (RCC) is a commonly diagnosed and histologically diverse urologic malignancy. Clear cell RCC (ccRCC) is by far the most common, followed by the papillary and chromophobe subtypes. Sarcomatoid differentiation is a morphologic change that can be seen in all subtypes that typically portends a poor prognosis. In the past, treatment options for RCC were limited to cytokine-based therapy with a high-toxicity profile and low response rate. An increased understanding of the molecular basis of RCC has led to substantial improvement in treatment options in the form of targeted therapy and immunotherapy. A significant early discovery in RCC was frequent inactivation of the Von Hippel Lindau gene in ccRCC, which ultimately led to the development of vascular endothelial growth factor and mammalian target of rapamycin inhibitors. Further genomic sequencing of ccRCC tumors has identified other common mutations including BAP-1, PBRM1, SETD2, and PIK3CA. Many recent studies have explored how these mutations can affect prognosis and response to treatment. Likewise, papillary RCC has also been studied at the molecular level, which has shown a high level of mutations in the MET gene; early clinical data suggest the utility of MET targeted therapy. Finally, regarding the rarer sarcomatoid tumors, mutations in TP53 and NF2 may be important to their development. As we continue to learn more about what drives RCC at the molecular level, treatment options for RCC patients are diversifying.

Incidencia de mutaciones genéticas en pacientes con cáncer de mama y ovario con patrón de origen hereditario / Incidence of genetic mutations in patients with breast cancer and ovarian cancer with hereditary pattern

Resumen OBJETIVO: Determinar las mutaciones genéticas en el cáncer de mama de patrón hereditario y demostrar si existe alguna asociación significativa entre las más comunes en población mexicana y el riesgo de padecerlo. MATERIALES Y MÉTODOS: Estudio transversal y observacional efectuado en el Hospital Ángeles México en coordinación con el Instituto Nacional de Medicina Genómica. Criterios de inclusión: pacientes con cáncer de mama y uno o más familiares de primer grado afectados por esta enfermedad y pacientes con cáncer de ovario. Criterios de exclusión: pacientes sin antecedentes de cáncer de mama ni ovario, o con algún familiar en el protocolo. Se empleó la técnica de rearreglos en placas RT2 Profiler para Master-Mix Quantinova probe PCR kit. Para el análisis estadístico se utilizó el programa SPSS versión 22 y Epi Info versión 7. RESULTADOS: Se estudiaron 39 pacientes con edad promedio de 53.2 ± 12.1 años. Los receptores de progesterona y estrógeno no mostraron diferencia entre grupos. Hubo mayor tendencia para BRCA1. Al estudiar las mutaciones con significación estadística, en las que sobresalieron los casos de BRCA2 versus sin significación y los casos negativos, no hubo diferencia estadística significativa, pero con una tendencia a mayor frecuencia de BCRA1. Al evaluar las estirpes de cáncer de mama y los grados nucleares comparados por edad, los tres grupos de grado nuclear comparados por edad mostraron diferencias. CONCLUSIÓN: Los datos obtenidos muestran que en la población mexicana el gen BRCA2 es el de mayor incidencia de cáncer hereditario, en edad de aparición más temprana y mayor grado nuclear al momento del diagnóstico.

Abstract OBJECTIVE: To determine the genetic mutations in hereditary pattern breast cancer and demonstrate whether there is a significant association between the most common in the Mexican population and the risk of suffering it. MATERIALS AND METHODS: Cross-sectional and observational study conducted at the Hospital Angeles México in coordination with the National Institute of Genomic Medicine. Inclusion criteria: patients with breast cancer and one or more first-degree relatives affected by this disease and patients with ovarian cancer. Exclusion criteria: patients without a history of breast or ovarian cancer, or with a family member in the protocol. The RT2 Profiler plate rearrangement technique was used for Master-Mix Quantinova probe PCR kit. The SPSS version 22 program and Epi Info version 7 were used for the statistical analysis. RESULTS: 39 patients with an average age of 53.2 ± 12.1 years were studied. Progesterone and estrogen receptors showed no difference between groups. There was a greater trend for BRCA1. When studying the mutations with statistical significance, in which the cases of BRCA2 versus without significance and the negative cases stood out, there was no significant statistical difference, but with a tendency to higher frequency of BCRA1. When evaluating breast cancer lines and nuclear grades compared by age, the three nuclear grade groups compared by age showed differences. CONCLUSION: The data obtained show that in the Mexican population the BRCA2 gene has a higher incidence in hereditary cancer, at an age of earlier onset and greater nuclear grade at the time of diagnosis.

Avanços na etiologia, no diagnóstico e no tratamento da puberdade precoce central / Advances in the etiology, diagnosis and treatment of central precocious puberty

O início da puberdade caracteriza-se pelo aumento de amplitude e frequência dos pulsos do hormônio secretor de gonadotrofinas (GnRH) após um período de relativa supressão hormonal durante a infância. A reemergência da secreção pulsátil do GnRH resulta em aumento na secreção de gonadotrofinas, hormônio luteinizante (LH) e folículo estimulante (FSH), pela hipófise anterior e consequente ativação gonadal. A ativação prematura do eixo hipotálamo-hipófise-gonadal resulta em puberdade precoce dependente de gonadotrofinas, também conhecida como puberdade precoce central (PPC), e se caracteriza pelo desenvolvimento dos caracteres sexuais secundários antes dos 8 anos nas meninas e 9 anos nos meninos. O início do desenvolvimento puberal provém da interação complexa de fatores genéticos, nutricionais, ambientais e socioeconômicos. O diagnóstico clínico da PPC baseia-se em reconhecimento de desenvolvimento puberal progressivo, concentrações púberes de LH em condição basal e/ou após estímulo com GnRH e avanço de idade óssea. A ressonância magnética de encéfalo é útil no estabelecimento de diagnóstico diferencial entre as formas orgânica ou idiopática. Os análogos de GnRH de ação prolongada representam o tratamento de escolha da PPC. O componente genético da PPC foi recentemente fortalecido pela evidência de mutações no gene MKRN3, localizado no braço longo do cromossomo 15, em crianças com PPC familial. Nessa revisão, dados clínicos e terapêuticos da PPC serão amplamente discutidos, visando à atualização e à conduta criteriosa dessa condição clínica de grande relevância na endocrinologia pediátrica.

The onset of puberty is first detected as an increase in the amplitude and frequency of pulses of gonadotropin-releasing hormone (GnRH) after a quiescent period during childhood. The reemergence of pulsatile GnRH secretion leads to increases in the secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) by the pituitary gland, and the consequent activation of gonadal function. Early activation of the hypothalamic–pituitary–gonadal axis results in gonadotropin-dependent precocious puberty, also known as central precocious puberty (CPP), which is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Pubertal timing is influenced by complex interactions among genetic, nutritional, environmental, and socioeconomic factors. CPP is diagnosed on the basis of clinical signs of progressive pubertal development before the age of 8 years in girls and 9 years in boys, pubertal basal and/or GnRH-stimulated LH levels, and advanced bone age. Magnetic resonance imaging of the central nervous system is essential for establishing the CPP form as organic or idiopathic. Depot GnRH-analogues represent the first-line of therapy in CPP. Very recently, the genetic component of CPP was demonstrated by the evidence that the deficiency of the MKRN3 gene, located on long arm of chromosome 15, causes familial CPP in humans. In this current review, clinical and therapeutic aspects of the CPP will be discussed, contributing to adequate diagnosis and criterious approach of this relevant condition of pediatric endocrinology.

Cáncer de mama asociado a mutaciones genéticas de los BRCA 1 y 2 / Breast cancer associated to BRCA 1 and 2 genetic mutations

Entre el 5 al 10 % de los cánceres de ovario y mama son atribuidos a una transmisión autosómica dominante de mutaciones heredadas en los genes BRCA 1 y BRCA 2. Estos explican el 90 % y el 50 % de los cánceres hereditarios de ovario y mama, respectivamente. Las mujeres que heredan la mutación en el gen BRCA tienen mayor riesgo de cáncer de mama, de ovario y los varones poseedores de dicho gen tienen un riesgo de cáncer de próstata. Las mujeres con la mutación en el gen BRCA 2 también tienen riesgo (aunque menor) de presentar cáncer de mama y de ovario, y en varones hay un riesgo de cáncer de mama. Sin embargo, hay otros síndromes que explican el cáncer hereditario de mama y ovario y otros genes que aún están por descubrirse. Entre estos están el Lynch II, el síndrome Li-Fraumeni, el síndrome de ataxia – telangiectasia, el síndrome de Cowden y el síndrome de Bloom. En la actualidad es posible ofrecer la identificación de estas mutaciones con base en el DNA y en una historia familiar completa, pero la utilidad de la predicción de las pruebas genéticas requiere de una adecuada asesoría para la interpretación de sus resultados.

Between 5 and 10 % of breast and ovarian cancers can be traced to an autosomal dominant mode of inheritance of hereditary mutations in a pair of genes known as BRCA 1 and BRCA 2. They explain 90 % and 50 % of hereditary breast and ovarian cancer, respectively . Women carrying a mutation in the BRCA 1 gene, have a life risk for developing breast cancer and for ovarian cancer, a higher risk of colon cancer and men have a high risk of prostatic cancer. Women having the BRCA 2 gene mutation also have the same risk to develop breast cancer but the ovarian cancer is lower (10 % at 70 years) and is characterized for a risk of 6 % of breast cancer in men. Besides there are other known causes of these hereditary syndromes, other implicated genes still to be discovered. The more renoume syndromes are Lynch II, Li-Fraumeni, Ataxia – Telangiectasia, Cowden and Bloom syndromes, etc. Currently, it is possible to convey detection of carriers of these mutations based on DNA and a complete family history, but the useful prediction of genetic tests requires a formal counseling to interpret the results.

Anomalías del desarrollo del segmento anterior / Anomalies in the development of the anterior segment

Las disgenesias del segmento anterior forman parte de un grupo de anomalías del desarrollo ocular que comparten características clínicas y se acompañan en su gran mayoría de glaucoma. En esta revisión se empleó la clasificación usada por Taylor, que las divide en anomalías originadas en las células de la cresta neural, anomalías ectodérmicas y anomalías de origen global, se describen sus características clínicas, tratamiento y alteraciones genéticas. Debido a la variabilidad de cuadros clínicos, se hace más necesaria la identificación de los genes en el desarrollo del segmento anterior que permite la clasificación de estas disgenesias, según la mutación genética subyacente.

The anterior segment dysgeneses are part of a group of anomalies of the ocular development that share clinical characteristics and are mostly accompanied by glaucoma. This article used Taylor´s classification, which divides them into anomalies originated in the the neural crest cells , ectodermic anomalies and anomalies of global origin, describing their clinical characteristics, treatment and genetic alterations. Taking into account the diversity of clinical findings, it is increasingly important to identify gens in the development of the anterior segment which allow the classification of these dysgeneses according to the underlying genetic mutation.

Síndromes nefróticos congénitos y hereditarios / Congenital and heritable nephrotic syndromes

En los últimos años se han identificado muchos síndromes nefróticos familiares y esporádicos que no responden a los tratamientos habituales (esteroides e inmunosupresores), evolucionan con relativa rapidez a la insuficiencia renal crónica y se producen por mutaciones genéticas. La mayoría de los síndromes nefróticos que se trasmiten genéticamente y que pueden ser congénitos, presentarse en el primer año de la vida, o en el niño mayor, son atribuidos a mutaciones en los genes NPHS1, NPHS2, WT1 y LAMB2. Otros síndromes nefróticos producidos por mutaciones genéticas pueden no manifestarse hasta la adultez. El objetivo fundamental de esta revisión fue llamar la atención sobre los síndromes nefróticos producidos por mutaciones genéticas en los que no sólo no se obtienen resultados con los tratamientos inmunosupresores, si no en los que dichos tratamientos pueden ser perjudiciales para el paciente(AU)

In past years many familial and sporadic nephrotic syndromes refractory to usual treatments (steroids and immunosuppressives), evolve quickly to a chronic renal failure produced by genetic mutations. Most of nephrotic syndromes genetically transmitted and that may be congenital, present in the first year of life or in the older child, are attributable to NPHS1, NPHS2, WT1 and KLAMB2 gen mutations. Other nephrotic syndromes produced by genetic mutations may not appear until adulthood. The main objective of present review was to alert on the nephrotic syndromes produced by genetic mutations without response to immunosuppressive treatments, but on those in which such treatment may be dangerous for patient(AU)

Síndromes nefróticos congénitos y hereditarios / Congenital and heritable nephrotic syndromes

En los últimos años se han identificado muchos síndromes nefróticos familiares y esporádicos que no responden a los tratamientos habituales (esteroides e inmunosupresores), evolucionan con relativa rapidez a la insuficiencia renal crónica y se producen por mutaciones genéticas. La mayoría de los síndromes nefróticos que se trasmiten genéticamente y que pueden ser congénitos, presentarse en el primer año de la vida, o en el niño mayor, son atribuidos a mutaciones en los genes NPHS1, NPHS2, WT1 y LAMB2. Otros síndromes nefróticos producidos por mutaciones genéticas pueden no manifestarse hasta la adultez. El objetivo fundamental de esta revisión fue llamar la atención sobre los síndromes nefróticos producidos por mutaciones genéticas en los que no sólo no se obtienen resultados con los tratamientos inmunosupresores, si no en los que dichos tratamientos pueden ser perjudiciales para el paciente

In past years many familial and sporadic nephrotic syndromes refractory to usual treatments (steroids and immunosuppressives), evolve quickly to a chronic renal failure produced by genetic mutations. Most of nephrotic syndromes genetically transmitted and that may be congenital, present in the first year of life or in the older child, are attributable to NPHS1, NPHS2, WT1 and KLAMB2 gen mutations. Other nephrotic syndromes produced by genetic mutations may not appear until adulthood. The main objective of present review was to alert on the nephrotic syndromes produced by genetic mutations without response to immunosuppressive treatments, but on those in which such treatment may be dangerous for patient