RESUMEN

Tumors with pathogenic DICER1 mutation are rare and encompass sporadic or hereditary benign, intermediate and malignant tumors. DICER1-associated sarcomas are heterogeneous; however, the prototypical ones in the GYN-tract include embryonal rhabdomyosarcoma, adenosarcoma and moderately to poorly differentiated Sertoli-Leydig tumor. In this report, we present three unique uterine sarcomas with DICER1 mutation and remarkable diffuse round/spindle cell morphology. The tumors occurred in cervix (n = 1), and uterine corpus (n = 2). The patient ages were 30, 37 and 59 years with tumor size of 8.8, 10 and 8.6 cm, respectively. Morphologically all three tumors were characterized by distinct spindle/round cell morphology and various amounts of neuroectodermal differentiation (yolk sac-like tubules, blastomatous areas and rosette formation). Other morphologic features of DICER1-sarcoma reported in the literature including cambium layer, focal or diffuse anaplasia, solid and cystic architecture, and chondroid/osteoid areas were absent. All three sarcomas were positive for SALL4 and had variable neuroendocrine marker expression. Whole genome methylation analysis was performed on one of the uterine sarcomas, which clustered the tumor with embryonal tumor with multilayered rosettes. Follow up information was available on all three cases. Two patients were alive with no evidence of disease 13 and 14 months post operation, while one patient had imaging evidence of local recurrence 4 months post operation. In summary, we describe three unique DICER1-sarcomas and expand the phenotypic spectrum of this emerging entity, particularly with GYN-tract origin.

Asunto(s)

ARN Helicasas DEAD-box , Mutación , Ribonucleasa III , Neoplasias Uterinas , Humanos , Ribonucleasa III/genética , Femenino , ARN Helicasas DEAD-box/genética , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Adulto , Persona de Mediana Edad , Sarcoma/genética , Sarcoma/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Predisposición Genética a la Enfermedad , Fenotipo , Metilación de ADN , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología

RESUMEN

The progression of hepatocellular carcinoma (HCC) is influenced by disrupted metabolic processes, presenting challenges in prognostic outcomes. Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality, is closely associated with metabolic reprogramming and stem cell-like properties in liver cancer stem cells (LCSCs). This study explored the potential molecular mechanisms by which tLyP-1-modified extracellular vesicles (EVs) delivering CTCF shRNA (tLyp-1-EV-shCTCF) regulate mitochondrial DNA methylation-induced glycolytic metabolic reprogramming and LCSC self-renewal. Through a series of methods, including Western blot, nanoparticle tracking analysis, and immunofluorescence, we demonstrated the successful delivery and internalization of tLyp-1-EV in HCC cells. Our results identified SALL3 as a critical factor underexpressed in HCC and LCSCs, while CTCF was overexpressed. Overexpression of SALL3 inhibited LCSC self-renewal and immune evasion by blocking the CTCF-DNMT3A interaction, thus repressing DNMT3A methyltransferase activity and subsequent mitochondrial DNA methylation-mediated glycolytic metabolic reprogramming. In vivo experiments further supported these findings, showing that tLyp-1-EV-shCTCF treatment significantly reduced tumor growth by upregulating SALL3 expression, thereby inhibiting glycolytic metabolic reprogramming and enhancing the immune response against HCC cells. This study provides novel insights into the role of SALL3 and mitochondrial DNA methylation in HCC progression, offering potential therapeutic targets for combating HCC and its stem cell-like properties.

RESUMEN

Breast carcinoma is the leading factor in women's cancer-related fatalities. Due to its numerous inherent molecular subtypes, breast cancer is an extremely diverse illness. The human epidermal growth factor receptor 2 (HER2) positive subtypes stands out among these subtypes as being especially prone to cancer development and illness recurrence. The regulation of embryonic stem cells' pluripotency and self-renewal is carried out by the SALL4 (Spalt-like transcription factor 4) family member. Numerous molecular pathways operating at the transcriptional, post-transcriptional, and epigenomic levels regulate the expression of SALL4. Many transcription factors control the expression of SALL4, with STAT3 being the primary regulator in hepatocellular carcinoma (HCC) and breast carcinoma. Moreover, this oncogene has been connected to a number of cellular functions, including invasion, apoptosis, proliferation, and resistance to therapy. Reduced patient survival rates and a worse prognosis have been linked to higher levels of SALL4. In order to target the undruggable SALL4 that is overexpressed in breast carcinoma, we investigated the prognostic levels of SALL4 in breast carcinoma and its interaction with various related proteins. Using TIMER 2.0 analysis, the expression pattern of SALL4 was investigated across all TCGA datasets. The research revealed that SALL4 expression was elevated in various cancers. The UALCAN findings demonstrated that SALL4 was overexpressed in all tumor samples including breast cancer especially TNBC (Triple negative breast cancer). The web-based ENRICHR program was used for gene ontology analysis that revealed SALL4 was actively involved in the development of the nervous system, positive regulation of stem cell proliferation, regulation of stem cell proliferation, regulation of the activin receptor signaling pathway, regulation of transcription using DNA templates, miRNA metabolic processes, and regulation of transcription by RNA Polymerase I. Using the STRING database, we analyzed the interaction and involvement of SALL4 with other abruptly activated proteins and used Cytoscape 3.8.0 for visualization. Additionally, using bc-GenExMiner, we studied the impact of SALL4 on pathways abruptly activated in different breast cancer subtypes that revealed SALL4 was highly correlated with WNT2B, NOTCH4, AKT3, and PIK3CA. Furthermore, to target SALL4, we evaluated and analyzed the impact of CLP and its analogues, revealing promising outcomes.

Asunto(s)

Biomarcadores de Tumor , Neoplasias de la Mama , Factores de Transcripción , Humanos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Femenino , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Pronóstico , Progresión de la Enfermedad

RESUMEN

Many salamanders can completely regenerate a fully functional limb. Limb regeneration is a carefully coordinated process involving several defined stages. One key event during the regeneration process is the patterning of the blastema to inform cells of what they must differentiate into. Although it is known that many genes involved in the initial development of the limb are re-used during regeneration, the exact molecular circuitry involved in this process is not fully understood. Several large-scale transcriptional profiling studies of axolotl limb regeneration have identified many transcription factors that are up-regulated after limb amputation. Sall4 is a transcription factor that has been identified to play essential roles in maintaining cells in an undifferentiated state during development and also plays a unique role in limb development. Inactivation of Sall4 during limb bud development results in defects in anterior-posterior patterning of the limb. Sall4 has been found to be up-regulated during limb regeneration in both Xenopus and salamanders, but to date it function has been untested. We confirmed that Sall4 is up-regulated during limb regeneration in the axolotl using qRT-PCR and identified that it is present in the skin cells and also in cells within the blastema. Using CRISPR technology we microinjected gRNAs specific for Sall4 complexed with cas9 protein into the blastema to specifically knockout Sall4 in blastema cells only. This resulted in limb regenerate defects, including missing digits, fusion of digit elements, and defects in the radius and ulna. This suggests that during regeneration Sall4 may play a similar role in regulating the specification of anterior-proximal skeletal elements.

Asunto(s)

Ambystoma mexicanum , Tipificación del Cuerpo , Extremidades , Regeneración , Factores de Transcripción , Animales , Regeneración/genética , Regeneración/fisiología , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Extremidades/fisiología , Extremidades/embriología , Ambystoma mexicanum/genética , Ambystoma mexicanum/fisiología , Tipificación del Cuerpo/genética , Regulación del Desarrollo de la Expresión Génica/genética , Proteínas Anfibias/genética , Proteínas Anfibias/metabolismo

RESUMEN

Testicular tumors (TTs) are rare in children, posing diagnostic and therapeutic challenges. This retrospective study evaluates the diagnostic and prognostic utility of SALL4 and OCT3/4 in pediatric TTs. We analyzed 18 cases of different types of TTs using immunohistochemistry (IHC) to assess SALL4 (Spalt-like transcription factor 4) and OCT3/4 (Octamer binding transcription factor 3/4) expression. SALL4 was positive in 83.3% of tumors, while OCT3/4 was positive in 38.9% of tumors, with a significantly higher prevalence in patients aged 12-18 years compared to those aged 0-11 years (p = 0.013). Mixed germinal cell tumors were significantly more frequently associated with OCT3/4 (p = 0.003), and a high immunostaining expression for SALL4 was observed primarily in yolk sac tumors and embryonal carcinoma. Our findings suggest that SALL4 and OCT3/4 immunostaining can aid in accurate diagnosis and treatment planning, and underscores the importance of OCT3/4 as a predictive factor in pediatric testicular tumors, highlighting its substantial correlation with tumor type and its impact on treatment response. These markers may guide personalized therapeutic strategies, potentially improving patient outcomes.

RESUMEN

Pediatric ovarian tumors exhibit unique diagnostic and therapeutic challenges. This study evaluates the expression of SALL4 and OCT3/4 biomarkers in pediatric ovarian tumors and their associations with tumor subtype, stage, and clinical outcome. A retrospective analysis was conducted on 64 patients under 18 years old, examining demographic data, tumor characteristics, immunohistochemical staining, and clinical outcomes. Our results show that SALL4 was significantly expressed in adenocarcinoma, dysgerminoma (DSG), mixed germ cell tumors (GCTs), and immature teratoma, while OCT3/4 was highly expressed in DSG and mixed GCTs. Both markers are associated with a higher tumor grade and stage, indicating a more aggressive disease. The SALL4 positivity expression was correlated with high alpha fetoprotein (AFP) and lactate dehydrogenase (LDH) levels, while OCT3/4 positivity significantly predicted the risk of subsequent metastasis. The mean progression-free survival (PFS) was notably shorter in patients with positive markers. These findings underscore the diagnostic and prognostic value of SALL4 and OCT3/4 in pediatric ovarian tumors, aligning with previous research and supporting their use in clinical practice for better disease management and patient outcomes.

Asunto(s)

Biomarcadores de Tumor , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Ováricas/genética , Biomarcadores de Tumor/metabolismo , Niño , Adolescente , Preescolar , Estudios Retrospectivos , Pronóstico , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , Rumanía/epidemiología , Lactante , Factores de Transcripción/metabolismo , Teratoma/metabolismo , Teratoma/diagnóstico , Teratoma/patología , Teratoma/genética

RESUMEN

Introduction: Townes-Brocks syndrome (TBS), a rare autosomal dominant genetic condition associated with SALL1 (Spalt like Transcription Factor 1), is reported to be present in 1:238,000 individuals in the general population. TBS is characterized by the triad of anorectal malformations, dysplastic ears, with or without hearing impairment, and hand or thumb anomalies. Although kidney involvement is less common in TBS, the disease can progress to kidney failure. Here, we sought to characterize the incidence of SALL1 variants in individuals undergoing broad-based genetic testing with a kidney gene panel and to quantify the presence of (extra)renal features. Methods: A retrospective analysis of the genetic data from a 385-gene panel identified cases with a pathogenic (P) or likely pathogenic (LP) variant in SALL1. Data including age, features, and disease progression were collected. Results: Of 35,044 samples, P or LP variants in SALL1 were identified in 22, yielding a prevalence of 1:1592 among patients tested for monogenic kidney disease, and 1:342 among cases identified with a monogenic kidney disease. Among this cohort, the median patient age was 23 years (range: 3 months-62 years) with chronic kidney disease (CKD) reported in 91% (20/22) of cases. Reported kidney features included renal agenesis/hypoplasia (7/22; 32%), focal segmental glomerulosclerosis (4/22; 18%), and kidney cysts (3/22; 14%). Confirmed extrarenal features included hearing loss and/or ear features (7/22; 32%), anorectal malformations (6/22; 27%) and hand or thumb abnormalities (4/22; 18%). Three patients (3/22; 14%) had both a priori TBS diagnoses and the traditional "triad." Conclusion: Traditionally, a molecular diagnosis was ascertained primarily in individuals presenting with cardinal features of TBS; therefore, individuals with mild or atypical presentations were often overlooked clinically. Our findings reveal that SALL1 P/LP variants could be a consequential contributor to monogenic kidney disease.

RESUMEN

Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.

Asunto(s)

Defectos del Tabique Interventricular , Humanos , Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad/genética , Defectos del Tabique Interventricular/genética , Mutación , Factores de Transcripción/genética

RESUMEN

Glioblastomas are the most common malignant brain tumors in adults; they are highly aggressive and heterogeneous and show a high degree of plasticity. Here, we show that methyltransferase-like 7B (METTL7B) is an essential regulator of lineage specification in glioblastoma, with an impact on both tumor size and invasiveness. Single-cell transcriptomic analysis of these tumors and of cerebral organoids derived from expanded potential stem cells overexpressing METTL7B reveal a regulatory role for the gene in the neural stem cell-to-astrocyte differentiation trajectory. Mechanistically, METTL7B downregulates the expression of key neuronal differentiation players, including SALL2, via post-translational modifications of histone marks.

Asunto(s)

Diferenciación Celular , Linaje de la Célula , Glioblastoma , Metiltransferasas , Glioblastoma/patología , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Metiltransferasas/metabolismo , Metiltransferasas/genética , Linaje de la Célula/genética , Animales , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Regulación Neoplásica de la Expresión Génica , Ratones , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Línea Celular Tumoral , Astrocitos/metabolismo , Astrocitos/patología , Organoides/metabolismo , Organoides/patología

RESUMEN

BACKGROUND: Townes-Brocks syndrome (TBS) is a rare genetic disorder characterized by imperforate anus, dysplastic ears, thumb malformations, and other abnormalities. Previous studies have revealed that mutations in the SALL1 gene can disrupt normal development, resulting in the characteristic features of Townes-Brocks syndrome. Spalt-like transcription factors (SALLs) are highly conserved proteins that play important roles in various cellular processes, including embryonic development, cell differentiation, and cell survival. Over 400 different variants or mutations have been reported in the SALL1 gene in individuals with TBS. Most of these variants lead to the formation of premature termination codons (PTCs), also known as nonsense mutations. The majority of these PTCs occur in a specific region of the SALL1 gene called the "hotspot region", which is particularly susceptible to mutation. METHODS: In this study, we conducted whole-exome sequencing on a three-generation Chinese family with anorectal malformations. RESULTS: We identified a novel heterozygous mutation (chr16:51175376:c.757 C > T p.Gln253*) in the SALL1 gene. Molecular analysis revealed a heterozygous C to T transition at nucleotide position 757 in exon 2 of the SALL1 (NM_002968) gene. This mutation is predicted to result in the substitution of the Gln253 codon with a premature stop codon (p.Gln253*). The glutamine-rich domain forms a long alpha helix, enabling the mutant protein to interact with the wild-type SALL1 protein. This interaction may result in steric hindrance effects on the wild-type SALL1 protein. CONCLUSIONS: Our findings have expanded the mutation database of the SALL1 gene, which is significant for genetic counseling and clinical surveillance in the affected family. Furthermore, our study enhances the understanding of Townes-Brocks syndrome and has the potential to improve its diagnosis and treatment.

Asunto(s)

Anomalías Múltiples , Ano Imperforado , Linaje , Factores de Transcripción , Femenino , Humanos , Masculino , Anomalías Múltiples/genética , Malformaciones Anorrectales/genética , Ano Imperforado/genética , Pueblo Asiatico/genética , China , Pueblos del Este de Asia , Pérdida Auditiva Sensorineural , Mutación , Enfermedades Raras/genética , Pulgar/anomalías , Factores de Transcripción/genética

RESUMEN

Esophageal adenocarcinoma (EAC) is one of the deadliest tumor entities worldwide, with a 5-year survival rate of less than 25%. Unlike other tumor entities, personalized therapy options are rare, partly due to the lack of knowledge about specific subgroups. In this publication, we demonstrate a subgroup of patients with EAC in a large screening cohort of 826 patients, characterized by specific morphological and immunohistochemical features. This subgroup represents approximately 0.7% (6/826) of the total cohort. Morphological features of this subgroup show a striking clear cytoplasm of the tumour cells and the parallel existence of rare growth patterns like yolk sac-like differentiation and enteroblastic differentiation. Immunohistochemistry reveals expression of the fetal gut cell-like proteins Sal-like protein 4 (SALL4), claudin-6, and glypican 3. Interestingly, we find a correlation with alterations of SWI/SNF-complex associated genes, which are supposed to serve as tumor suppressor genes in various tumour entities. Our results suggest a possible implication of rare tumour subtypes in the WHO classification for EACs according to the classification for gastric cancer. Furthermore, claudin-6 positive tumors have shown promising efficacy of CAR T cell therapy in the recently published BNT-211-01 trial (NCT04503278). This represents a personalized therapeutic option for this tumor subtype.

Asunto(s)

Adenocarcinoma , Diferenciación Celular , Neoplasias Esofágicas , Humanos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Adenocarcinoma/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patología , Femenino , Masculino , Anciano , Claudinas/metabolismo , Claudinas/genética , Persona de Mediana Edad , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética

RESUMEN

CD44 and SALL4 are markers of stemness and expressed in cancer stem cells (CSCs). Their deregulated expression was seen in various tumors and has been correlated with clinical severity. We evaluated immunohistochemical expression of CD44 and SALL4 in leukoplakia and oral squamous cell carcinoma (OSCC). CD44 was expressed in all the cases of leukoplakia and Its expression correlated with severity of the dysplasia in leukoplakia but varied with differentiation in OSCC. SALL4 did not express in leukoplakia. Its expression was varied in OSCC cases. We opine that CD44 expression is consistent with the progression of dysplasia in leukoplakia and differentiation in OSCC.

RESUMEN

Aim: This study aimed to investigate the role of brain-derived neurotrophic factor (BDNF) in colon adenocarcinoma, specifically its impact on sensitivity to carboplatin.Methods: mRNA and clinical information of colon adenocarcinoma samples were obtained from TCGA database. Differential expression analysis, transcription factor prediction, gene set enrichment analysis were performed in silico. qRT-PCR, western blot, CCK-8 and CHIP assay were employed.Results: BDNF demonstrated high expression in colon adenocarcinoma. Silencing of BDNF enhanced carboplatin sensitivity, while exerting opposite effects on epithelial-mesenchymal transition (EMT). BDNF was enriched in Hedgehog (HH) signaling pathway. SALL4 was identified as an upstream regulator of BDNF. Upregulation of BDNF by SALL4 promoted EMT and inhibited carboplatin sensitivity.Conclusion: SALL4 promoted BDNF expression to facilitate the aggressive phenotypes of colon adenocarcinoma.

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Asunto(s)

Adenocarcinoma , Factor Neurotrófico Derivado del Encéfalo , Carboplatino , Neoplasias del Colon , Proteínas Hedgehog , Transducción de Señal , Factores de Transcripción , Regulación hacia Arriba , Humanos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Carboplatino/uso terapéutico , Carboplatino/farmacología , Proteínas Hedgehog/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Regulación hacia Arriba/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/genética , Factores de Transcripción/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos

RESUMEN

Townes-Brocks syndrome (TBS) is a rare syndrome characterized by triad of anal, ear, and thumb anomalies. Further malformations/anomalies include congenital heart diseases, foot malformations, sensorineural and/or conductive hearing impairment, genitourinary malformations, and anomalies of eye and nervous system. Definitive diagnosis for TBS is confirmed by molecular analysis for mutations in the SALL1 gene. Only one known case of TBS with absent pulmonary valve syndrome (APVS) has been previously described to our knowledge. Here, we report a newborn diagnosed with TBS with APVS and tetralogy of Fallot (TOF) who was found to carry the most common pathogenic SALL1 gene mutation c.826C > T (p.R276X), with its surgical repair and postoperative follow-up. To our knowledge, this is the first genotyped case of TBS from Turkey to date. TBS should be suspected in the presence of ear, anal, and thumb malformations in a neonate. If a patient with TBS and TOF-APVS needs preoperative ventilation within the first months of life, this implies prolonged postoperative intubation and increased risk of mortality.

RESUMEN

BACKGROUND: The transcription factor SALL4 is associated with embryonic pluripotency and has proposed as a novel immunohistochemistry (IHC) marker for diagnosing germ cell tumours. SALL4 comprises three isoforms, and SALL4-A being the full-length isoform. Studying its isoforms could revolutionize testicular cancer prognosis and subtype differentiation. METHODS: The expression and clinical significance of isoform 'A' of SALL4 was evaluated in 124 testicular germ cell tumours (TGCTs) subtypes, adjacent 67 normal tissues and 22 benign tumours, using immunohistochemistry on tissue microarrays (TMA). RESULTS: A statistically significant higher expression of nuclear and cytoplasmic SALL4-A was detected in TGCTs histological subtypes and benign tumours compared to the normal tissues. Seminoma and yolk sac tumours had the highest nuclear and cytoplasmic expression of SALL4-A. A significant correlation was detected between the higher nuclear expression of SALL4-A and increased pT stages (P = 0.026) in seminomas. Whereas in embryonal carcinomas, cytoplasmic expression of SALL4-A was associated with the tumour recurrence (P = 0.04) and invasion of the epididymis (P = 0.011). CONCLUSIONS: SALL4-A isoform expression in the cytoplasm and nucleus of TGCTs may be associated with histological differentiation. In the seminoma subtype of TGCTs, higher expression of SALL4-A may be used as a predictive indicator of poorer outcomes and prognosis.

Asunto(s)

Biomarcadores de Tumor , Neoplasias de Células Germinales y Embrionarias , Isoformas de Proteínas , Neoplasias Testiculares , Factores de Transcripción , Humanos , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patología , Masculino , Neoplasias de Células Germinales y Embrionarias/metabolismo , Neoplasias de Células Germinales y Embrionarias/patología , Isoformas de Proteínas/metabolismo , Factores de Transcripción/metabolismo , Biomarcadores de Tumor/metabolismo , Pronóstico , Progresión de la Enfermedad , Inmunohistoquímica , Seminoma/metabolismo , Seminoma/patología , Adulto , Citoplasma/metabolismo , Núcleo Celular/metabolismo , Análisis de Matrices Tisulares

RESUMEN

Effective therapeutic targets and early diagnosis are major challenges in the treatment of gastrointestinal tract (GIT) cancers. SALL4 is a well-known transcription factor that is involved in organogenesis during embryonic development. Previous studies have revealed that SALL4 regulates cell proliferation, survival, and migration and maintains stem cell function in mature cells. Additionally, SALL4 overexpression is associated with tumorigenesis. Despite its characterization as a biomarker in various cancers, the role of SALL4 in GIT cancers and the underlying mechanisms are unclear. We describe the functions of SALL4 in GIT cancers and discuss its upstream/downstream genes and pathways associated with each cancer. We also consider the possibility of targeting these genes or pathways as potential therapeutic options for GIT cancers.

Asunto(s)

Neoplasias Gastrointestinales , Factores de Transcripción , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Neoplasias Gastrointestinales/genética , Células Madre/metabolismo , Desarrollo Embrionario , Línea Celular Tumoral

RESUMEN

Extragonadal germ cell tumors (GCTs) are challenging to diagnose. We present a case of suprarenal GCT, with hepatic infiltration where differential diagnosis included neuroblastoma and hepatoblastoma. The positive positron emission tomography scan further obfuscated the situation. The diagnosis was clinched by fine-needle aspiration cytology and cell block immunohistochemistry.

RESUMEN

Townes-Brocks syndrome (TBS) is an autosomal dominant disorder characterised by the triad of anorectal, thumb, and ear malformations. It may also be accompanied by defects in kidney, heart, eyes, hearing, and feet. TBS has been demonstrated to result from heterozygous variants in the SALL1 gene, which encodes zinc finger protein believed to function as a transcriptional repressor. The clinical characteristics of an atypical TBS phenotype patient from a Chinese family are described, with predominant manifestations including external ear dysplasia, unilateral renal hypoplasia with mild renal dysfunction, and hearing impairment. A novel heterozygous variant c.3060T>A (p.Tyr1020*) in exon 2 of the SALL1 gene was identified in this proband. Pyrosequencing of the complementary DNA of the proband revealed that the variant transcript accounted for 48% of the total transcripts in peripheral leukocytes, indicating that this variant transcript has not undergone nonsense-mediated mRNA decay. This variant c.3060T > A is located at the terminal end of exon 2, proximal to the 3' end of the SALL1 gene, and exerts a relatively minor impact on protein function. We suggest that the atypical TBS phenotype observed in the proband may be attributed to the truncated protein retaining partial SALL1 function.

Asunto(s)

Anomalías Múltiples , Pérdida Auditiva Sensorineural , Factores de Transcripción , Femenino , Humanos , Masculino , Anomalías Múltiples/genética , Ano Imperforado/genética , Ano Imperforado/diagnóstico , China , Análisis Mutacional de ADN , Oído/anomalías , Pueblos del Este de Asia/genética , Predisposición Genética a la Enfermedad , Herencia , Heterocigoto , Mutación , Linaje , Fenotipo , Pulgar/anomalías , Fístula Traqueoesofágica/genética , Factores de Transcripción/genética

RESUMEN

Human pluripotent stem cell (hPSC) cultures are prone to genetic drift, because cells that have acquired specific genetic abnormalities experience a selective advantage in vitro. These abnormalities are highly recurrent in hPSC lines worldwide, but their functional consequences in differentiating cells are scarcely described. In this work, we show that the loss of chromosome 18q impairs neuroectoderm commitment and that downregulation of SALL3, a gene located in the common 18q loss region, is responsible for this failed neuroectodermal differentiation. Knockdown of SALL3 in control lines impaired differentiation in a manner similar to the loss of 18q, and transgenic overexpression of SALL3 in hESCs with 18q loss rescued the differentiation capacity of the cells. Finally, we show that loss of 18q and downregulation of SALL3 leads to changes in the expression of genes involved in pathways regulating pluripotency and differentiation, suggesting that these cells are in an altered state of pluripotency.

Asunto(s)

Células Madre Embrionarias Humanas , Células Madre Pluripotentes , Humanos , Diferenciación Celular/genética , Células Madre Pluripotentes/metabolismo , Cromosomas

RESUMEN

Enteroblastic carcinoma is clinically characterized by an elevated serum level of alpha-fetoprotein (AFP) and is histologically characterized by cancer cells with a clear cytoplasm and 'blastic' coarse chromatin. It sometimes has an element of hepatoid carcinoma; therefore, these two neoplasms are often regarded as sister entities. Although hepatoid carcinoma in the biliary tree has been reported, enteroblastic cholangiocarcinoma is extremely uncommon. In the present study, four cases of enteroblastic cholangiocarcinoma were examined. Tumors were located inside the liver (n = 2) or common bile duct (n = 2). The two intrahepatic cases had a history of primary sclerosing cholangitis, and serum AFP levels were elevated in both. One unresectable case was diagnosed by needle liver biopsy, while the remaining three underwent surgical resection. Histologically, all cases showed similar microscopic features. Cuboidal or polygonal cancer cells with the characteristic clear cytoplasm and subnuclear vacuoles were arranged in a papillary, micropapillary, tubular, or solid architecture. One case had an element of pancreatobiliary-type adenocarcinoma, while a hepatoid carcinoma element was not observed in any cases. All cases were positive for AFP, glypican 3, and SALL4, with SALL4 being the most widely expressed. Heppar-1 and arginase-1 were negative, except for one case, which was positive for Heppar-1. In conclusion, enteroblastic cholangiocarcinoma is an uncommon subtype of biliary tract malignancy. These cases may have been categorized as 'clear cell' cholangiocarcinoma. Although enteroblastic cholangiocarcinoma seems to occur more commonly in extrahepatic regions, including the gallbladder, it may also develop in the liver, particularly in patients with primary sclerosing cholangitis.

Asunto(s)

Adenocarcinoma , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Colangitis Esclerosante , Humanos , alfa-Fetoproteínas , Colangitis Esclerosante/patología , Colangiocarcinoma/cirugía , Colangiocarcinoma/patología , Adenocarcinoma/patología , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología