RESUMEN
Schwannomatosis refers to a group of rare genetic syndromes characterized by a predisposition to develop nerve sheath tumors, specifically schwannomas. Although germline and mosaic (described in the NF2 gene) pathogenic variants in NF2, SMARCB1, and LZTR1 account for the majority of cases, a subset of affected individuals remains without a definitive molecular diagnosis, including those associated with 22q loss of heterozygosity at the tumor level. The absence of a specific disease cause limits effective risk assessment, clinical surveillance, and genetic counselling. In recent years, advances in sequencing technologies have facilitated the identification of novel candidate driver genes. However, the rarity of these findings makes it challenging to establish their pathogenic relevance. This review aims to evaluate the current knowledge of genetic contributors to schwannomatosis in patients for whom routine genetic testing fails to detect a molecular cause in the known associated genes. On chromosome 22, DGCR8 and SOX10 have emerged as novel susceptibility genes, supported by accumulating molecular and clinical data. In addition, genes such as CDKN2A and SMARCA4 may also contribute to schwannomatosis in the context of broader tumor predisposition syndromes. These emerging genetic associations may help explain a proportion of schwannomatosis cases that currently lack a molecular diagnosis, while there is still room for the discovery of non-coding alleles or mosaic forms of known schwannomatosis-related conditions as well as novel genes that could explain unresolved cases.
Asunto(s)
Predisposición Genética a la Enfermedad , Neurilemoma , Neurofibromatosis , Proteína SMARCB1 , Neoplasias Cutáneas , Factores de Transcripción , Humanos , Neurilemoma/genética , Neurofibromatosis/genética , Proteína SMARCB1/genética , Neoplasias Cutáneas/genética , Factores de Transcripción/genética , Factores de Transcripción SOXE/genética , Proteínas Nucleares/genética , ADN Helicasas/genética , Pruebas Genéticas , Proteínas de Unión al ADN/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Neurofibromina 2RESUMEN
FGFR1 genetic alterations are associated with brain malignancies, including FGFR1 mutations in familial and sporadic cases of low-grade glioneuronal tumors, suggesting intrinsic mechanisms of selective pressure toward FGFR1 multiple events arising in the context of a quiet genome. To decipher the molecular mechanisms triggered by multiple concurrent FGFR1 mutations, we have mapped the proximal interactome of wild-type, single- and double-mutant FGFR1 proteins through a BioID-MS approach. Our data reveal novel oncogenic functionality for the two hotspot mutations N546K and K656E, linked to evasion of lysosomal degradation. Further, we identified a modulatory tumor-suppressive role for the susceptibility variant R661P, which hampers the oncogenic potential of both hotspot N546K and K656E mutations by rescuing receptor degradation and reducing N546K affinity for the downstream effector PLCγ. Introducing the R661P missense variant was sufficient to abolish self-renewal capacity of oligodendroglioma cells and downregulate genes involved in neurodevelopment and neuro-glial cell fate decisions, both aspects overcome in the double mutants. This study sheds light on contextual oncogenic effects associated with FGFR1 alterations and their recurrence in low-mutation burden and therapy naive tumors.
Asunto(s)
Neoplasias Encefálicas , Carcinogénesis , Glioma , Mutación , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Carcinogénesis/genética , Línea Celular Tumoral , Fosfolipasa C gamma/metabolismo , Fosfolipasa C gamma/genética , Glioma/genéticaRESUMEN
Attenuated familial adenomatous polyposis (AFAP) is a disorder caused by germline pathogenic variants in APC and is characterized by the presence of <100 colonic polyps and a high lifetime risk of developing colorectal cancer. Salivary gland basal cell tumours are uncommon and have not previously been reported in AFAP. We present a family with AFAP and multiple salivary gland tumours, including basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC). The colon and salivary gland tumours showed abnormal nuclear ß-catenin staining. Genomic analysis of both parotid BCACs showed copy-number-neutral loss of heterozygosity (CNN-LOH) at the APC locus, implicating loss of full-length APC in the aetiology of parotid BCACs. In contrast, the submandibular BCAC showed a p.(Ile35Thr) CTNNB1 mutation. Spatial transcriptomic analysis revealed a stepwise increase in the expression of WNT pathway genes across the proband's salivary lesions, from benign (intercalated duct hyperplasia and BCAs) to malignant (BCACs). Our results showcase BCA and BCAC as potential new phenotypes of AFAP. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Asunto(s)
Adenoma , Proteína de la Poliposis Adenomatosa del Colon , Poliposis Adenomatosa del Colon , Neoplasias de las Glándulas Salivales , Vía de Señalización Wnt , Humanos , Masculino , Vía de Señalización Wnt/genética , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/patología , Femenino , Proteína de la Poliposis Adenomatosa del Colon/genética , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Transcriptoma , Perfilación de la Expresión Génica , Persona de Mediana Edad , Adulto , Linaje , Pérdida de Heterocigocidad , beta Catenina/genética , Adenoma/genética , Adenoma/patología , Predisposición Genética a la EnfermedadRESUMEN
PURPOSE: DICER1 tumor predisposition syndrome (DTPS) is a hereditary condition affecting children and young adults. Identification of DICER1 carriers is key for prevention and actionability in families. However, DTPS diagnosis is hindered by its incomplete penetrance and broad phenotypic spectrum. METHODS: We performed an analysis of DICER1 sequencing data from 92 children and 6108 adults with suspected cancer predisposition syndrome. Clinical and DICER1 somatic data from selected carriers and public data sets were studied. RESULTS: The prevalence of germline DICER1 pathogenic variants was 1:30 in children and 1:3054 in adults. No adult referral phenotype was a known DTPS-associated tumor, although 3 of 5 carriers developed thyroid alterations. We provide functional evidence supporting the pathogenicity of a novel in-frame deletion. A 56-year-old woman with ovarian carcinoma and toxic diffuse thyroid hyperplasia was found to have a postzygotic hotspot missense variant. CONCLUSION: The prevalence of DICER1 pathogenic variants in cancer predisposition populations was 5 to 6 times that reported in the general population. Pediatric-onset DTPS is well characterized, whereas adult carriers mainly present with thyroid abnormalities in the absence of DICER1-related family history, thus requiring accurate criteria for its identification when in constellation with other tumor types. Postzygotic hotspot missense variants may exist without the expected severe phenotype.
Asunto(s)
ARN Helicasas DEAD-box , Predisposición Genética a la Enfermedad , Neoplasias , Síndromes Neoplásicos Hereditarios , Ribonucleasa III , Humanos , Ribonucleasa III/genética , ARN Helicasas DEAD-box/genética , Femenino , Niño , Fenotipo , Mosaicismo , Adulto , Masculino , Persona de Mediana Edad , Mutación de Línea Germinal/genética , Preescolar , Prevalencia , Neoplasias/genética , Neoplasias/epidemiología , Adolescente , Adulto Joven , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/epidemiologíaRESUMEN
Early detection of cancer predisposition syndromes (CPS) is crucial to determine optimal treatments and follow-up, and to provide appropriate genetic counseling. This study outlines an approach in a pediatric oncology unit, where 50 randomly selected patients underwent clinical assessment, leading to 44 eligible for genetic testing. We identified 2 pathogenic or likely pathogenic variants in genes associated with CPS and 6 variants of uncertain significance (VUS) potentially associated with cancer development. We emphasize the importance of a thorough and accurate collection of family history and physical examination data and the full coordination between pediatric oncologists and geneticists.
Asunto(s)
Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Niño , Masculino , Pruebas Genéticas/métodos , Femenino , Preescolar , Adolescente , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/diagnóstico , Neoplasias/genética , Neoplasias/diagnóstico , LactanteRESUMEN
BACKGROUND: Sarcomas are a rare and diverse group of cancers occurring mainly in young individuals for which an underlying germline genetic cause remains unclear in most cases. METHODS: Germline DNA from 177 children, adolescents and young adults with soft tissue or bone sarcomas was tested using multigene panels with 113 or 126 cancer predisposing genes (CPGs) to describe the prevalence of germline pathogenic/likely pathogenic variants (GPVs). Subsequent testing of a subset of tumours for loss of heterozygosity (LOH) evaluation was performed to investigate the clinical and molecular significance of these variants. RESULTS: GPVs were detected in 21.5% (38/177) of the patients (15.8% in children and 21.6% in adolescents and young adults), with dominant CPGs being altered in 15.2% overall. These variants were found in genes previously associated with the risk of developing sarcomas (TP53, RB1, NF1, EXT1/2) but also in genes where that risk is still emerging/limited (ERCC2, TSC2 and BRCA2) or unknown (PALB2, RAD50, FANCM and others). The detection rates of GPVs varied from 0% to 33% across sarcoma subtypes and GPV carriers were more likely to present more than one primary tumour than non-carriers (21.1%×6.5%; p=0.012). Loss of the wild-type allele was detected in 48% of tumours from GPV carriers, mostly in genes definitively associated with sarcoma risk. CONCLUSION: Our findings reveal that a high proportion of young patients with sarcomas presented a GPV in a CPG, underscoring the urgency of establishing appropriate genetic screening strategies for these individuals and their families.
Asunto(s)
Predisposición Genética a la Enfermedad , Sarcoma , Niño , Adulto Joven , Adolescente , Humanos , Prevalencia , Mutación de Línea Germinal/genética , Sarcoma/epidemiología , Sarcoma/genética , Células Germinativas , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , ADN Helicasas/genéticaRESUMEN
MicroRNAs (miRNAs) play vital roles in the regulation of gene expression, a process known as miRNA-induced gene silencing. The human genome codes for many miRNAs, and their biogenesis relies on a handful of genes, including DROSHA, DGCR8, DICER1, and AGO1/2. Germline pathogenic variants (GPVs) in these genes cause at least three distinct genetic syndromes, with clinical manifestations that range from hyperplastic/neoplastic entities to neurodevelopmental disorders (NDDs). Over the past decade, DICER1 GPVs have been shown to lead to tumor predisposition. Moreover, recent findings have provided insight into the clinical consequences arising from GPVs in DGCR8, AGO1, and AGO2. Here we provide a timely update with respect to how GPVs in miRNA biogenesis genes alter miRNA biology and ultimately lead to their clinical manifestations.
Asunto(s)
MicroARNs , Humanos , MicroARNs/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Ribonucleasa III/genética , Ribonucleasa III/metabolismo , Genotipo , Genoma Humano , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismoAsunto(s)
Neoplasias de la Mama , Neoplasias , Humanos , Femenino , Heterocigoto , Proteína BRCA1/genética , Mutación , Neoplasias de la Mama/genéticaRESUMEN
Sertoli-Leydig cell tumors (SLCTs) are uncommon ovarian sex cord-stromal neoplasms which are currently classified into well, moderately, and poorly differentiated and retiform types. Well-differentiated SLCT is the least common and typically occurs in pure form, whereas moderately and poorly differentiated and retiform types often comprise a morphologic spectrum with an admixture of all 3. DICER1 pathogenic variants are very common in SLCTs but, as far as we are aware, have not been reported in well-differentiated neoplasms, although the number of cases studied is small due to the rarity of this neoplasm. We undertook DICER1 molecular testing in a cohort of 18 well-differentiated SLCTs and show all these to be DICER1 wild-type. None of the cases harbored the p. FOXL2 C134W hotspot mutation. Based upon the DICER1 molecular results, together with morphologic observations, we propose that well-differentiated SLCT is an unrelated neoplasm to the more common moderately/poorly differentiated and retiform SLCTs and is a fundamentally distinct and unrelated tumor type within the ovarian sex cord-stromal tumor family. The implications for tumor nomenclature and recommendations for future tumor classification are discussed within the context of tumors collectively known as SLCTs.
Asunto(s)
Neoplasias Ováricas , Tumor de Células de Sertoli-Leydig , Tumores de los Cordones Sexuales y Estroma de las Gónadas , Masculino , Femenino , Humanos , Tumor de Células de Sertoli-Leydig/genética , Tumor de Células de Sertoli-Leydig/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Mutación , Técnicas de Diagnóstico Molecular , Ribonucleasa III/genética , ARN Helicasas DEAD-box/genéticaRESUMEN
Homologous recombination (HR) plays an essential role in the maintenance of genome stability by promoting the repair of cytotoxic DNA double strand breaks (DSBs). More recently, the HR pathway has emerged as a core component of the response to replication stress, in part by protecting stalled replication forks from nucleolytic degradation. In that regard, the mammalian RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) have been involved in both HR-mediated DNA repair and collapsed replication fork resolution. Still, it remains largely obscure how they participate in both processes, thereby maintaining genome stability and preventing cancer development. To gain better insight into their contribution in cellulo, we mapped the proximal interactome of the classical RAD51 paralogs using the BioID approach. Aside from identifying the well-established BCDX2 and CX3 sub-complexes, the spliceosome machinery emerged as an integral component of our proximal mapping, suggesting a crosstalk between this pathway and the RAD51 paralogs. Furthermore, we noticed that factors involved RNA metabolic pathways are significantly modulated within the BioID of the classical RAD51 paralogs upon exposure to hydroxyurea (HU), pointing towards a direct contribution of RNA processing during replication stress. Importantly, several members of these pathways have prognostic potential in breast cancer (BC), where their RNA expression correlates with poorer patient outcome. Collectively, this study uncovers novel functionally relevant partners of the different RAD51 paralogs in the maintenance of genome stability that could be used as biomarkers for the prognosis of BC.
Asunto(s)
Inestabilidad Genómica , Recombinasa Rad51 , Animales , Humanos , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismo , Inestabilidad Genómica/genética , Recombinación Homóloga/genética , Roturas del ADN de Doble Cadena , ARN , Reparación del ADN/genética , Mamíferos/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismoRESUMEN
CDC20 is a coactivator of the anaphase promoting complex/cyclosome (APC/C) and is essential for mitotic progression. APC/CCDC20 is inhibited by the spindle assembly checkpoint (SAC), which prevents premature separation of sister chromatids and aneuploidy in daughter cells. Although overexpression of CDC20 is common in many cancers, oncogenic mutations have never been identified in humans. Using whole-exome sequencing, we identified heterozygous missense CDC20 variants (L151R and N331K) that segregate with ovarian germ cell tumors in two families. Functional characterization showed these mutants retain APC/C activation activity but have impaired binding to BUBR1, a component of the SAC. Expression of L151R and N331K variants promoted mitotic slippage in HeLa cells and primary skin fibroblasts derived from carriers. Generation of mice carrying the N331K variant using CRISPR-Cas9 showed that, although homozygous N331K mice were nonviable, heterozygotes displayed accelerated oncogenicity of Myc-driven cancers. These findings highlight an unappreciated role for CDC20 variants as tumor-promoting genes. SIGNIFICANCE: Two germline CDC20 missense variants that segregate with cancer in two families compromise the spindle assembly checkpoint and lead to aberrant mitotic progression, which could predispose cells to transformation. See related commentary by Villarroya-Beltri and Malumbres, p. 3432.
Asunto(s)
Neoplasias , Huso Acromático , Ciclosoma-Complejo Promotor de la Anafase/genética , Animales , Proteínas Cdc20/genética , Proteínas Cdc20/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Germinativas/metabolismo , Células HeLa , Humanos , Ratones , Mitosis/genética , Neoplasias/metabolismo , Unión Proteica , Huso Acromático/metabolismoRESUMEN
Defects in DNA repair genes have been extensively associated with cancer susceptibility. Germline pathogenic variants (GPV) in genes involved in homologous recombination repair pathways predispose to cancers arising mainly in the breast and ovary, but also other tissues. The RAD51 paralogs RAD51C and RAD51D were included in this group 10 years ago when germline variants were associated with non-BRCA1/2 familial ovarian cancer. Here, we have reviewed the landscape of RAD51C and RAD51D germline variants in cancer reported in the literature during the last decade, integrating this list with variants identified by in-house patient screening. A comprehensive catalog of 341 variants that have been classified applying ACMG/AMP criteria has been generated pinpointing the existence of recurrent variants in both genes. Recurrent variants have been extensively discussed compiling data on population frequencies and functional characterization if available, highlighting variants that have not been fully characterized yet to properly establish their pathogenicity. Finally, we have complemented this data with relevant information regarding the conservation of mutated residues among RAD51 paralogs and modeling of putative hotspot areas, which contributes to generating an exhaustive update on these two cancer predisposition genes.
Asunto(s)
Proteínas de Unión al ADN , Predisposición Genética a la Enfermedad , Neoplasias Ováricas , Proteínas de Unión al ADN/genética , Femenino , Células Germinativas , Mutación de Línea Germinal/genética , Humanos , Neoplasias Ováricas/genéticaRESUMEN
OBJECTIVES: Crossed cerebro-cerebellar BOLD activations have recently come to light as additional diagnostic features for patients with brain tumors. The covert verb generation (VG) task is a widely used language paradigm to determine these language-related crossed activations. Here we demonstrate these crossed activations in two additional language paradigms, the semantic and phonological association tasks. We propose the merit of these tasks to language lateralization determination in the clinic as they are easy to monitor and suitable for patients with aphasia. METHODS: Patients with brain tumors localized at different cortical sites (n = 71) performed three language paradigms, namely the VG task as well as the semantic (SA) and phonological (PA) association tasks with button-press responses. Respective language activations in disparate cortical regions and the cerebellum were assigned laterality. Agreements in laterality between the two new tasks and the verb generation task were tested using Cohen's kappa. RESULTS: Both tasks significantly agreed in cortical and cerebellar lateralization with the verb generation task in patients. Additionally, a McNemar test confirmed the presence of crossed activations in the cortex and the cerebellum in the entire subject population. CONCLUSION: We demonstrated that the semantic and phonological association tasks resulted in crossed cerebro-cerebellar language lateralization activations as those observed due to the covert verb generation task. This may suggest the possibility of these tasks being used conjointly with the traditional verb generation task, especially for subjects that may be unable to perform the latter. KEY POINTS: ⢠The semantic and phonological association tasks can be useful as additional presurgical fMRI language lateralization paradigms for brain tumor patients along with the standard verb generation task. ⢠All three tasks also confirm the presence of crossed cerebro-cerebellar language activations in the current subject population.
Asunto(s)
Neoplasias Encefálicas , Lenguaje , Mapeo Encefálico , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/diagnóstico por imagen , Cerebelo/diagnóstico por imagen , Humanos , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: The crossed cerebro-cerebellar (CCC) activation facilitates the diagnosis of cortical language lateralization, but needs to be explored with language tasks suitable for patients with different age ranges, educational attainment and eventual presence of language deficits. AIM: To determine the effect of demographic variables in the performance of three language tasks in healthy volunteers and to determine the CCC activation of these tasks as a functional magnetic resonance imaging (fMRI) paradigm in brain tumor patients. MATERIAL AND METHODS: The behavioral performance (correct responses and reaction time) of three language tasks (verbal fluency, semantic and phonological decision tasks) was first examined in 76 healthy volunteers balanced by age and educational level. Later, these tasks were implemented as fMRI paradigms to explore CCC language activation of 20 patients with potential diagnosis of brain tumors. RESULTS: The performance of the verbal fluency task was affected by age. The CCC language activation was reproducible with the semantic and phonological tasks. The combination of the tasks determined typical and atypical language lateralization in 60% and 40% of our patients, respectively. CONCLUSIONS: The verbal fluency task must be implemented with care as a clinical fMRI paradigm. Our results suggest that semantic and phonological tasks can be a good alternative for brain tumor patients with language deficits.
Asunto(s)
Neoplasias Encefálicas , Lenguaje , Encéfalo , Mapeo Encefálico , Neoplasias Encefálicas/diagnóstico por imagen , Lateralidad Funcional , Humanos , Imagen por Resonancia MagnéticaRESUMEN
Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome responsible for 1% of colorectal cancers (CRCs). Up to 90% of classic FAPs are caused by inactivating mutations in APC, and mosaicism has been previously reported in 20% of de novo cases, usually linked to milder phenotypic manifestations. This study aimed to explore the prevalence of mosaicism in 11 unsolved cases of classic FAP and to evaluate the diagnostic yield of somatic testing. Paired samples of colorectal polyps, tumors, and/or mucosa were analyzed using a custom next-generation sequencing panel targeting 15 polyposis and CRC-predisposing genes. Whenever possible, the extension of mosaicism to blood or sperm was also examined. Of 11 patients with classic adenomatous polyposis, a mosaic pathogenic variant in APC was identified in 7 (64%). No other altered genes were identified. In two of seven patients (29%), mosaicism was found restricted to colonic tissues, whereas in five of seven patients (71%), it was extended to the blood. Germline affectation was confirmed in one patient. We report the first analysis at a somatic level of 15 genes associated with CRC susceptibility, which highlights the role of APC mosaicism in classic FAP etiology. The results further reinforce the importance of testing target tissues when blood test results are negative.
Asunto(s)
Proteína de la Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/genética , Neoplasias Colorrectales/genética , Genes APC , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/métodos , Mutación de Línea Germinal , Mosaicismo , Poliposis Adenomatosa del Colon/patología , Adulto , Anciano , Estudios de Cohortes , Neoplasias Colorrectales/patología , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
It was hypothesized that variants in underexplored homologous recombination repair (HR) genes could explain unsolved multiple-case breast cancer (BC) families. We investigated HR deficiency (HRD)-associated mutational signatures and second hits in tumor DNA from familial BC cases. No candidates genes were associated with HRD in 38 probands previously tested negative with gene panels. We conclude it is unlikely that unknown HRD-associated genes explain a large fraction of unsolved familial BC.
RESUMEN
The MRN complex, composed of MRE11A, RAD50, and NBN, mediates vital molecular functions to maintain genomic stability and hence protect against related disorders. Germline mutations in the MRN genes predispose to three different syndromes: ataxia-telangiectasia-like disorder (MRE11A deficiency), Nijmegen breakage syndrome (NBS; NBN deficiency), and NBS-like disorder (RAD50 deficiency). The potential cancer component of these syndromes in addition to the close physical and functional proximity of the MRN complex to BRCA1 has promoted the MRN genes as candidate risk genes for developing breast cancer. This notion has been challenged by independent large-scale population-based studies. Despite having their two-decade old candidacy as breast cancer genes close to being refuted, it has recently been reported that the MRN genes rise to have potential new roles in clonal hematopoiesis. In this article, we discuss the history and current status of MRN genes' clinical utility in breast cancer and then focus on their recently uncovered and less understood roles in clonal hematopoiesis that likely predispose to health-related disorders such as hematologic malignancies and/or cardiovascular morbid events.
Asunto(s)
Ácido Anhídrido Hidrolasas/genética , Neoplasias de la Mama/etiología , Neoplasias de la Mama/genética , Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Proteína Homóloga de MRE11/genética , Mutación , Proteínas Nucleares/genética , Neoplasias de la Mama/epidemiología , Femenino , Humanos , Medición de RiesgoRESUMEN
Background: The crossed cerebro-cerebellar (CCC) activation facilitates the diagnosis of cortical language lateralization, but needs to be explored with language tasks suitable for patients with different age ranges, educational attainment and eventual presence of language deficits. Aim: To determine the effect of demographic variables in the performance of three language tasks in healthy volunteers and to determine the CCC activation of these tasks as a functional magnetic resonance imaging (fMRI) paradigm in brain tumor patients. Material and Methods: The behavioral performance (correct responses and reaction time) of three language tasks (verbal fluency, semantic and phonological decision tasks) was first examined in 76 healthy volunteers balanced by age and educational level. Later, these tasks were implemented as fMRI paradigms to explore CCC language activation of 20 patients with potential diagnosis of brain tumors. Results: The performance of the verbal fluency task was affected by age. The CCC language activation was reproducible with the semantic and phonological tasks. The combination of the tasks determined typical and atypical language lateralization in 60% and 40% of our patients, respectively. Conclusions: The verbal fluency task must be implemented with care as a clinical fMRI paradigm. Our results suggest that semantic and phonological tasks can be a good alternative for brain tumor patients with language deficits.