RESUMEN
BACKGROUND: Multiple meningiomas occur in <10% of meningioma patients. Their development may be caused by the presence of a predisposing germline mutation in the neurofibromatosis type 2 (NF2) gene. The predisposing gene in patients with non-NF2 associated multiple meningiomas remains to be identified. Recently, SMARCB1 was reported to be a potential predisposing gene for multiple meningiomas in a family with schwannomatosis and multiple meningiomas. However, involvement of this gene in the development of the meningiomas was not demonstrated. RESULTS: Five affected members of a large family with multiple meningiomas were investigated for the presence of mutations in SMARCB1 and NF2. A missense mutation was identified in exon 2 of SMARCB1 as the causative germline mutation predisposing to multiple meningiomas; furthermore, it was demonstrated that, in accordance with the two-hit hypothesis for tumourigenesis, the mutant allele was retained and the wild-type allele lost in all four investigated meningiomas. In addition, independent somatically acquired NF2 mutations were identified in two meningiomas of one patient with concomitant losses of the wild-type NF2 allele. CONCLUSION: It is concluded that, analogous to the genetic events in a subset of schwannomatosis associated schwannomas, a four-hit mechanism of tumour suppressor gene inactivation, involving SMARCB1 and NF2, might be operative in familial multiple meningiomas associated meningiomas.
Asunto(s)
Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Genes de la Neurofibromatosis 2 , Mutación de Línea Germinal/genética , Meningioma/genética , Factores de Transcripción/genética , Secuencia de Bases , Análisis Mutacional de ADN , Cartilla de ADN/genética , Femenino , Genotipo , Humanos , Masculino , Meningioma/patología , Repeticiones de Microsatélite/genética , Datos de Secuencia Molecular , Mutación Missense/genética , Linaje , Proteína SMARCB1RESUMEN
Schwannomatosis is characterized by the development of multiple schwannomas of the nervous system, but without the occurrence of vestibular schwannomas. Most cases of schwannomatosis are thought to be sporadic, representing the first case in a family due to a new mutation in the causative gene. We recently identified SMARCB1/INI1 as a schwannomatosis-predisposing gene. Here, we analyzed this gene in a schwannomatosis family with two affected children, but with clinically unaffected parents. Both affected individuals carried a constitutional SMARCB1 mutation, c.1118+ 1G>A, that changes the donor splice site sequence of intron 8, causing skipping of exon 8 and resulting in the in-frame deletion of 132 nucleotides in the transcript. The mutation was not evident in constitutional DNA of the parents. Haplotyping revealed that the chromosome 22 segment that carries the mutant SMARCB1 allele originated from the mother. She transferred the same chromosome 22 segment, however, with a wild-type SMARCB1 copy, to a third unaffected child. Our findings indicate that the mother is germ line mosaic for the SMARCB1 mutation. In conclusion, our study shows for the first time that germ line mosaicism may occur in schwannomatosis, which has implications for genetic counseling in this disease.
Asunto(s)
Proteínas Cromosómicas no Histona/genética , Cromosomas Humanos Par 22/genética , Proteínas de Unión al ADN/genética , Mosaicismo , Neurilemoma/genética , Factores de Transcripción/genética , Adulto , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Masculino , Persona de Mediana Edad , Linaje , Sitios de Empalme de ARN , Proteína SMARCB1RESUMEN
OBJECTIVE: We report on a patient who developed a meningioma more than two decades after removal at a young age of an atypical teratoid/rhabdoid tumour (AT/RT), which was due to a germline INI1 mutation, and radio- and chemotherapy. MATERIALS AND METHODS: We present genetic evidence that the meningioma is not a recurrence or metastasis of the AT/RT and not due to the INI1 mutation, but is a radiation-induced tumour. CONCLUSION: This is the first case illustrating that improved survival of young patients with an AT/RT after aggressive treatment may be gained at the cost of an increased risk for the development of radiation-induced, non-INI1-related tumours.
Asunto(s)
Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Meningioma/secundario , Mutación/genética , Tumor Rabdoide/genética , Factores de Transcripción/genética , Adulto , Predisposición Genética a la Enfermedad , Humanos , Pérdida de Heterocigocidad , Masculino , Meningioma/genética , Polimorfismo de Nucleótido Simple , Radioterapia/efectos adversos , Radioterapia/métodos , Tumor Rabdoide/patología , Tumor Rabdoide/radioterapia , Proteína SMARCB1RESUMEN
Rhabdoid tumour predisposition syndrome (RTPS) is a rare syndrome caused by inheritance of a mutated INI1 gene for which only two multigeneration families have been reported. To further characterise the genotype and phenotype of RTPS, we present a third family in which at least three cousins developed an atypical teratoid/rhabdoid tumour (AT/RT) at a young age. Two of these patients showed unusual long survival, and one of these developed an intracranial meningioma and a myoepithelioma of the lip in adulthood. Mutation analysis of INI1 revealed a germline G>A mutation in the donor splice site of exon 4 (c.500+1G>A) in the patients and in their unaffected fathers. This mutation prevents normal splicing and concomitantly generates a stop codon, resulting in nonsense-mediated mRNA decay. Biallelic inactivation of INI1 in the tumours, except for the meningioma, was confirmed by absence of nuclear INI1-protein staining. The myoepithelioma of one of the patients carried an identical somatic rearrangement in the NF2 gene as the AT/RT, indicating that both tumours originated from a common precursor cell. In conclusion, this study demonstrates for the first time transmission of a germline INI1-mutation in a RTPS family via nonpenetrant males, long-term survival of two members of this family with an AT/RT, and involvement of INI1 in the pathogenesis of myoepithelioma.
Asunto(s)
Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Familia , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Patrón de Herencia , Penetrancia , Tumor Rabdoide/genética , Factores de Transcripción/genética , Adolescente , Adulto , Secuencia de Bases , Preescolar , Cromosomas Humanos Par 22 , Análisis Mutacional de ADN , Femenino , Humanos , Lactante , Masculino , Repeticiones de Microsatélite/genética , Linaje , Tumor Rabdoide/mortalidad , Proteína SMARCB1 , Caracteres Sexuales , Análisis de Supervivencia , Síndrome , Factores de TiempoRESUMEN
BACKGROUND: Due to their invasive growth, gliomas usually cannot be removed completely and almost always recur as same grade or higher grade malignancies. OBJECTIVE: To determine whether there were differences in the accumulation of genetic changes between the two types of glioma recurrence. METHODS: We genetically characterised 14 cases of lower grade glioma with a same grade recurrence, 12 cases of glioblastoma recurrence, and 14 cases of lower grade glioma with a higher grade recurrence. We investigated LOH (loss of heterozygosity) at 1p36, 10p15, the PTEN region in 10q23, the DMBT1 region in 10q25, 19q13, 22q13, LOH and mutation of TP53, and EGFR amplification. RESULTS: Genetic heterogeneity in the primary tumour was inferred in 3 cases of lower grade glioma with a higher grade recurrence. The cases of lower grade glioma with a higher grade recurrence displayed increased genetic instability in the recurrence (mean of 2.0 additional genetic changes per case) compared to cases with a same lower grade recurrence or those with a glioblastoma recurrence (mean of 0.6 and 0.8 additional changes per case, respectively). Compared to unselected primary glioblastomas, the glioblastomas that recurred as an operable tumour had infrequent EGFR amplification (8% v 30-40% of cases). CONCLUSIONS: Gliomas recurring as higher grade lesions might be genetically heterogeneous and accumulate more genetic changes than gliomas recurring as same grade lesions (whether originally low or high grade). Primary glioblastomas from patients for which the recurrence is operated because of prognostically more favourable clinical indices have infrequent EGFR amplification.