Medulloblastoma Development in a Patient with a Constitutional Balanced t(5;22)(q35.1;q11.2) Involving the NF2 Gene

Abstract

Neurofibromatosis type 2 (NF2) is a brain tumor predisposing syndrome caused by inactivating alterations of the NF2 gene mapped at chromosome 22q. Currently, no genetic information exists on medulloblastomas occurring in NF2 patients. We herein report on the genetic alterations observed in a girl in which the NF2 gene was de novo altered due to a constitutional translocation: t(5;22)(q35.1;q11.2). This girl had a particularly aggressive disease course. At the age of 4, she had already been diagnosed with three lesions classified as schwannomas and a meningioma. At 10 years old, she developed a medulloblastoma. She died at the age of 14 due to a refractory acute myeloid leukemia (AML). From the genetic point of view, we observed that (1) the NF2 gene was rearranged in all patient samples: blood, tumor, and leukemic cells; (2) loss of 3' region of NF2 and the downstream regions of chromosome 22 were only detected in medulloblastoma cells; (3) the known cancer AML-related gene: NPM1 which is mapped at 5q35.1 was not the target of any alteration in our patient. Our data suggest that inactivation of the NF2 gene was relevant for the medulloblastoma pathogenesis. Furthermore, we know that malignant cancers are the result of a multi-epi-genetic sequence of events, and although, unquestionably limited to the genetic findings in one case. We may hypothesize, that as described for a fraction of medulloblastomas, the alteration of a gene mapped at 5q might also have been relevant for medulloblastoma development in our patient.

Keywords: Constitutional translocation; Medulloblastoma; NF2; Translocation.

Fig. 1.

a MRI (sagittal T1-weighted image with gadolinium) showing a contrast-enhanced solid cerebellar lesion. b MRI (axial T1-weighted image with gadolinium) showing leptomeningeal dissemination in cerebellum and left cerebellopontine angle (arrows). c Medulloblastoma of the histological defined classic form: poorly differentiated round and polyhedric embryonal cells with high mitotic activity (arrows) (H&E ×40). d Immunoreactivity for neurofilament antibody (×40).

Fig. 2.

a Tumor metaphase showing the two der(22)t(5;22)(q35.1;q11.2) chromosomes. b Peripheral blood metaphase of the patient showing the constitutional t(5;22)(q35.1; q11.2). cNF2 FISH in a tumor metaphase; the 5′ NF2 BAC probe was labelled with a red fluorochrome (spectrum orange) and the 3′ NF2 BAC probe was labelled with a green fluorochrome (spectrum green). dNF2 FISH in a peripheral metaphase of the patient, as previously mentioned; the 5′ NF2 BAC probe was labelled with a red fluorochrome (spectrum orange) and the 3′ NF2 BAC probe was labelled with a green fluorochrome (spectrum green).