Identification of genetic aberrations on chromosome 22 outside theNF2locus in schwannomatosis and neurofibromatosis type 2

Abstract

Schwannomatosis is characterized by multiple peripheral and cranial nerve schwannomas that occur in the absence of bilateral 8th cranial nerve schwannomas. The latter is the main diagnostic criterion of neurofibromatosis type 2 (NF2), which is a related but distinct disorder. The genetic factors underlying the differences between schwannomatosis and NF2 are poorly understood, although available evidence implicates chromosome 22 as the primary location of the gene(s) of interest. To investigate this, we comprehensively profiled the DNA copy number in samples from sporadic and familial schwannomatosis, NF2, and a large cohort of normal controls. Using a tiling-path chromosome 22 genomic array, we identified two candidate regions of copy number variation, which were further characterized by a PCR-based array with higher resolution. The latter approach allows the detection of minute alterations in total genomic DNA, with as little as 1.5 kb per measurement point of nonredundant sequence on the array. In DNA derived from peripheral blood from a schwannomatosis patient and a sporadic schwannoma sample, we detected rearrangements of the immunoglobulin lambda (IGL) locus, which is unlikely to be due to a B-cell specific somatic recombination of IGL. Analysis of normal controls indicated that these IGL rearrangements were restricted to schwannomatosis/schwannoma samples. In the second candidate region spanning GSTT1 and CABIN1 genes, we observed a frequent copy number polymorphism at the GSTT1 locus. We further describe missense mutations in the CABIN1 gene that are specific to samples from schwannomatosis and NF2 and make this gene a plausible candidate for contributing to the pathogenesis of these disorders.

Lack of Neurofibromatosis Type 2 Gene Promoter Methylation in Sporadic Vestibular Schwannomas

“…However, several studies suggest a subset of VS with no NF2 gene-related aberrations and retention of wild-type NF2 expression [11,[18][19][20][21] . The lack of NF2 aberrations in such cases prompts the question of how the NF2 pathway is abolished in these tumors.…”

Microarray‐based survey of CpG islands identifies concurrent hyper‐ and hypomethylation patterns in tissues derived from patients with breast cancer

“…High-resolution, nonredundant array fabrication technology has proven successful in several studies for analytical level measurements of DNA copy number (Mantripragada et al, 2004;Buckley et al, 2005;Dhami et al, 2005;Mantripragada et al, 2005;de Bustos et al, in press). We aimed here to test the usefulness of this approach to analyze tissue-specific CpG island methylation.…”

Gene expression signature for recurrence in stage III colorectal cancers

“…17,18 CABIN1 gene is located immediately downstream of the GSTT1, and increased expression of GSTT1 is known to prevent some cancers. 7,16 Conversely, GSTT1 gene coding is polymorphic, and null genotype shows significantly poorer differentiation of colorectal cancer. 19 In the present study as well, GSTT1 showed lower expression in patients with recurrence.…”

“…A previous study showed that alteration of the DNA copy number in a region near CABIN1 was associated with numerous cancer types. 7 Therefore, we further examined the DNA copy number of CABIN1 and could show a significant relation between copy number and recurrence. To the best of our knowledge, CABIN1 has not been reported in the context of recurrence in malignancy.…”