Laura Papi

Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria.

Schwannomatosis is the third major form of neurofibromatosis and is characterized by the development of multiple schwannomas in the absence of bilateral vestibular schwannomas. The 2011 Schwannomatosis Update was organized by the Childrens Tumor Foundation (www.ctf.org) and held in Los Angeles, CA, from June 5–8, 2011. This article summarizes the highlights presented at the Conference and represents the “state‐of‐the‐field” in 2011. Genetic studies indicate that constitutional mutations in the SMARCB1 tumor suppressor gene occur in 40–50% of familial cases and in 8–10% of sporadic cases of schwannomatosis. Tumorigenesis is thought to occur through a four‐hit, three‐step model, beginning with a germline mutation in SMARCB1 (hit 1), followed by loss of a portion of chromosome 22 that contains the second SMARCB1 allele and one NF2 allele (hits 2 and 3), followed by mutation of the remaining wild‐type NF2 allele (hit 4). Insights from research on HIV and pediatric rhabdoid tumors have shed light on potential molecular pathways that are dysregulated in schwannomatosis‐related schwannomas. Mouse models of schwannomatosis have been developed and promise to further expand our understanding of tumorigenesis and the tumor microenvironment. Clinical reports have described the occurrence of intracranial meningiomas in schwannomatosis patients and in families with germline SMARCB1 mutations. The authors propose updated diagnostic criteria to incorporate new clinical and genetic findings since 2005. In the next 5 years, the authors expect that advances in basic research in the pathogenesis of schwannomatosis will lead toward clinical investigations of potential drug therapies.

Screening for mutations in the neurofibromatosis type 2 (NF2) gene in sporadic meningiomas

Meningiomas are benign tumors of the central nervous system. They are usually sporadic but can also occur associated with the neurofibromatosis type 2 (NF2) syndrome. The gene responsible for NF2, recently isolated from chromosome 22, encodes a membrane-organizing protein that shows high sequence homology to a protein family thought to link the cytoskeleton with membrane proteins. Mutations of the NF2 gene have been described in sporadic meningiomas, exclusively in tumors that show loss of heterozygosity (LOH) of 22q. These preliminary results indicate that the NF2 gene is involved in the pathogenesis of at least a subset of meningiomas, where it does indeed behave as a tumor suppressor gene. In order to characterize better the role of the NF2 gene in the genesis of meningiomas we have examined the entire coding sequence of the gene in 125 meningiomas by single-strand conformational polymorphism analysis; furthermore, LOH analysis for markers of 22q has been carried out. Inactivating mutations were identified in 30% of our samples, all of which also showed LOH of 22q. The majority of mutations identified were frameshifts and nonsense mutations, which are predicted to produce a truncated or non-functional protein. We also found two missense and three in-frame deletions that may pinpoint specific regions of the protein critical to its function. Furthermore, the distribution of mutations throughout the gene, suggested that exons 2, 3, 5, 11 and 13 are more frequently involved. Our results reconfirm the importance of the NF2 gene in the pathogenesis of meningiomas and also suggest that there may be a nonrandom clustering of mutations throughout the gene.

The location of constitutional neurofibromatosis 2 ( NF2 ) splice site mutations is associated with the severity of NF2

Neurofibromatosis 2 (NF2) patients with constitutional splice site NF2 mutations have greater variability in disease severity than NF2 patients with other types of mutations; the cause of this variability is unknown. We evaluated genotype-phenotype correlations, with particular focus on the location of splice site mutations, using mutation and clinical information on 831 patients from 528 NF2 families with identified constitutional NF2 mutations. The clinical characteristics examined were age at onset of symptoms of NF2 and number of intracranial meningiomas, which are the primary indices of the severity of NF2. Two regression models were used to analyse genotype-phenotype correlations. People with splice site mutations in exons 1–5 had more severe disease than those with splice site mutations in exons 11–15. This result is compatible with studies showing that exons 2 and 3 are required for self-association of the amino terminal of the NF2 protein in vitro, and that deletions of exons 2 and 3 in transgenic and knockout mouse models of NF2 cause a high prevalence of Schwann cell derived tumours.

Schwannomatosis associated with multiple meningiomas due to a familial SMARCB1 mutation

Schwannomatosis (MIM 162091) is a condition predisposing to the development of central and peripheral schwannomas; most cases are sporadic without a clear family history but a few families with a clear autosomal dominant pattern of transmission have been described. Germline mutations in SMARCB1 are associated with schwannomatosis. We report a family with multiple schwannomas and meningiomas. A SMARCB1 germline mutation in exon 1 was identified. The mutation, c.92A>T (p.Glu31Val), occurs in a highly conserved amino acid in the SMARCB1 protein. In addition, in silico analysis demonstrated that the mutation disrupts the donor consensus sequence of exon 1. RNA studies verified the absence of mRNA transcribed by the mutant allele. This is the first report of a SMARCB1 germline mutation in a family with schwannomatosis characterized by the development of multiple meningiomas.

Somatic mutations in the neurofibromatosis type 2 gene in sporadic meningiomas

Meningiomas are benign tumors of the central nervous system. Although usually sporadic, they can occur in patients affected by the autosomal dominant syndrome, neurofibromatosis type 2 (NF2). The NF2 gene has recently been isolated from chromosome 22. The presence of germline mutations in NF2 patients and the loss of heterozygosity (LOH) on 22q in NF2 tumors support the hypothesis that the NF2 gene acts as a tumor suppressor. Cytogenetic and LOH studies have suggested that the gene responsible for the development of meningiomas is located in the region of 22q in which the NF2 gene maps. The meningioma gene could therefore be the NF2 gene itself. Recently, somatic mutations of the NF2 gene have been identified in sporadic meningiomas, thus supporting the hypothesis that the NF2 gene is also important in meningioma pathogenesis. In this study, we analyzed sixty-one sporadic meningiomas for LOH of 22q and for mutations in the NF2 gene. LOH was detected in 36 of the 60 informative tumors. Single-strand conformational polymorphism analysis was used to identify nine mutations in five of the eight exons of the NF2 gene studied. The nine tumors with an altered NF2 gene also showed LOH for 22q markers. These results further support the hypothesis that mutations in the NF2 gene are a critical pathogenetic event in at least some meningiomas.

Types, stability, and phenotypic consequences of chromosome rearrangements leading to interstitial telomeric sequences.

Using in situ hybridisation, we identified interstitial telomeric sequences in seven chromosomal translocations present in normal and in syndromic subjects. Telomeric sequences were also found at the centromeric ends of a 4p and a 4q caused by centric fission of one chromosome 4. We found that rearrangements leading to interstitial telomeric sequences were of three types: (1) termino-terminal rearrangements with fusion of the telomeres of two chromosomes, of which we report one case; (2) rearrangements in which an acentric fragment of one chromosome fuses to the telomere of another chromosome. We describe four cases of Prader-Willi syndrome with the 15q1-qter transposed to the telomeric repeats of different recipient chromosomes; (3) telomere-centromere rearrangements in which telomeric sequences of one chromosome fuse with the centromere of another chromosome. We describe two examples of these rearrangements in which not only telomeric sequences but also remnants of alphoid sequences were found at the fusion point. Instability at the fusion point of the derivative chromosome was found in the Prader-Willi translocations but we were unable to correlate this instability with culture conditions. The two subjects with the termino-terminal rearrangement and the centric fission respectively have normal phenotypes. The two patients with telomere-centromere fusions were unbalanced for the short arm of an acrocentric chromosome and had failure to thrive; one of them also had dysmorphic facies. We postulate that these phenotypes could be the result of uniparental disomy.

Genetic insights into familial tumors of the nervous system.

Nervous system tumors represent unique neoplasms that arise within the central and peripheral nervous system. While the vast majority of nervous system neoplasm occur sporadically, most of the adult and pediatric forms have a hereditary equivalent. In a little over a decade, we have seen a tremendous increase in knowledge of the primary genetic basis of many of the familial cancer syndromes that involve the nervous system, syndromes that are mostly inherited as autosomal dominant traits. In this review, we discuss the most recent findings on the genetic basis of hereditary nervous system tumors. The identification of genes associated with familial cancer syndromes has in some families enabled a “molecular diagnosis” that complements clinical assessment and allows directed cancer surveillance for those individuals determined to be at‐risk for disease.

An Italian family affected by Nasu-Hakola disease with a novel genetic mutation in the TREM2 gene

Polycystic lipomembranous osteodysplasia with sclerosing leucoencephalopathy (PLOSL; MIM 221770), also known as Nasu-Hakola disease, is a recessively inherited disorder characterised by systemic bone cysts and progressive presenile dementia associated with sclerosing leucoencephalopathy.1 The onset usually occurs in the third decade of life with pathological fractures; later on, symptoms of frontal lobe dysfunction appear, with upper motor neurone involvement and epileptic seizures. Some patients, however, do not have clinically manifest osseous problems despite the radiological demonstration of cystic bone lesions. The disease leads to death before the age of 50.1 The disease is characterised by genetic heterogeneity: mutations in two genes (TYROBP and TREM2) encoding different subunits of a membrane receptor complex in natural killer and myeloid cells have been associated with the disease.2,3 This rare disorder was initially described in Finland and Japan but is now recognised to have a worldwide distribution.1 In particular, sporadic cases have been described in Italy,4,5 and a homozygous mutation in the splice donor consensus site at intron 3 of TREM2 has been identified in two affected siblings.3 We report here the clinical and genetic analysis of an Italian family in which two siblings are affected by PLOSL. After giving …

A kindred with MYH-associated polyposis and pilomatricomas

MYH‐associated polyposis (MAP) is a recently described autosomal recessive form of familial adenomatous polyposis (FAP) associated with susceptibility to colorectal carcinoma (CRC). MAP is caused by biallelic inactivating mutations of the MYH gene, a component of the base excision repair (BER) machinery, whose dysfunction leads to an increase in the rate of G > T transversions following DNA oxidative damage. MAP patients can present with either classic or attenuated polyposis. However, the MAP colonic and extracolonic phenotype has yet to be defined. We report on two siblings, born from consanguineous parents, who were found to be homozygotes for an MYH frameshift mutation. The propositus presented with a low number of colonic lesions and an early‐onset CRC. Both siblings had a history of pilomatricomas, benign tumors derived from hair follicles, in childhood. The findings presented provide further evidence of phenotypic variability in MAP, and suggest that multiple pilomatricomas may be a useful cutaneous marker of MAP.

Interleukin-10 promoter polymorphisms influence susceptibility to ulcerative colitis in a gender-specific manner

Objective. Pathological evidence supports a potential role of the pro- and anti-inflammatory cytokine network in the pathogenesis of inflammatory bowel disease (IBD). Moreover, associated studies suggest a possible involvement of cytokine-related genes in IBD susceptibility. In this study, we evaluated the effect of the anti-inflammatory interleukin-10 (IL10) gene on ulcerative colitis (UC). Material and methods. Two functional single nucleotide polymorphisms (−1082 G/A, −819 T/C) in the IL10 promoter in 203 Italian sporadic UC patients and 391 controls were determined using high-resolution melting analysis. Results. The frequency of the −1082A allele was significantly higher in the UC patients than in controls (p=0.00003); −1082 genotype frequencies were also significantly different between UC patients and controls (p=0.0001). Allele and genotype frequencies of −819 T/C were not significantly associated with UC. Furthermore, the frequencies of haplotypes −1082A/−819C and −1082A/−819T, which have been reported to have a lower promoter activity, were significantly higher in UC patients than in controls (p=0.0004). After gender stratification, we found a significant difference in the −1082A allele (p=0.00004) and genotype (p=0.0002) frequencies only between female UC patients and controls; the same result was obtained for the −1082A/−819C and −1082A/−819T haplotypes (p=0.0006). Conclusions. A gender effect is observed, with women of AG/AA IL10 genotypes and AC/AT haplotypes having a higher risk of developing UC at a younger age. This finding could be related to the previously documented lower IL10 production associated with the −1082A allele and to the IL10 down-regulating effect of estrogens.