51684

SUFU

PRO1280|SUFUH|SUFUXL;suppressor of fused homolog (Drosophila);SUFU;suppressor of fused homolog (Drosophila)

suppressor of fused homolog

10q24.32

protein-coding

Abnormalities of chromosome 10 are frequently observed in the development of medulloblastoma, the most common malignant brain tumor of childhood. To identifycritical genetic loci involved, we performed detailed physical mapping of regions of allelic loss on this chromosome. 18% of cases (5/32 primary tumors, 2/8 cell lines) harbored allelic losses on 10q. Refined mapping identified a 21.7Mb common interval, affecting the region 10q23.3-10q25.3. This region contains three genes, MXI1, SUFU and BTRC, which represent putative medulloblastoma tumor suppressor (TS) genes on the basis of either (i) negative regulation of critical medulloblastoma pathways, or (ii) mutation in other cancer types. We therefore sought evidence of their genetic inactivation in 46 cases, by mutational analysis of their entire coding regions. A MXI1 mutation was identified which abolishes its translation initiation site (A1G; MET1VAL), however no further tumor-specific sequence variations were detected. We next identified and characterised CpG islands associated with 5' regions of the MXI1, SUFU and BTRC genes; analysis ofthese regions for evidence of DNA hypermethylation, alongside expression analysis of their respective transcripts, revealed no evidence to support epigenetic inactivation of any gene. These findings implicate the inactivation of critical TS loci at 10q23.3-25.3 in medulloblastoma, however comprehensive analysis of SUFU, BTRC and MXI1 indicates they are unlikely to represent major targets of these allelic losses. MXI1 mutation appears to play a role in the pathogenesis of a small subset of cases, and suggests an alternative mechanism to MYC amplification for disruption of the MYC/MAD/MAX network in medulloblastoma.

BACKGROUND: Recent advances in multidisciplinary treatment approaches have improved the overall prognosis of pediatric brain tumors, but some patients remain refractory to treatment and do poorly. Several molecularly targeted therapies are under development for the treatment of brain tumors, and high-grade gliomas in adults are a particular area of study. PROCEDURE: To better understand if these new therapies can be used in pediatric populations, we examined the expression of the following seven marker genes involved in signaling pathways targeted by new therapies: beta-catenin, suppressor of fused (SUFU), erythroblastic leukemia viral oncogene homolog (ERBB) 2, platelet-derived growthfactor receptoralpha (PDGFRalpha), proliferating cell nuclear antigen (PCNA), secreted protein acid and rich in cysteine (SPARC), and granulocyte colony-stimulating factor receptor (G-CSFR). Samples from 27 patients with the primitive neuroectodermal tumor (PNET)/medulloblastomas (MBs) (n = 8), ependymomas (n = 5), or gliomas (n = 14) were assessed by quantitative real-timePCR. [Correction made here after initial online publication]. We assigned an EXPscore to compare across samples and determined the levels of gene expression among tumor cell types. RESULTS: Gene expression varied among the different tumors, but, within a tumor type, clear expression patterns were seen. The expression of SUFU, ERBB2, and PCNA in metastatic MBs were greater than that seen in non-metastatic MBs. Most glioma cases highly expressed PDGFRalpha and G-CSFR.Additionally, the expression patterns of gliomas and ependymomas were similar (r= 0.77, P = 0.04), but PNET/MBs substantially differed from gliomas (r = -0.37, P = 0.41) or ependymomas (r = 0.23, P = 0.62). CONCLUSIONS: The development of newdrugs targeting up-regulated pathways may be useful for the treatment of pediatric brain tumors. As new drugs are developed, gliomas and ependymomas may be treated with similar compounds.#CI- Copyright (c) 2011 Wiley Periodicals, Inc.

Meningiomas are the most common primary tumors of the CNS and account for up to 30% of ALL CNS tumors. An increased risk of meningiomas has been associated withcertain tumor-susceptibility syndromes, especially neurofibromatosis type II, but no gene defects predisposing to isolated familial meningiomas have thus far beenidentified. Here, we report on a family of five meningioma-affected siblings, four of whom have multiple tumors. No NF2 mutations were identified in the germline or tumors. We combined genome-wide linkage analysis and exome sequencing, and we identified in suppressor of fused homolog (Drosophila), SUFU,a c.367C>T (p.Arg123Cys) mutation segregating with the meningiomas in the family. The variation was not present in healthy controls, and ALL seven meningiomas analyzed displayed loss of the wild-type allele according to the classic two-hitmodel for tumor-suppressor genes. In silico modeling predicted the variant to affect the tertiary structure of the protein, and functional analyses showed that the activity of the altered SUFU was significantly reduced and therefore led to dysregulated hedgehog (Hh) signaling. SUFU is a known tumor-suppressor gene previously associated with childhood medulloblastoma predisposition. Our geneticand functional analyses indicate that germline mutations in SUFU also predisposeto meningiomas, particularly to multiple meningiomas. It is possible that other genic mutations resulting in aberrant activation of the Hh pathway might underlie meningioma predisposition in families with an unknown etiology.#CI- Copyright (c) 2012 The American Society of Human Genetics. Published by ElsevierInc. ALL rights reserved.