Loss of SUFU Function in Familial Multiple Meningioma

Abstract

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 with certain tumor-susceptibility syndromes, especially neurofibromatosis type II, but no gene defects predisposing to isolated familial meningiomas have thus far been identified. 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-hit model 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 genetic and functional analyses indicate that germline mutations in SUFU also predispose to 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.

Recent developments in brain tumor predisposing syndromes

“…The most well described gene is the SHH receptor PTCH1 [63], and recently germline mutations in the downstream regulator SUFU were found in a subset of the NBCCS patients [64]. In addition, germline mutation in SUFU has also been described in a large Finnish family with hereditary meningiomas [65].…”

Members of the Rusc protein family interact with Sufu and inhibit vertebrate Hedgehog signaling

“…Loss of Sufu elevates vertebrate Hh signaling and induces severe patterning defects during development (Wolff et al, 2003;Cooper et al, 2005;Svard et al, 2006;Min et al, 2011). In humans, oncogenic mutations in SUFU have been identified from medulloblastoma, basal cell carcinoma and other cancers (Taylor et al, 2002;Pastorino et al, 2009;Brugieres et al, 2010;Aavikko et al, 2012;Kijima et al, 2012;Schulman et al, 2015). Despite the fundamental roles played by Sufu in development and cancer, it is largely unclear how the Sufu protein itself is regulated.…”

“…As expected, Sufu-depleted Xenopus embryos develop severely reduced eyes (Min et al, 2011). In humans, inherited and sporadic mutations in SUFU have been identified in a wide variety of cancers, including medulloblastoma (Taylor et al, 2002;Brugieres et al, 2010), meningioma (Aavikko et al, 2012) and basal cell carcinoma (Pastorino et al, 2009;Kijima et al, 2012;Schulman et al, 2015). Interestingly, in contrast to Sufu in other vertebrate species, zebrafish Sufu is a weak Hh inhibitor, and knockdown of Sufu causes only a marginal increase in Hh signaling during zebrafish embryonic development (Wolff et al, 2003).…”

A novel mutation of the FAT2 gene in spinal meningioma

“…In Drosophila, the PCP signaling molecules have been well characterized, and include Frizzled [human homologs, frizzled class receptor (FZD) 3 (8,9). The current study performed whole exome sequencing (WES) analysis to identify mutated genes in spinal meningioma by screening the human homologs of Drosophila PCP genes, in addition to Ft-Hpo signaling genes.…”

“…Based on molecular pathogenesis, meningiomas are classified as neurofibromin 2 [NF2; Drosophila Merlin (Mer)] mutant meningiomas (NF2-associated meningiomas) and non-NF2 meningiomas, with the loss of NF2 observed in 40-60% of sporadic meningioma cases (1,2). Hedgehog (Hh) signaling molecules are considered to be involved in the pathogenesis of meningioma due to the detection of suppressor of fused (SUFU), a component of the Hh signaling pathway, in familial multiple meningioma (3). However, the frequency of mutations in SUFU is extremely low, with no SUFU mutations detected in a study of 162 individuals with sporadic meningioma (3).…”