38 Biology and Genetics of Skull Base Tumors This chapter summarizes our current knowledge of the cell biology and genetics of common skull base tumors, including aspects of stem cell biology, genetics, epigenetics, proteomics, receptor signaling, cell cycle and cell death pathways, predictors of aggressive biological behavior, and associations. Lactoferrin expression is shared with fetal chondroblasts and osteoblasts.1 These tumors have no recurrent chromosomal aberrations or IDH1 mutations.2 These tumors demonstrate Sox9 transcription factor expression. Sox9 is involved in signaling differentiation from chondrogenic mesenchymal cells to early chondroblasts.3 Growth plate signaling involves Indian hedgehog and parathyroid hormone–related protein (IHH/PThrP) and fibroblast growth factor (FGF) pathways.4 Sex-hormone receptor signaling is also present.5 • Diffuse expression of SRD5A1, an enzyme that catalyzes the conversion of testosterone to dihydrotestosterone. Diffuse expression of CYP19, converts testosterone to estrogen. Diffuse expression of ESR1 (estrogen receptor alpha). Low/absent expression of CA-RP X (carbonic anhydrase protein X). Malignant transformation to chondrosarcoma can occur after radiotherapy, and therefore radiation should be avoided in this tumor.6 This tumor shares similar histological and molecular features with chondromyxoid fibroma. Liver kinase b1 (Lkb1)-dependent inhibition of mammalian target of rapamycin (mTOR) C1 regulates the transition from mitotic chondrocytes to mature post-mitotic chondrocytes. Loss of Lkb1 function results in enchondroma-like masses in mice, and this phenotype can be reversed with the mTOR C1 inhibitor.7 Seventy-one percent of patients with this tumor harbor the IDH1 mutation (R132C is the most frequent).8 The IHD2 mutation is also observed, but is infrequent (2% in Ollier disease and Maffucci syndrome patients). In one study, the R150C mutation in the parathyroid hormone receptor 1 (PTHR1) gene was found in two of six patients with Ollier disease and was shown to be pathogenic for chondromas in mice by slowing chondrocyte differentiation.9 The epigenetics of this tumor are evident as hypermethylation.10 Expression of IDH1 R132H mutant protein shows intraneoplastic mosaicism.10 Overexpression of the Gli2 transcription factor is sufficient to cause enchondroma-like lesions in mice.9 Among patients with multiple enchondromas (Maffucci and Ollier disease), there is a 44–50% risk of developing chondrosarcoma when the enchondromas are located in the axial skeleton.11 Ollier disease is associated with multiple enchondromas. Maffucci syndrome is associated with multiple enchondromas and subcutaneous spindle cell hemangiomas. Ollier disease and Maffucci syndrome are also associated with somatic mosaic mutations in IDH1 and IDH2.12 Chondrosarcoma types recapitulate the cellular phenotypic heterogeneity found during fetal chondrogenesis, suggesting that the most likely origin of the neoplastic cell is multipotent mesenchymal cells.13 Expression of mutant IDH2 in murine mesenchymal progenitor cells generates undifferentiated sarcomas in vivo.14 Forty-six percent to 59% of patients carry the IDH1/2 mutations, with the IDH1 R132C mutation occurring most frequently.15,16 The alpha chain of type II collagen, the major cartilage collagen, is encoded by the COL2A1 gene. Mutations that affect the coding sequence of COL2A1 are found in 44% of chondrosarcomas. These mutations are predicted to affect the collagen maturation process and may therefore impair chondrocyte differentiation.16 COL2A1 gene mutations are more frequent in higher grade chondrosarcoma.16 Tumors with the IDH mutation show C–phosphate –G (CpG) island hypermethylation in regions containing genes involved in stem cell differentiation and lineage specification.14 Chondrosarcoma expresses Sox9, a transcription factor that regulates the synthesis of type II collagen.17 The IHH signaling pathway is affected in 18% of cases.16 Six to nine percent of high-grade chondrosarcomas harbor alterations in the retinoblastoma protein (pRb) tumor suppressor signaling pathway involving decreased CDKN2A expression, increased CDK4 expression, and/or expression of cyclin D1.18 A subset of high-grade tumors shows inactivation of wild-type p53 by mouse double-minute 2-homologue (MDM2) overexpression.18 Expression of antiapoptotic proteins (Bcl-2, Bcl-xL, XIAP) confers radio- and chemoresistance.19,20 Leukemia/lymphoma-related factor (LRF) expression is a survival factor for chondrosarcoma cells and correlates with malignancy and chemoresistance.21 High expression of hypoxia inducible factor 2α and low expression of Beclin-1 are associated with poor overall survival.22 Chondrosarcoma can arise from enchondroma. Genes under the transcriptional control of the transcription factor activator protein 1 (AP-1) regulate chondroblast/osteoblast growth. The components of the AP-1 heterodimer are c-Jun and c-Fos which are overexpressed in osteosarcomas and chondrosarcomas.23 Interaction of runt-related transcription factor 2 (RUNX2) with p27, which is required for osteoblast differentiation, is disrupted in osteosarcoma. Genomic instability is present, possibly due to chromothripsis.24 A gain of chromosome 6p, 8q, and 17p is seen.24 Up to 50% of patients harbor a p53 gene alteration (allelic loss, point mutation, gene rearrangement).25 Rb1 gene alterations occur in 70% of cases. Osteosarcoma expresses vascular endothelial growth factor (VEGF).26 The absence of biglycan expression may contribute to defective mineralization of collagen fibrils.27 The hepatocyte growth factor receptor (MET) is overexpressed and is associated with tumor progression. Increased CDK4 expression is seen, as are CDKN2A mutations and gene methylation.28 • High survivin expression correlates with the presence of metastasis and with poor survival.29 High expression of CCN3 gene correlates with a worse prognosis.30 • Polymorphisms in nucleotide excision repair genes may predict the response to cisplatin therapy.31 • Osteosarcoma is associated with previous radiation, Paget’s disease, fibrous dysplasia, and chronic osteomyelitis. • Hereditary retinoblastoma patients have a 1,000-fold higher risk of osteosarcoma as compared with the general population. Chordomas are characterized by expression of brachyury (T-gene), a transcription factor expressed in the developing notochord.32 Chordoma cells lose stemcell marker expression and can differentiate along an osteogenic lineage when exposed to all-trans-retinoic acid.33 It is thought that chordoma arises from the embryonic notochord cell remnant in the vertebral body or nucleus pulposus. However, a chordoma cell of origin has not been proven, and it is important to note that benign notochordal cell tumors do not transform into chordoma.34 Most skull base chordomas have normal karyotypes (74%). Abnormal karyotypes are observed in 75% of recurrent tumors, involving chromosome 3 or 13 in most cases.35 Chromosomal alterations resulting in gain of the T-gene locus are found in at least 50% of sporadic chordomas.36 T-gene (Chr 6) duplication is associated with familial chordoma.37 Other familial susceptibility loci have been mapped to 1p36 and 7q33.38 CDKN2A/2B gene loss is a feature of 70% of sacral chordomas but only 22% of skull base chordomas.39,40 No IDH1/2 mutations are present in chordoma.15 Hypermethylation of three known tumor suppressor genes (RASSF1, KL, HIC1) has been described in a series of 10 chordomas.41 Expression levels of brachyury are the same whether the T-gene encoding brachyury is amplified or not36; 94% of chordomas express at least one type of FGF receptor.42 Fragile histidine triad protein (FHIT) tumor suppressor (Chr3) expression is lost in 98% of sacral and 67% of clival chordomas.40 Increases in copy number of the epidermal growth factor receptor (EGFR) gene are observed in 40% of chordomas.43 Receptor tyrosine kinases located on the cell membrane are triggered by specific ligands involved in paracrine and autocrine growth signaling. Chordoma cells express platelet-derived growth factor receptors (PDGFR) α and β, epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), KIT, and c-MET.44 Chordomas express anti-apoptotic proteins Bcl-xL and MCL1.45 T-gene expression is required for chordoma cell proliferation in vitro.36 Decreased expression of micro-RNA (miRNA) 1 and associated overexpression of its target genes c-MET and histone deacetylase 4 (HDAC4) is observed in chordoma. Reintroduction of miRNA 1 into chordoma cells reduces cell proliferation.46 No biological predictors of chordomas have been identified yet. Chordomas arising in patients with tuberous sclerosis have been reported.47 Paraganglioma cells express neural stem cell markers (Nestin and CD33) as well as lineage-specific markers of differentiated cells of neural stem cell origin. Norepinephrine- or dopamine-secreting tumors show high expression of hypoxia-inducible factor 2α (HIF2α). Cells expressing high HIF2α levels show a less mature chromaffin cell developmental phenotype. This fact implicates HIF2α activation as an early event in tumor development, maintaining an undifferentiated phenotype in paragangliomas with loss of function mutations in von Hippel–Landau (VHL) disease or succinate dehydrogenase genes.48 Hereditary tumors with germline mutation occur in 35% of patients, and sporadic tumors are found in 65%. Among sporadic tumors, 14% cluster with transcriptional profiles similar to those of tumors with germline mutations49; 54% of head and neck paragangliomas harbor a germline mutation in one of the succinate dehydrogenase genes (SDHx).50IDH mutations are extremely rare (< 1%).51 Genes involved in the hypoxia-angiogenesis pathway are overexpressed in paragangliomas associated with von Hippel–Lindau (VHL) or SDHx gene mutations.48 Head and neck paragangliomas also have VHL or SDH AF2/B/C/D mutations. Only one patient with multiple head and neck paragangliomas has shown a TMEM127 mutation. RET, NF1, or MAX mutations are not seen in head and neck paragangliomas, but are found in paragangliomas at other sites.52 The risk of malignant paraganglioma varies according to mutation type as follows, in order of decreasing risk: SDHB (66–83%), SDHD (< 5%), VHL (3%), SDHC (< 2%), and TMEM127.53SDHD- linked paragangliomas are associated with loss of the maternally imprinted chromosome 11.49 Accumulation of succinate in SDHx mutant tumors inhibits histone demethylases, resulting in increased histone H3 methylation.54 SDHx- and VHL-related tumors do not produce epinephrine because they lack PNMT. VHL-related tumors produce norepinephrine, whereas SDHx tumors produce dopamine and its O-methylated metabolite methoxytyramine.55 Recurrences are associated with the presence of germline mutations.56 Paragangliomas are associated with VHL disease arising from VHL gene germline mutation. Familial paragangliomas are associated with autosomal dominant germline mutations, as follows: • PGL-1: SDHD gene on chromosome 11q23 • PGL-2: SDHAF2 gene on chromosome 11q13 • PGL-3: SDHC gene on chromosome 1q21 • PGL-4: SDHB gene on chromosome 1p36 The Carney triad is a very rare condition with gastrointestinal stromal tumor, pulmonary chondroma, and extra-adrenal paragangliomas. Tumor cells express the human homologue of the Drosophila achaete-scute gene (HASH1) that is a marker of immature olfactory neurons.57 Expression of neuroendocrine granules, chromogranins, neurofilament proteins, and synaptophysin point to a neural crest cell origin.58–60 Complex chromosomal aberrations and copy number changes over the entire genome are found in esthesioneuroblastoma. These tumors also exhibit copy number changes shared with carcinomas such as 7q11.2 gain, chr 2 losses, and 6q21-22 loss.61 Aneuploidy is associated with higher Kadish stage.61 The epigenetics of esthesioneuroblastoma are unknown. Marked Trk-A and Trk-B neurotrophin receptor expression is frequent (90%).62 Sonic hedgehog receptor PTCH1 as well as downstream signaling molecules Gli1 and Gli2 are upregulated in esthesioneuroblastoma.63 Maintenance of the cell-cycle in esthesioneuroblastoma cells requires sonic hedgehog signaling.63 About 70% of tumors show expression of the antiapoptotic factor Bcl-2.64 Bcl-2 expression increases with histopathological grade.65 Tumors with lower Hyams grade histopathology have a lower recurrence rate and longer overall and disease-free survival.66 None. Ligand-mediated activation of EGFR and PDGFR results in enhanced expression of stem-cell genes in vestibular schwannoma cells.67 Loss of Merlin (NF2 gene) expression results in increased expression of CD44 and Nestin stem cell markers in human Schwann cells.68 It has been found that 88% of sporadic schwannomas harbor a mutation in the NF2 gene (located on chromosome 22q12.2).69 Schwannomas are a feature of three autosomal dominant inherited syndromes: neurofibromatosis type 2, schwannomatosis, and Carney complex type 1 (see Associations, below). Inactivation of the NF2 tumor suppressor gene follows the Knudson’s two-hit hypothesis, whereby germline mutation of the gene locus on one allele combines with somatic loss of heterozygosity or subsequent mutation of the wild-type allele, resulting in loss of function of the tumor suppressor.70 The NF2 gene encodes Merlin, which is a membrane protein that acts as a negative growth regulator. Merlin protein shares sequence similarity with the Ezrin-Radixin-Moesin family proteins that function to link the actin cytoskeleton to extracellular glycoproteins; 86% of sporadic schwannomas show reduced expression of Merlin protein, and lower expression is related to a higher growth index.71 Vestibular schwannomas express neuroregulin-1 (NRG1) and its receptors ERBB2 (Her2/neu) and ERBB3, which are involved in signaling proliferation of Schwann cells.72–74 Vestibular schwannoma cells also express VEGF receptor 1 and VEGF protein. Recurrent tumors are characterized by high VEGF expression.75 Expression of antiapoptotic protein Bcl-2 is frequent in vestibular schwannomas (64%).76 Schwannoma cells also express the antiapoptotic protein Survivin.77 Merlin is a negative regulator of at least three key factors involved in signaling cell proliferation: Rac, Akt, and mTOR. Thus, loss of Merlin serves to release a cellular block on cell division.78 Some vestibular schwannomas may not respond to standard radiation doses due to the action of multiple radioresistance molecular pathways.79 Schwannoma is associated with neurofibromatosis type 2 (NF2). A germline mutation in NF2 observed in 33 to 60% of patients with NF2. Mutations that result in a truncated protein produce a more severe clinical phenotype.70 • Carney complex type 1 is characterized by psammomatous melanotic schwannomas. These tumors show loss of heterozygosity in the gene encoding type 1A regulatory subunit of protein kinase A (PRKAR1A) on chromosome 17. PRKAR1A mutation in the remaining allele produces a nonfunctional protein, resulting in activation of protein kinase A, decreased expression of neurofibromin, and enhanced activation of Rac1. Protein kinase A phosphorylates Merlin at residue serine 518, which results in inactivation of Merlin function, a key feature in sporadic and NF2-related schwannomas.78 The inner part of the dura (dural border cells) and the outer part of the arachnoid (arachnoid barrier cells) derive from a common prostaglandin D-synthase (PGDS) expressing progenitor. Inactivation of NF2 in the PTGDS-expressing common progenitor resulted in meningothelial (arachnoid barrier cell derived) or fibroblastic (dural border cell derived) meningiomas. Meningiomas only formed if NF2 was inactivated in fetal or neonatal meninges.80 The majority (> 60%) of meningiomas are monoclonal.81 Typical meningiomas (World Health Organization [WHO] grade I) show a normal karyotype or loss of one chromosome 22 in all or some of the cells.82 Loss of heterozygosity for chromosome 22 markers flanking the NF2 gene is observed in 60% of sporadic meningiomas. The majority of these tumors carry an inactivating mutation in the remaining NF2 gene.83NF2 loss is most commonly observed in fibroblastic meningiomas.84 Atypical or anaplastic meningiomas show loss of up to six further chromosomes in addition to chromosome 22 or partial/complete loss of the short arm of chromosome 1.82 Deletion of 1p36 (including the alkaline phosphatase gene ALPL) is found in 27% of typical meningiomas, 70% of atypical meningiomas, and 100% of anaplastic meningioma.85 Suppressor of fused (SUFU) homologue is a negative regulator of sonic hedgehog signaling and important for control of stem cell differentiation in adults. Loss of SUFU due to frequent chromosome 10 long arm deletion is thought to contribute to meningioma development. This is supported by the observation that a SUFU loss of function germline mutation segregates with family members affected with meningioma in a family with five siblings affected with meningioma.86 Mutation of the chromatin-remodeling gene SMARCB1 has been observed in familial multiple meningioma.87 Atypical and anaplastic meningiomas are associated with aberrant CpG island hypermethylation of multiple genes.88 Tissue inhibitor of metalloproteinase 3 gene located on 22q12.3 is hypermethylated in meningiomas that have allelic loss of 22q12. Increased frequency of tissue inhibitor of metalloproteinase-3 (TIMP3) hypermethylation is observed in higher grade meningiomas (67% anaplastic, 22% atypical, 17% typical). Hypermethylation results in decreased TIMP3 expression levels. TIMP3 normally acts to inhibit matrix metalloproteinases, thereby blocking invasion and metastasis. TIMP3 also functions to induce apoptosis and suppression of tumor growth and angiogenesis.88 Basic FGF, a potent mitogen for mesoderm-derived cells, is abundantly produced in meningiomas.89 Activation of the WNT/beta-catenin, Notch, sonic hedgehog, phosphoinositide 3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) pathways is observed in meningiomas83,90; 72% of genes in the sonic hedgehog signaling pathway are differentially expressed in meningioma compared with normal tissue.91 Multiple autocrine ligand-receptor signaling pathways involved in growth response are upregulated in meningioma including PDGF BB and its receptor PDGFR-β. Transforming growth factor-α (TGF-α) and epidermal growth factor (EGF) and its receptor EGFR, stromal cell derived factor 1 and its receptor CXCR, as well as bone morphogenic protein and its receptors are also found.90 Loss of cell-cycle regulatory factors encoded by CDKN2A, CDKN2B, and ARF takes place in the majority of anaplastic meningiomas.83 High expression of insulin-like growth factor II is associated with anaplastic histology and tumor invasiveness.92 Radiation-induced meningiomas are more often atypical and show aggressive clinical features such as multiplicity, brain invasion, and recurrence.93 Meningiomas are seen in 50% of patients with NF2.94 Meningiomas have also been reported in other inherited tumor syndromes including Cowden, Werner, Gorlin, Li-Fraumeni, Turcot, Gardener, VHL, and multiple endocrine neoplasia type I.83 • The risk of developing meningioma is increased with exposure to low- or high-dose radiation, and the latency period for development of the tumor is dependent on the dose and age at exposure.93 Hemangiopericytoma is thought to derive from a mesenchymal progenitor that gives rise to pericytes and expresses prostaglandin D synthase.95
Cartilaginous Tumors
Chondroblastoma
Stem Cell Biology
Genetics
Proteomics
Receptor Signaling
Biological Predictors
Association
Enchondroma
Stem Cell Biology
Genetics
Epigenetics
Proteomics
Biological Predictors
Association
Chondrosarcoma
Stem Cell Biology
Genetics
Epigenetics
Proteomics
Receptor Signaling
Cell-Cycle Pathways
Cell-Death Pathways
Biological Predictors
Association
Noncartilaginous Tumors
Osteosarcoma
Stem Cell Biology
Genetics
Proteomics
Receptor Signaling
Cell-Cycle Pathways
Biological Predictors
Association
Chordoma
Stem Cell Biology
Genetics
Epigenetics
Proteomics
Receptor Signaling
Cell-Death Pathways
Cell-Cycle Pathways
Biological Predictors
Association
Head and Neck Paraganglioma
Stem Cell Biology
Genetics
Epigenetics
Proteomics
Biological Predictors
Association
Esthesioneuroblastoma
Stem Cell Biology
Genetics
Epigenetics
Receptor Signaling
Cell-Cycle Pathways
Cell-Death Pathways
Biological Predictors
Associations
Schwannoma
Stem Cell Biology
Genetics
Receptor Signaling
Cell-Death Pathways
Cell-Cycle Pathways
Biological Predictors
Associations
Meningioma
Stem Cell Biology
Genetics
Epigenetics
Receptor Signaling
Cell-Cycle Pathways
Biological Predictors
Associations
Hemangiopericytoma
Stem Cell Biology
Genetics
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