GLIOMAS TUMOURS (INCLUDING ASTROCYTOMA AND GLIOBLASTOMA)
Astrocytoma and glioblastoma account for about 4 % of brain tumours in childhood and 17 % in adults. Genetic conditions associated with a predisposition to glioma include neurofibromatosis type 1 (NF1), NF2, Li–Fraumeni syndrome, tuberose sclerosis, Gorlin syndrome, Turcot syndrome, and Maffucci syndrome. The precise tumour type in some cases can be correlated with specific disorders, for example, in tuberose sclerosis a benign astrocytic tumour (subependymal nodule) is typically seen, although giant cell astrocytoma can occur. However, in NF1 and Turcot syndrome, both astrocytoma and glioblastoma multiforme may be seen. Kibirige et al. (1989) found that of 282 children with astrocytoma, 21 had neurofibromatosis and 4 had tuberose sclerosis, and there was evidence that a similar proportion might have had Li–Fraumeni syndrome.
Familial glioma not associated with the inherited syndromes described above occurs but is uncommon. In a review by Vieregge et al. (1987), of 39 reports, most (60 %) were of affected siblings, and one-quarter was of affected twins or of individuals with affected relatives in two generations.
There were three pairs of monozygotic twins with glioma. In most affected sibling cases, the onset in the second sibling was usually within 5 years of that of the first sibling. A high incidence of cerebral glioma was found in an isolated inbred community by Armstrong and Hanson (1969) and Thuwe et al. (1979). Glioblastoma multiforme is rare in children, but Duhaime et al. (1989) reported an affected sib pair aged 2 and 5 years with the simultaneous onset of symptoms.
Rare families have been reported with a combination of melanoma and gliomas. In some families, submicroscopic germline deletions of 9p21 have been identified which completely or partially involve CDKN2A ± CDKN2B (Bahuau et al. 1998; Tachibana et al. 2000). The CDKN2A locus encodes two gene products, p14 and p16, and there is evidence that p14 loss is critical for this disorder (Randerson-Moor et al. 2001). Thus, in brain tumor–melanoma kindreds, deletion studies of this region may be warranted if clinical testing for CDKN2A mutations has been undertaken and is negative.
In general, candidate gene analysis in non-syndromic familial glioma cases has been largely unproductive. Thus, although a study from the Mayo Clinic of 15 brain cancer patients who had a family history of brain tumors found that one had a germline TP53 mutation, and another had a germline hemizygous deletion of the CDKN2A/CDKN2B region (Tachibana et al. 2000), a more recent, larger analysis (n = 101) of familial glioma cases did not detect germline CDKN2A mutations and only one TP53 mutation (Robertson et al. 2010).
In the light of the evidence that lower-penetrance genes might represent a major contribution to familial risks for nervous system tumors (Hemminki et al. 2009), large collaborations such as the GLIOGENE consortium have undertaken genome-wide association studies and identified a number of polymorphic variants that predispose to glioma (Scheurer et al. 2010; Shete et al. 2011). Among the genes linked with susceptibility variants are TERT, EGFR, CDKN2A/CDKIN2B, and PHLDB1, but only a small part of familial risk can be explained by the linked variants (Shete et al. 2009, 2011).
Cavernous hemangiomas may occur sporadically or as a familial trait when they are inherited as a dominant trait with incomplete penetrance (Riant et al. 2010). Familial cases, which account for about 20 % of the total, frequently develop multiple cavernous hemangiomas, but these may be asymptomatic and only detected by magnetic resonance imaging (MRI) scanning. Retinal cavernous angiomas may be found in some patients.
Familial cavernous hemangiomas are genetically heterogeneous. The first gene to be mapped and identified was CCM1/KRIT1 and accounts for about 40 % of all cases (Laberge-le Couteulx et al. 1999). Subsequently, two further genes were described (CCM2/MGC4607 and CCM3/PDCD10) which account for about 20 and 40 % of all familial cases, respectively (Dubovsky et al. 1995; Craig et al. 1998; Riant et al. 2010). There is a significant (40–60
%) mutation detection rate in sporadic individuals with multiple lesions, and some mutation-negative cases might be mosaic (Riant et al. 2010).
Meningeal hemangioma and facial nevus flammeus constitute the Sturge– Weber syndrome, and cerebral vascular lesions occur in Rendu–Osler–Weber syndrome. Although the Sturge–Weber syndrome is sometimes designated the fourth phakomatosis, there is no evidence of a genetic basis and there is no predisposition to neoplasia.