PRIMITIVE NEUROECTODERMAL TUMOURS
Cerebral primitive neuroectodermal Tumours (PNETs) can occur predominantly in childhood and arise most frequently in the posterior fossa, but can occur anywhere in the brain. Medulloblastoma is the most common form of PNET, but CNS malignant rhabdoid Tumours are another subset. Germline mutations in TP53, PTCH (Gorlin syndrome), and APC may be associated with susceptibility to central PNETs. In contrast to the peripheral type, such as Ewing sarcoma, t(11;22)(q24;q12) is uncommon in the central type.
Rhabdoid Tumours are rare aggressive neoplasms that can occur in a variety of locations including the kidney, central nervous system, and soft tissues. Taylor et al. (2000) reported a kindred with two affected relatives with a posterior fossa brain Tumours in infancy (cerebellar malignant rhabdoid Tumours) and posterior fossa choroids plexus carcinoma and a germline SMARCB1 (hSNF5) splice site mutation. Inheritance was autosomal dominant with incomplete penetrance, and mice heterozygous for an Snf5 deletion developed T cell lymphomas and rhabdoid Tumours (Roberts et al. 2002). Germline mutations in SMARCB1 can cause familial schwannomatosis and rhabdoid Tumours predisposition syndrome. Occasionally an SMARCB1 mutation has been associated with both phenotypes (Eaton et al. 2011). Molecular analysis of sporadic rhabdoid Tumours shows evidence of SMARCB1 inactivation in most cases, and germline SMARCB1 mutations have been reported to be frequent in patients with such apparently sporadic rhabdoid Tumours(Bourdeaut et al. 2011; Eaton et al. 2011). Thus, Bourdeaut et al. (2011) detected mutations in about a quarter of these cases, with the highest frequency in the younger children (60 % in those aged <2 years) and those with multifocal disease. Germline SMARCB1 mutations associated with rhabdoid Tumours tend to be highly penetrant, and mean age at diagnosis of rhabdoid Tumours was 6 months (Bourdeaut et al. 2011). However, non- penetrance and gonadal mosaicism have been reported (Eaton et al. 2011). It has been suggested that SMARCB1 missense and splice site mutations are preferentially associated with schwannomatosis and deletions and truncating mutations with rhabdoid Tumours predisposition. SMARCB1 is a member of the SWI/SNF chromatin-remodeling complex, and germline mutation in another member of this complex, the ATPase subunit SMARCA4(BRG1), was detected in two sisters with rhabdoid Tumours (one brain and one renal) (Schneppenheim et al. 2010).
Supratentorial PNETs (sPNETs) are very rare and highly aggressive embryonal Tumours of the cerebrum, pineal gland, and suprasellar region. sPNETs are associated with homozygous PMS2 mutations (De Vos et al. 2004). Other features of recessively inherited PMS2 mutations are café-au- lait lesions and susceptibility to hematological malignancies. A family history of colorectal cancer is often absent. Homozygous recessive mutations in BRCA2 causing Fanconi anemia subtype D1 predispose to solid Tumours including medulloblastoma (Offit et al. 2003; Hirsch et al. 2004).