14q22.3

CPHD6,MCOPS5

Pediatric CNS cancer (medulloblastoma)

5-year survival rates average 50-60%; predictors of poor outcome include young age (younger than 3 years old) and presence of metastases. OTX2 copy number gain has been associated with shorter survival (Adamson et al., 2010).

Various broad and focal copy number changes have been identified in medulloblastoma (reviewed in: Northcott et al., 2010), whereas OTX2 is the most common target of focal copy number gain in the medulloblastoma genome (Adamson et al., 2010).

Otx2 is overexpressed in the majority (~74%) of medulloblastomas (Adamson et al., 2010). A subset of these tumors (~21%) harbor copy number gains of the OTX2 genomic locus; the mechanism of Otx2 overexpression in the remaining tumors remains unidentified. Otx2 is distinctly overexpressed in Shh-independent medulloblastomas (i.e. tumor subtypes not expressing gene signatures of Shh pathway activation; Adamson et al., 2010). Otx2 has been implicated in medulloblastoma tumor progression and is required for tumor maintenance. One mechanism of Otx2 oncogenic activity is transcriptional activation of MYC (Adamson et al., 2010).

Retinoblastoma

Secondary events cooperating with loss of Rb gene function have remained elusive. However, genomewide copy number analysis has revealed recurrent regions of gain or loss at the megabase resolution, and chromosome 14 aberrations have indeed been described (Zielinski et al., 2005).

Considering the restricted expression pattern of OTX2 mRNA in adult tissues (Boon et al., 2002) and the well-established oncogenic function of Otx2 in medulloblastomas (Adamson et al., 2010), expression of Otx2 in retinoblastoma may indicate a role for this gene in retinoblastoma pathogenesis (Glubrecht et al., 2009). Interestingly, Otx2 is expressed in the most undifferentiated compartments of retinoblastomas (Glubrecht et al., 2009). Although, Otx2 is expressed broadly among retinoblastoma samples, its potential role as an oncogene in this tumor type has not been experimentally assessed; the possibility that Otx2 is solely a cell lineage marker maintained in transformed retinal progenitor cells has yet to be excluded based on functional studies.

Coloboma

Developmental defects of the eye.

Coloboma, defined as a fissure in the ocular tissue (Onwochei et al., 2000). These result from incomplete closure of the fetal fissure (an invagination of the optic stalk and optic vesicle), whose function is to provide a scaffold for the formation of the optic cup and for the vessels responsible for retinal vascularization. Colobomata are predominately developmental defects that present at birth. Various genes, including OTX2, have been implicated in hereditary syndromes predisposing to coloboma (Omwochei et al., 2000; Wyatt et al., 2008), and sporadic cases have implicated teratogens, though evidence implicating particular agents is generally anecdotal (Omwochei et al., 2000).

Germline OTX2 mutations have been identified in patients with bilateral eye defects including colobomata and anophthalmia (Wyatt et al., 2008).

Anophthalmia and microphthalmia (absent or small eyes, respectively)

Developmental defects of the eye.

Microphthalmia is clinically defined as an eye with an axial diameter measuring at least two standard deviations below the mean for the corresponding age group (Omwochei et al., 2000), whereas anophthalmia is diagnosed when no clinically apparent eye structure is present. Those affected generally harbor bilateral malformations. Like coloboma, some forms of anophthalmia/microphthalmia are clearly inheritable, while for other cases environmental factors have been implicated but not definitively so (Verma et al., 2007). Anophthalmia/microphthalmia can present as secondary malformations following colobomata.

Various genes have been implicated, including SOX2 (autosomal dominant inheritance), OTX2 (autosomal dominant), CHX10 (autosomal recessive), and RAX (autosomal recessive; Verma et al., 2007; Wyatt et al., 2008).