Abundant mutations of b-catenin in adamantinomatous craniopharyngiomas but not in other variants of intra- and suprasellar neoplasms

Dysregulation of the Wnt signaling pathway contributes to structural abnormalities and the development of different tumour types. Here, we examined b-catenin and APC by mutational analysis and immunohistochemistry in a large series of tumors of the sellar region: pituitary adenomas (PA=57), craniopharyngiomas (CP=69), xanthogranulomas (XG=8) and Rathke's cleft cysts (RC=10). Whereas no APC mutations were detectable, b-catenin mutations were present in 70% of CP (23 out of 33), exclusively of the adamantinomatous subtype, but no PA. A novel 85bp deletion was detected in one CP. All mutations and the deletion affected exon 3 encoding the degradation targeting box of b-catenin leading to accumulation of nuclear b-catenin protein. Fourty-six out of 61 CP (75%) showed indead an abnormal nuclear accumulation of b-catenin, once again only in the adamantinomatous tumour subtype (46 out of 53, means 87%). Nuclear expression was absent in PA, XG and RC. The particular immunohistochemical distribution pattern of aberrant nuclear b-catenin accumulation is compatible with a role during morphogenesis, i.e. the formation of whorls and the invasion towards normal brain parenchyma.

The abundance of activating mutations in the b-catenin gene indicates an important role in the molecular pathogenesis of adamantinomatous craniopharyngiomas, distinct from papillary craniopharyngiomas and other neoplasms of the sellar region, i.e. pituitary adenomas, xanthogranuloma or Rathke's cleft cysts.