β-catenin mutations in craniopharyngiomas and pituitary adenomas

Abstract

Craniopharyngiomas and pituitary adenomas are both tumors of the hypothalamic and pituitary region, respectively that are frequently associated with endocrine defects either because of direct involvement of hormone producing cells (most pituitary tumors) or because of secondary defects due to disturbance of hypothalamic function (some pituitary tumors and craniopharyngiomas). Some studies suggest that mutant beta-catenin gene cells in craniopharyngiomas and pituitary adenomas contribute to their tumorigenesis. DNA was extracted from 73 cranial tumors and subjected to polymerase chain reaction (PCR) with previously described primers encompassing glycogen synthase kinase-3beta phosphorylation sites of the beta-catenin gene. Sequenced PCR products for possible beta-catenin gene mutations showed a total of 7/43 alterations in adamantinomatous craniopharyngioma-derived DNA samples. Two previously described beta-catenin mutations in codon 33 TCT(Ser) > TGT(Cys) and codon 37 TCT(Ser) > TTT(Phe), whereas three novel mutations in codon 41 ACC(Thr) > ATC(Ile), codon 33 TCT(Ser) > TAT(Tyr) and codon 32 GAC(Asp) > AAC(Asn) were observed. None of the 22 pituitary adenomas and the eight papillary craniopharyngiomas analyzed presented any sequence alterations. These findings demonstrate an association between beta-catenin gene alterations and craniopharyngiomas of the adamantinomatous type. Since this gene product is involved with development, these results suggest that beta-catenin mutations may contribute to the initiation and subsequent growth of congenital craniopharyngiomas.

Molecular oncogenesis of craniopharyngioma: current and future strategies for the development of targeted therapies

“…Mutations in the b-catenin gene (CTNNB1) on chromosome 3 and aberrations in b-catenin expression have been well documented in multiple cancers, including colorectal 3,4,7,56,70,80 and hepatocellular 25,52,58 carcinomas, which prompted early studies in other solid tumors. CTNNB1 mutations were subsequently found in the Wnt subtype of medulloblastomas 42 and adamantinomatous craniopharyngiomas, 16,21,47,66,78 suggesting that, in addition to being clinically and histopathologically distinct, these subtypes also have distinct genetic origins. Wnt normally binds to a cell-surface receptor complex composed of Frizzled (Fz) and low-density lipoprotein receptor-related protein (LRP).…”

60 YEARS OF NEUROENDOCRINOLOGY: Biology of human craniopharyngioma: lessons from mouse models

“…Mouse tumour β-catenin immuno β-catenin immuno 18.5 dpc Mutations in CTNNB1 cause mouse and human ACP Initial molecular studies of human ACP revealed an association with mutations in CTNNB1, the gene that encodes b-catenin, a central regulator of the Wnt pathway (Sekine et al 2002, Kato et al 2004, Buslei et al 2005, Oikonomou et al 2005, Brastianos et al 2014. These mutations were mostly located in exon 3, which encodes amino acids with important regulatory functions (Aberle et al 1997).…”

“…However, two independent groups failed to detect copy number variations in more than 30 ACP and nine PCP tumours; they concluded that chromosomal imbalances are a rare event (Rickert & Paulus 2003, Yoshimoto et al 2004. So far, the most common genetic changes identified in human ACP are mutations in CTNNB1, although mutation frequencies vary from 16 to 100% depending on the study (Sekine et al 2002, Kato et al 2004, Buslei et al 2005, Oikonomou et al 2005, Brastianos et al 2014, Larkin et al 2014. In a recent report, other mutations were identified in several loci by exome sequencing, but they were not recurrent and were possibly not involved in tumour survival or growth (Brastianos et al 2014).…”

Primary intracranial ectopic craniopharyngioma in a patient with probable Gardner's syndrome

“…The mutations of genes encoding b-catenin (CTNNB1 and APC) are an exclusive characteristic of adamantinomatous CPG and may play a role in CPG initiation and growth. 9,14,19 Mutations in bcatenin encoding genes and overexpression of b-catenin are considered to be characteristics of adamantinomatous CPGs. All mutations affect exon 3, which encodes the degradation targeting box of b-catenin, consistent with an accumulation of nuclear b-catenin.…”