Mutations in components of the Wnt signaling pathway in adenoid cystic carcinoma

Abstract

The Wnt signaling pathway is essential for normal development and organogenesis. However, inappropriate activation of Wnt signaling, which results in the nuclear translocation of b-catenin, is associated with the development of various types of neoplasm. In this study, we investigated possible mutations in the genes for components of this pathway, namely, CTNNB1 (the gene for b-catenin), AXIN1, and APC, in adenoid cystic carcinoma, by PCR, analysis of single-strand conformational polymorphism, and sequencing. Among a total of 20 cases of adenoid cystic carcinoma, seven cases (35%) were associated with mutations in one or more of these three components. A mutation in CTNNB1 was detected in one case. Five cases, including the case with a mutation in CTNNB1, were associated with missense mutations in AXIN1. An aberration in the mutation cluster region of APC was detected in two cases. Mutations trended to be detected more frequently in adenoid cystic carcinoma with solid growth pattern than that with tubular and cribriform growth pattern. In the cases in which we detected mutations, it is possible that the presence of the abnormal products of the mutated genes resulted in the inappropriate activation of the Wnt signaling pathway to tumorigenesis and the growth of adenoid cystic carcinoma.

Clinical Significance of Axin and β-catenin Protein Expression in Primary Hepatocellular Carcinomas

“…Axin has different mutation frequencies in colon cancer (Jin et al, 2003) and bladder tumour tissue (Daa et al, 2004). In Axin gene mutations in primary HCC cells, β-catenin accumulation was found in the cytoplasm and the nucleus, and β-catenin/Tcf transcription activity was enhanced.…”

Adenoid cystic carcinoma: A review of recent advances, molecular targets, and clinical trials

“…Analysis of tumor RNA by microarray revealed that ACCs express genes associated with myoepithelial differentiation along with high levels of the transcription factor Sox4 18. The latter normally regulates embryonic development and is also a candidate human oncogene 19. Other overexpressed genes include casein kinase 1‐epsilon and frizzled‐7 , which are implicated in the Wnt/β‐catenin signaling pathway and in tumorigenesis.…”

Expression profile of frizzled receptors in human medulloblastomas

“…This might be true even if no nuclear b-catenin immunoreactivity was found in the two MBs that over-expressed both FZD1 and MYC and were investigated for b-catenin positivity (samples 9 and 16 in Table 1). Indeed, it has been previously proved that negative immunohistochemical results do not eliminate the possibility of increased nuclear localization of CTNNB1-with consequent WNT/CTNNB1 pathway activation-because weak nuclear staining may be difficult to evaluate [23]. Moreover, the lack of nuclear b-catenin staining has been reported in tumors arising from WNT/ CTNNB1 pathway deregulation, and a variety of WNT/ CTNNB1 pathway target genes, such as MYC, may be upregulated even in the absence of nuclear b-catenin immunoreactivity [12,23].…”

“…Indeed, it has been previously proved that negative immunohistochemical results do not eliminate the possibility of increased nuclear localization of CTNNB1-with consequent WNT/CTNNB1 pathway activation-because weak nuclear staining may be difficult to evaluate [23]. Moreover, the lack of nuclear b-catenin staining has been reported in tumors arising from WNT/ CTNNB1 pathway deregulation, and a variety of WNT/ CTNNB1 pathway target genes, such as MYC, may be upregulated even in the absence of nuclear b-catenin immunoreactivity [12,23]. Finally, as observed by Merle et al in human hepatocellular carcinomas, over-expression of FZD receptors might lead to levels of nuclear b-catenin sufficient to induce target genes, but not strong enough to be detected by immunohistochemistry [6].…”