Identification of novel polymorphisms in the AXIN1 and CDX-2 genes

Lin, Yu‐Min; Kato, Takehito; Satoh, Seiji; Nakamura, Yusuke; Furukawa, Yoichi

doi:10.1007/s100380070036

Cited by 11 publications

(9 citation statements)

References 11 publications

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“…We confirmed three previously published single-nucleotide polymorphisms (SNPs) (Lin et al, 2000;Dahmen et al, 2001). One polymorphism resulted in an amino-acid substitution, and the others were silent SNPs.…”

Section: Mutation Of the Axin1 Gene In Oesophageal Sccsupporting

confidence: 90%

Reduced expression of Axin correlates with tumour progression of oesophageal squamous cell carcinoma

et al. 2003

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Axin is a negative regulator of the Wnt signalling pathway, and genetic alterations of AXIN1 have been suggested to be an important factor of carcinogenesis in some tumours. The objective of this study was to clarify the clinicopathologic and prognostic significance of Axin in oesophageal squamous cell carcinoma (SCC). Immunohistochemical staining for Axin was performed on surgical specimens obtained from 81 patients with oesophageal SCC. Western and Northern blottings were performed on proteins and RNA from oesophageal SCC cell lines. Then polymerase chain reaction -single-strand conformational analysis (PCR -SSCP) was performed on DNA from oesophageal SCC patients and cell lines. Axin expression was found to be correlated inversely with depth of invasion, lymph node metastasis, and lymphatic invasion. Although univariate analysis showed Axin to be a negative predictor, multivariate analysis showed that it was not an independent prognostic marker. In all but one of the seven cell lines examined, the levels of protein expression were equivalent to RNA expression. PCR -SSCP showed that five patients and three cell lines had polymorphisms in exon 4 or 5 of the AXIN1 gene, but none of the 81 patients with oesophageal SCC had mutations. Our findings suggest that reduced expression of Axin is correlated with tumour progression of oesophageal SCC. However, additional studies will be necessary to elucidate the mechanism responsible for loss of Axin expression in tumour cells.

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Section: Mutation Of the Axin1 Gene In Oesophageal Sccsupporting

confidence: 90%

Reduced expression of Axin correlates with tumour progression of oesophageal squamous cell carcinoma

et al. 2003

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“…We screened 35 endometrial carcinomas for AXIN1 mutations in which either b-or g-catenin nuclear expression had been detected and did not find any mutations in AXIN1 but observed 12 single-nucleotide polymorphisms (SNPs). SNPs, with and without aminoacid changes, have been described in exons 1, 4, 5, 9 and 10 and intron 4 of the AXIN1 gene (Lin et al, 2000;Webster et al, 2000). Liu et al (2000) reported that AXIN2 was mutated in 11 out of 45 colorectal carcinomas with MSI, but in none out of 60 tumours without MSI.…”

Section: Discussionmentioning

confidence: 99%

Abnormalities of the APC/β-catenin pathway in endometrial cancer

et al. 2002

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The activation of the APC/b-catenin signalling pathway due to b-catenin mutations has been implicated in the development of a subset of endometrial carcinomas (ECs). However, up to 25% of ECs have b-catenin nuclear accumulation without evidence of b-catenin mutations, suggesting alterations of other molecules that can modulate the Wnt pathway, such as APC, g-catenin, AXIN1 and AXIN2. We investigated the expression pattern of b-and g-catenin in a group of 128 endometrial carcinomas, including 95 endometrioid endometrial carcinomas (EECs) and 33 non-endometrioid endometrial carcinomas (NEECs). In addition, we evaluated the presence of loss of heterozygosity and promoter hypermethylation of the APC gene and mutations in the APC, b-and g-catenin, AXIN1, AXIN2, and RAS genes, and phospho-Akt expression. No APC mutations were detected but LOH at the APC locus was found in 24.3% of informative cases. APC promoter 1A hypermethylation was observed in 46.6% of ECs, and was associated with the endometrioid phenotype (P=0.034) and microsatellite instability (P=0.008). Neither LOH nor promoter hypermethylation of APC was associated with nuclear catenin expression. Nuclear b-catenin expression was found in 31.2% of EECs and 3% of NEECs (P=0.002), and was significantly associated with b-catenin gene exon 3 mutations (P50.0001). b-catenin gene exon 3 mutations were associated with the endometrioid phenotype, and were detected in 14 (14.9%) EECs, but in none of the NEECs (P=0.02). g-catenin nuclear expression was found in 10 ECs; it was not associated with the histological type but was associated with more advanced stages (P=0.042). No mutations in g-catenin, AXIN1 and 2 genes were detected in this series. Neither RAS mutations nor phospho-Akt expression, which were found in 16 and 27.6% of the cases, respectively, were associated with bcatenin nuclear expression. Our results demonstrated a high prevalence of alterations in molecules of the APC/ b-catenin pathway, but only mutations in b-catenin gene are associated with aberrant nuclear localization of bcatenin.

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“…The entire coding sequence, including the exon–intron boundaries, was investigated by PCR-SSCP using the previously described 23 sets of primers with slight modifications (Lin et al , 2000). All amplifications were performed in 15 μ l PCR containing 50–100 ng DNA, 1.5 m MgCl 2 , 0.02 m dATP, 0.2 m dGTP, dCTP and dTTP each, 0.8 μ Ci of [ 32 P]dATP (Amersham Biosciences, Buckinghamshire, UK), 20 pmol of each primer and 0.3 U AmpliTaq Gold polymerase (Perkin-Elmer Applied Biosystems, Foster City, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Frequent loss of the AXIN1 locus but absence of AXIN1 gene mutations in adenocarcinomas of the gastro-oesophageal junction with nuclear β-catenin expression

et al. 2004

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Up to 60% of gastro-oesophageal junction (GEJ) adenocarcinomas show nuclear β-catenin expression, pointing to activated T-cell factor (TCF)/β-catenin-driven gene transcription. We demonstrate in five human GEJ adenocarcinoma cell lines that nuclear β-catenin expression indeed correlates with enhanced TCF-mediated transcription of a reporter gene. In several tumour types, TCF/β-catenin activation is caused by mutations in either adenomatous polyposis coli (APC), β-catenin exon 3, AXIN1, AXIN2 or β-transducin repeat-containing protein (β-TrCP). In GEJ adenocarcinomas, very few APC and β-catenin mutations have been found. Therefore, the mechanism of Wnt pathway activation remains unclear. In the present study, we did not find AXIN1 gene mutations in 17 GEJ tumours with nuclear β-catenin expression (without β-catenin exon 3 mutations). Six intragenic single nucleotide polymorphisms (SNPs) were identified. One of these, the AXIN1 gene T1942C SNP, has a frequency of 21% but is only very recently described despite numerous AXIN1 gene mutational studies. We provide evidence why this SNP was missed in single strand conformation polymorphism analyses. The AXIN1 gene G2063A variation was previously described as a gene mutation but we demonstrate that this is a polymorphism. With these six SNPs loss of heterozygosity (LOH) was found in 11 of 15 (73%) informative tumours. To investigate a possible AXIN1 gene dosage effect in GEJ tumours expressing nuclear β-catenin, AXIN1 locus LOH was determined in 20 tumours expressing membranous and no nuclear β-catenin. LOH was found in 10 of 13 (77%) informative cases. AXIN1 protein immunohistochemistry revealed cytoplasmic expression in all tumours irrespective of the presence of AXIN1 locus LOH. These data indicate that nuclear β-catenin expression is indicative for activated Wnt signalling and that neither AXIN1 gene mutations nor AXIN1 locus LOH are involved in Wnt pathway activation in GEJ adenocarcinomas.

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Identification of novel polymorphisms in the AXIN1 and CDX-2 genes

Cited by 11 publications

References 11 publications

Reduced expression of Axin correlates with tumour progression of oesophageal squamous cell carcinoma

Reduced expression of Axin correlates with tumour progression of oesophageal squamous cell carcinoma

Abnormalities of the APC/β-catenin pathway in endometrial cancer

Frequent loss of the AXIN1 locus but absence of AXIN1 gene mutations in adenocarcinomas of the gastro-oesophageal junction with nuclear β-catenin expression

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