The products of the two mammalian Axin genes (Axin1 and its homologue Axin2) are essential for the degradation of β catenin, a component of Wnt signalling that is frequently dysregulated in cancer cells. Axin is a multidomain scaffold protein that has many functions in biological signalling pathways. Overexpression of axin results in axis duplication in mouse embryos. Wnt signalling activity determines dorsal–ventral axis formation in vertebrates, implicating axin as a negative regulator of this signalling pathway. In addition, Wnts modulate pattern formation and the morphogenesis of most organs by influencing and controlling cell proliferation, motility, and fate. Defects in different components of the Wnt signalling pathway promote tumorigenesis and tumour progression. Recent biochemical studies of axins indicate that these molecules are the primary limiting components of this pathway. This review explores the intriguing connections between defects in axin function and human diseases.

SUMMARY:Immunohistochemical expression analysis of mismatch repair gene products has been suggested for the prediction of hereditary nonpolyposis colorectal cancer (HNPCC) carrier status in cancer families and the selection of microsatellite instability (MSI)-positive tumors in sporadic colorectal cancer. In this study, we aimed to evaluate hMSH2 and hMLH1 immunohistochemistry in familial and sporadic colorectal cancer. We found that immunohistochemistry allowed us to identify patients with germline mutations in hMSH2 and many cases with germline mutations in hMLH1. However, some missense and truncating mutations may be missed. In addition, hMLH1 promoter methylation, commonly occurring in familial and sporadic MSI-positive colorectal cancer, can complicate the interpretation of immunohistochemical expression analyses. Our results suggest that immunohistochemistry cannot replace testing for MSI to predict HNPCC carrier status or identify MSI-positive sporadic colorectal cancer. (Lab Invest 2001, 81:535-541).

There is evidence supporting a multistep genetic model for colorectal tumorigenesis. In familial adenomatosis polyposis (FAP), the inherited defect is a mutation in the APC gene. The vast majority of all sporadic colorectal cancers also show mutations in the APC gene, and the tumorigenesis in sporadic colorectal cancer and FAP is assumed to involve the same genes. Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with germline mutations in DNA mismatch repair genes and, as a result of defective mismatch repair, microsatellite instability (MSI) is frequently seen. Tumorigenesis in HNPCC was first thought to involve mutations in the same genes as in FAP and sporadic colorectal cancer. Recently, however, an alternative pathway to development of colorectal cancer has been suggested in colorectal tumors with MSI, compared to those tumors without the MSI phenotype. We used a consecutive series of 191 sporadic colorectal cancers to find out if there were any differences between the two groups of tumors regarding the prevalence of mutations in the APC, KRAS, TP53, and TGFβR2 genes. As expected, 86% (19/22) of MSI‐positive tumors showed a mutation in TGFβR2, while only one of 164 (0.6%) MSI‐negative tumors did. A highly statistically significant negative association was found between MSI and alterations in APC and TP53. The MSI‐positive tumors were screened for mutations in exon 3 of β‐catenin, which has been suggested to substitute for the APC mutation in the genesis of colorectal cancer, without finding mutations in any of the 22 MSI‐positive tumors. The number of mutations found in KRAS was lower in MSI‐positive than in MSI‐negative tumors but the difference was not statistically significant. Our results strongly support the idea that carcinogenesis in MSI‐positive and MSI‐negative colorectal cancer develops through different pathways. Genes Chromosomes Cancer 26:247–252, 1999. © 1999 Wiley‐Liss, Inc.

Mutations and diminished expression of the E-cadherin gene (CDH1) have been identified in a number of epithelial malignancies. Although somatic CDH1 mutations were detected in lobular breast cancer with a frequency ranging from 10 -56%, CDH1 alterations in more frequent ductal tumors appear to be rare. Here we have analyzed the coding region of CDH1 for mutations using denaturing high performance liquid chromatography and found 4 mutations in 83 ductal carcinomas (5%) and 3 mutations in 25 lobular carcinomas (12%). The germline of 13 patients with familial lobular tumors was also analyzed for mutations, but none were detected. In a case-control study, we also tested whether a variant adenine allele in the promoter polymorphism ؊161C3 A with a putative influence on the transcriptional activity of CDH1 in vitro confers any detectable risk of breast cancer. No significant difference in the allelic frequency between patients with breast cancer (326/1,152, 28.3%) and controls (190/696, 27.3%, p > 0.05; relative risk 1.05, 95% confidence interval 0.85-1.30) was found. A novel promoter polymorphism was identified at position ؊152, but the frequency of the variant cytosine allele was also similar in patients with breast cancer and controls (0.71% vs. 0.21%, p ‫؍‬ 0.23). Transient transfection experiments using reporter constructs containing the nucleotide substitutions ؊161C/ ؊152C and ؊161A/؊152T showed only a slight decrease in the transcription activity compared to the wild-type construct. These results do not support CDH1 as a prominent low-penetrance cancer susceptibility gene, but indicate that CDH1 mutations contribute to the progression of both lobular and ductal tumors. © 2002 Wiley-Liss, Inc. Key words: E-cadherin; mutation; breast cancer; promoter; SNPThe E-cadherin gene (CDH1, OMIM 192090) encodes an adhesion molecule important for establishing cell polarity and maintaining normal tissue morphology and cellular differentiation. 1 E-cadherin was suggested to act as an invasion and metastasis suppressor since its loss in benign tumors could lead to a rapid progression into invasive, metastatic carcinomas. 2 CDH1 was mapped to the chromosome region 16q22.1, 3 which shows frequent allelic imbalance in a variety of tumors and is believed to harbor a tumor-suppressor gene. Mutation analysis of the coding region has been carried out in endometrial and ovarian carcinomas, 4 thyroid, 5 prostate, 6 bladder, 7 colorectal, 8 gastric, 9 breast 10 -14 and colon cancer, 15 but frequent CDH1 mutations were only found in diffuse gastric and infiltrative lobular breast carcinomas. 10,11,16 Although ductal tumors are much more common than lobular breast cancer, CDH1 mutations have been observed in lobular carcinomas at a frequency exceeding 50%, 11 but were not found in ductal tumors in several studies, 10,11,16,17 suggesting a differential role for CDH1 in the development of the 2 malignancies. However, recent studies reported CDH1 alterations in cell lines derived from ductal tumors 18 and in a single case of ductal carcinom...

Summary Hereditary non-polyposis colorectal cancer (HNPCC) is linked to an inherited defect in the DNA mismatch repair system. DNA from HNPCC tumours shows microsatellite instability (MSI). It has been reported that HNPCC patients have a better prognosis than patients with sporadic colorectal cancer. We examined whether the presence of MSI in a series of unselected colorectal tumours carries prognostic information. In a series of 181 unselected colorectal tumours, 22 tumours (12%) showed MSI. Survival analysis at 5-10 years follow-up showed no statistically significant difference in prognosis between MSI-positive and -negative tumours. Our results suggest that the MSI phenotype as such is not an independent prognostic factor.