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Several important syndromes are caused by deleterious germline mutations of individual genes. In both clinical and research applications it is useful to evaluate the probability that an individual carries an inherited genetic variant of these genes, and to predict the risk of disease for that individual, using information on his/her family history. Mendelian risk prediction models accomplish these goals by integrating Mendelian principles and state-of-the-art statistical models to describe phenotype/genotype relationships. Here we introduce an R library called BayesMendel that allows implementation of Mendelian models in research and counseling settings. BayesMendel is implemented in an object-oriented structure in the language R and distributed freely as an open source library. In its first release, it includes two major cancer syndromes: the breast-ovarian cancer syndrome and the hereditary non-polyposis colorectal cancer syndrome, along with up-to-date estimates of penetrance and prevalence for the corresponding genes. Input genetic parameters can be easily modified by users. BayesMendel can also serve as a generic tool for genetic epidemiologists to flexibly implement their own Mendelian models for novel syndromes and local subpopulations, without reprogramming complex statistical analyses and prediction tools.
Stat Appl Genet Mol Biol 2004
PMID:BayesMendel: an R environment for Mendelian risk prediction. 1664

Aberrant activation of Wnt/beta-catenin signaling and subsequent up-regulation of beta-catenin response transcription (CRT) is a critical event in the development of human colon cancer. Thus, Wnt/beta-catenin signaling is an attractive target for the development of anticancer therapeutics. In this study, we identified hexachlorophene as an inhibitor of Wnt/beta-catenin signaling from cell-based small-molecule screening. Hexachlorophene antagonized CRT that was stimulated by Wnt3a-conditioned medium by promoting the degradation of beta-catenin. This degradation pathway is Siah-1 and adenomatous polyposis colidependent, but glycogen synthase kinase-3beta and F-box beta-transducin repeat-containing protein-independent. In addition, hexachlorophene represses the expression of cyclin D1, which is a known beta-catenin target gene, and inhibits the growth of colon cancer cells. Our findings suggest that hexachlorophene attenuates Wnt/beta-catenin signaling through the Siah-1-mediated beta-catenin degradation.
Mol Pharmacol 2006 Sep
PMID:Hexachlorophene inhibits Wnt/beta-catenin pathway by promoting Siah-mediated beta-catenin degradation. 1673 6

Pms2 protein is a component of the DNA mismatch repair complex responsible both for post-replication correction of DNA nucleotide mispairs and for early steps in apoptosis. Germline mutations in DNA mismatch repair genes give rise to hereditary non-polyposis colon cancer, which accounts for about 4% of colon cancers. However, little is known about the expression of mismatch repair proteins in relation to sporadic colon cancer, which accounts for the great majority of colon cancers. Multiple samples were taken from the non-neoplastic flat mucosa of colon resections from patients with no colonic neoplasia, a tubulovillous adenoma, or an adenocarcinoma. Expression of Pms2 was assessed using semiquantitative immunohistochemistry. Apoptosis was assessed in polychrome-stained epoxy sections using morphologic criteria. Samples from patients without colonic neoplasia had moderate to strong staining for Pms2 in cell nuclei at the base of crypts, while samples from 2 of the 3 colons with a tubulovillous adenoma, and from 6 of the 10 colons with adenocarcinomas, showed reduced Pms2 expression. Samples from patients with an adenocarcinoma that had reduced Pms2 expression also exhibited reduced apoptosis capability in nearby tissue samples, evidenced when this paired tissue was stressed ex vivo with bile acid. Reduced Pms2 expression in the colonic mucosa may be an early step in progression to colon cancer. This reduction may cause decreased mismatch repair, increased genetic instability, and/or reduced apoptotic capability. Immunohistochemical determination of reduced Pms2 expression, upon further testing, may prove to be a promising early biomarker of risk of progression to malignancy.
Appl Immunohistochem Mol Morphol 2006 Jun
PMID:Reduced Pms2 expression in non-neoplastic flat mucosa from patients with colon cancer correlates with reduced apoptosis competence. 1678 84

The evolutionary conserved mismatch repair proteins correct a wide range of DNA replication errors. Their importance as guardians of genetic integrity is reflected by the tremendous decrease of replication fidelity (two to three orders of magnitude) conferred by their loss. Germline mutations in mismatch repair genes, predominantly MSH2 and MLH1, have been found to underlie the Lynch syndrome (also called hereditary non-polyposis colorectal cancer, HNPCC), a hereditary predisposition for cancer. Lynch syndrome affects predominantly the colon and accounts for 2-5% of all colon cancer cases. During more than 30 years of biochemical, crystallographic and clinical research, deep insight has been achieved in the function of mismatch repair and the diseases that are associated with its loss. We review the biochemistry of mismatch repair and also introduce the clinical, diagnostic and genetic aspects of Lynch syndrome.
J Mol Histol 2006 Sep
PMID:DNA mismatch repair and Lynch syndrome. 1682 Oct 93

Peutz-Jeghers syndrome (PJS, OMIM 175200) is an unusual inherited intestinal polyposis syndrome associated with distinct peri-oral blue/black freckling. Variable penetrance and clinical heterogeneity make it difficult to determine the exact frequency of PJS. PJS is a cancer predisposition syndrome. Affected individuals are at high risk for intestinal and extra-intestinal cancers. In 1997, linkage studies mapped PJS to chromosome 19p, and subsequently a serine/threonine kinase gene defect (LKB1) was noted in a majority of PJS cases. A phenotypically similar syndrome has been produced in an LKB1 mouse knockout model. Several PJS kindred without LKB1 mutations have been described, suggesting other PJS loci. The management of PJS is complex and evolving. New endoscopic technologies may improve management of intestinal polyposis. Identification of specific genetic mutations and their targets will more accurately assess the clinical course, and help gage the magnitude of cancer risk for affected individuals.
Cell Mol Life Sci 2006 Sep
PMID:Peutz-Jeghers syndrome: clinicopathology and molecular alterations. 1695 58

Cowden syndrome is a non-adenomatous gastrointestinal polyposis syndrome with inactivation of PTEN, a dual-phosphatase tumor suppressor gene. Patients with loss of wildtype PTEN expression from one allele carry an increased risk of malignant breast, thyroid and brain tumors. However, the risk of malignant transformation in gastrointestinal polyps is still unclear. In this study, we describe a kindred with Cowden syndrome and identify a heterozygous germline mutation causing truncation of the PTEN tumor suppressor. The index patient was a 56 year-old woman having multiple facial papules, acral keratosis, oral papillomatosis, multiple benign breast and thyroid tumors and gastrointestinal polyposis. Progression to invasive adenocarcinoma occured in two pre-existing hamartomatous polyps. Analysis of one of the carcinomas revealed somatic inactivation of the wildtype PTEN allele by exon-skipping. This case demonstrates that gastrointestinal hamartomas in Cowden syndrome patients can progress to invasive adenocarcinomas and should therefore be carefully monitored.
Int J Mol Med 2006 Oct
PMID:Multiple colon carcinomas in a patient with Cowden syndrome. 1696 17

The cellular DNA mismatch repair (MMR) pathway, involving the DNA mismatch repair genes MLH1 and MSH2, detects and repairs DNA replication errors. Defects in MSH2 and MLH1 account for most cases of hereditary non-polyposis colorectal cancer as well as for sporadic colorectal tumors. Additionally, increased expression of MSH2 RNA and/or protein has been reported in various malignancies. Loss of DNA MMR in mammalian cells has been linked to resistance to certain DNA damaging agents including clinically important cytotoxic chemotherapeutics. Due to other functions besides its role in DNA repair, that include regulation of cell proliferation and apoptosis, MSH2 has recently been shown to be of importance for pathogenesis and progression of cancer. This review summarizes our present understanding of the function of MSH2 for DNA repair, cell cycle control, and apoptosis and discusses its importance for pathogenesis, progression and therapy of cancer.
J Mol Histol 2006 Sep
PMID:The role of the human DNA mismatch repair gene hMSH2 in DNA repair, cell cycle control and apoptosis: implications for pathogenesis, progression and therapy of cancer. 1708 Feb 93

Familial adenomatous polyposis is an inherited condition associated with hundreds to thousands of colorectal adenomas conferring a very high risk of cancer at a young age. In addition to "classical" form, there is also an attenuated polyposis, with fewer than 100 polyps and a delayed age of cancer onset. Both classical and attenuated polyposis are characterized by a relevant phenotypic heterogeneity. The disease has been linked to constitutive mutations of either APC tumor suppressor gene, or less frequently, MYH base-excision repair gene. However, the genetic cause remains undetected in up to 70-80% of patients with the attenuated form. This analysis was performed on 26 polyposis patients with the attenuated phenotype. All patients had formerly proven to be negative for APC truncating mutations that typically represent the majority of APC gene alterations. We evaluated the APC mRNA constitutional level by real-time quantitative reverse transcription polymerase chain reaction (PCR). Eleven patients (42%) showed an anomalous APC transcription level. One patient with reduced mRNA was a carrier of a whole APC gene deletion. In seven out of the ten remaining cases, we found the increased expression of an APC mRNA isoform resulting from exon 10/15 connection and giving rise to a stable truncated peptide. Mutations neither in the invariant splice sites nor in the known transcription regulatory signals were found. Our results support the notion that in attenuated polyposis patients, a detailed investigation of APC transcription can allow detection of rare alterations. Although functional data are required, the isoform we observed might have some pathogenic role, accounting for the heterogeneous phenotype that characterizes the polyposis syndrome.
J Mol Med (Berl) 2007 Mar
PMID:Constitutional high expression of an APC mRNA isoform in a subset of attenuated familial adenomatous polyposis patients. 1714 20

Germline mutations in the DNA mismatch repair (MMR) gene MLH1 are associated with a large percentage of hereditary non-polyposis colorectal cancers. There are approximately 250 known human mutations in MLH1. Of these, one-third are missense variants that are often difficult to characterize with regards to pathogenicity. We analysed 28 alleles of baker's yeast MLH1 that correspond to non-truncating human mutant alleles listed in online HNPCC databases, 13 of which had not been previously studied in functional assays. Using the highly sensitive lys2::InsE-A(14) reversion rate assay, we determined the MMR proficiency conferred by each allele in the S288c strain of Saccharomyces cerevisiae. Seven alleles conferred a null phenotype for MMR and eight others showed significant MMR defects, suggesting that all 15 are likely to be pathogenic in humans. In addition, we observed a strong correlation between these results, limited results from previous functional assays and clinical data. To test whether the potential pathogenicity of certain alleles depends on the genetic background of the host, we examined the mutation rates conferred by the mlh1 alleles in a second yeast strain, SK1, which is approximately 0.7% divergent from S288c. Many alleles displayed a difference in MMR efficiency between strain backgrounds with decreasing differences as the severity of the MMR defect increased. These findings suggest that genetic background can play an important role in determining the pathogenicity of MMR alleles and may explain cases of atypical colorectal cancer inheritance.
Hum Mol Genet 2007 Feb 15
PMID:The effect of genetic background on the function of Saccharomyces cerevisiae mlh1 alleles that correspond to HNPCC missense mutations. 1721 Jun 69

Colorectal cancer is one of the leading causes of cancer-related death in the Western society, and the incidence is rising. Rare hereditary gastrointestinal polyposis syndromes that predispose to colorectal cancer have provided a model for the investigation of cancer initiation and progression in the general population. Many insights in the molecular genetic basis of cancer have emerged from the study of these syndromes. This review discusses the genetics and clinical manifestations of the three most common syndromes with gastrointestinal polyposis and an increased risk of colorectal cancer: familial adenomatous polyposis (FAP), juvenile polyposis (JP) and Peutz-Jeghers syndrome (PJS).
Curr Mol Med 2007 Feb
PMID:Gastrointestinal polyposis syndromes. 1731 31


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