transforming-growth-factor-beta and Colorectal-Neoplasms--Hereditary-Nonpolyposis

TGF-beta is a member of a superfamily associated with development and regulation of cell growth. Recently, its two receptors and intracellular components of signal transduction, a Smad family, have been identified. The type II receptor gene has been found to be mutated specifically in hereditary colon cancers, HNPCC. Alterations of the Smad 4 gene were also detected in pancreatic and colorectal cancers.

Topics: Colonic Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Humans; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta

Mlh1-knockout mice have been developed as a useful model of hereditary non-polyposis colorectal cancer (HNPCC). In this study, we analyzed the pathology of gastrointestinal tumours (GIT) in these mice in detail and examined the possible effects of ionizing radiation on the induction of intestinal tumours to evaluate the late response to radiotherapy in HNPCC. Mlh1-/- mice spontaneously developed GIT and thymic lymphomas by 48 weeks. GIT included not only well differentiated adenocarcinomas but also poorly differentiated and mucinous adenocarcinomas, suggesting that this mouse is a good model for HNPCC. In contrast to colon cancers from HNPCC patients, however, carcinomas of Mlh1-/- mice expressed p53 and showed a lack of transforming growth factor (TGF)-betaRII mutation, which resulted in the expression of TGF-betaRII protein. Irradiation of 10-week-old Mlh1-/- mice accelerated GIT development but had little effect at 2 weeks. Mlh1+/- and Mlh1+/+ mice were not susceptible to spontaneous or radiation-induced thymic lymphomas and GIT until 72 weeks after birth. The development and pathology of GIT in Mlh1-/- mice suggest that this mouse is a good model for HNPCC, although tumour-related responsible genes might be different from HNPCC. As X-ray exposure promoted carcinogenesis of GIT in adult Mlh1-/- mice, an increased risk of secondary cancers after radiotherapy for HNPCC patients should be taken into consideration.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Animals; Base Pair Mismatch; beta Catenin; Carrier Proteins; Colorectal Neoplasms, Hereditary Nonpolyposis; Disease Models, Animal; Disease Progression; Gastrointestinal Neoplasms; Genes, Neoplasm; Immunohistochemistry; Lymphoma; Mice; Mice, Knockout; Mutation; MutL Protein Homolog 1; Neoplasm Proteins; Nuclear Proteins; Radiotherapy; Receptors, Transforming Growth Factor beta; Thymus Neoplasms; Transforming Growth Factor beta; Transforming Growth Factor beta2; Tumor Suppressor Protein p53

Endoglin (CD105) is a proliferation-associated protein that is strongly expressed in endothelial tissue and has a role in tumor angiogenesis. Mutations in endoglin are also linked to Hereditary Hemorrhagic Telangiectasia type 1 (HHT1), an autosomal dominant disease associated with aberrant angiogenesis. We report an unusual association of HHT1 and Hereditary Nonpolyposis Colorectal Cancer (HNPCC) in the same kindred. Genetic analysis indicates that these 2 syndromes are genetically unrelated and separately segregated within the family. The mutation in the endoglin gene leads to a truncated protein. The mutation in the mismatch repair gene MLH1 causes a splicing defect, giving synthesis to an unstable mRNA from this mutated allele. The potential protective role of an endoglin mutation in patients with HNPCC is discussed.

Topics: Adaptor Proteins, Signal Transducing; Adult; Alleles; Antigens, CD; Base Pair Mismatch; Carrier Proteins; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Repair; Endoglin; Exons; Female; Genetic Linkage; Humans; Male; Middle Aged; Mutation; MutL Protein Homolog 1; Neoplasm Proteins; Nuclear Proteins; Receptors, Cell Surface; Telangiectasia, Hereditary Hemorrhagic; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1

Topics: Base Sequence; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mutational Analysis; DNA-Binding Proteins; DNA, Neoplasm; Female; Germ-Line Mutation; Humans; Male; Molecular Sequence Data; Signal Transduction; Smad2 Protein; Smad3 Protein; Smad4 Protein; Trans-Activators; Transforming Growth Factor beta

Topics: Animals; Cell Differentiation; Cell Division; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA-Binding Proteins; Gene Rearrangement; Genes, Tumor Suppressor; Mice; Phosphorylation; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta

A subset of hereditary and sporadic colorectal carcinomas is defined by microsatellite instability (MSI), but the spectra of gene mutations have not been characterized extensively. Thirty-nine hereditary nonpolyposis colorectal cancer syndrome carcinomas (HNPCCa) and 57 sporadic right-sided colonic carcinomas (SRSCCa) were evaluated. Of HNPCCa, 95% (37/39) were MSI-positive as contrasted with 31% (18/57) of SRSCCa (P < 0.000001), but instability tended to be more widespread in SRSCCa (P = 0.08). Absence of nuclear hMSH2 mismatch repair gene product by immunohistochemistry was associated with germline hMSH2 mutation (P = 0.0007). The prevalence of K-ras proto-oncogene mutations was similar in HNPCCa and SRSCCa (30% (11/37) and 30% (16/54)), but no HNPCCa from patients with germline hMSH2 mutation had codon 13 mutation (P = 0.02), and two other HNPCCa had multiple K-ras mutations attributable to subclones. 18q allelic deletion and p53 gene product overexpression were inversely related to MSI (P = 0.0004 and P = 0.0001, respectively). Frameshift mutation of the transforming growth factor beta type II receptor gene was frequent in all MSI-positive cancers (85%, 46/54), but mutation of the E2F-4 transcription factor gene was more common in HNPCCa of patients with germline hMSH2 mutation than in those with germline bMLH1 mutation (100% (8/8) versus 40% (2/5), P = 0.04), and mutation of the Bax proapoptotic gene was more frequent in HNPCCa than in MSI-positive SRSCCa (55% (17/31) versus 13% (2/15), P = 0.01). The most common combination of mutations occurred in only 23% (8/35) of evaluable MSI-positive cancers. Our findings suggest that the accumulation of specific genetic alterations in MSI-positive colorectal cancers is markedly heterogeneous, because the occurrence of some mutations (eg, ras, E2F-4, and Bax genes), but not others (eg, transforming growth factor beta type II receptor gene), depends on the underlying basis of the mismatch repair deficiency. This genetic heterogeneity may contribute to the heterogeneous clinical and pathological features of MSI-positive cancers.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma, Mucinous; Adult; Aged; Aged, 80 and over; bcl-2-Associated X Protein; Carrier Proteins; Cell Cycle Proteins; Chromosomes, Human, Pair 18; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mutational Analysis; DNA-Binding Proteins; DNA, Neoplasm; E2F Transcription Factors; E2F4 Transcription Factor; Female; Genes, APC; Humans; Male; Microsatellite Repeats; Middle Aged; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplasm Proteins; Nuclear Proteins; Point Mutation; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins p21(ras); Retinoblastoma-Binding Protein 1; Transcription Factor DP1; Transcription Factors; Transforming Growth Factor beta; Tumor Suppressor Protein p53

We analyzed microsatellite instability, alterations of the polyadenine tract in TGF-beta RII (transforming growth factor beta type II receptor gene), and mutations of hMSH2 and hMLH1 in 32 patients with familial colorectal cancer (29 kindreds) fulfilling the clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC), defined at the 34th Annual Meeting of Japanese Society for Cancer of the Colon and Rectum (Tokushima, Japan, 1991), including five kindreds fulfilling the Amsterdam criteria. Eighteen of 32 (56%) cases were replication error positive (RER+) at two or more microsatellite loci analyzed. The clinicopathological characteristics of RER+ cases corresponded well with those reported previously. Eleven of 18 RER+ cases showed RER+ at most of the microsatellite loci examined. Among these 11 cases (10 kindreds), 3 kindreds fulfilled the Amsterdam criteria and 7 kindreds did not. For these 10 kindreds, germ-line mutations in hMSH2 and hMLH1 were detected for 6 kindreds by PCR-SSCP analysis and direct sequencing. Only two of these six fulfilled the Amsterdam criteria; more than one germ-line mutation was detected in hMSH2 and/or hMLH1. Specifically, two point mutations of hMSH2 were detected in two kindreds, one point mutation of both hMSH2 and hMLH1 was detected in one kindred, two point mutations of hMSH2 and one point mutation of hMLH1 were detected in one kindred, and two point mutations of hMLH1 and one point mutation of hMSH2 were detected in one kindred. In addition, 19 of 26 (74%) cancer lesions of these 11 cases with the RER phenotype showed alterations of the polyadenine tract in TGF-beta RII. From our data, although seven kindreds did not fulfill the Amsterdam criteria, we considered them as HNPCC. Therefore, we suggest that the "Japanese criteria" have the advantage of being able to detect more HNPCC kindreds from borderline HNPCC kindreds.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carrier Proteins; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA-Binding Proteins; Exons; Female; Genetic Markers; Germ-Line Mutation; Humans; Japan; Male; Microsatellite Repeats; Middle Aged; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplasm Proteins; Nuclear Proteins; Pedigree; Phenotype; Proto-Oncogene Proteins; Sequence Analysis, DNA; Transforming Growth Factor beta

Topics: Animals; Cell Division; Colonic Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Repair; Endometrial Neoplasms; Female; Genes, Tumor Suppressor; Humans; Mice; Mice, Nude; Mutation; Ovarian Neoplasms; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta; Tumor Cells, Cultured

Transforming growth factor-beta (TGF-beta) is a potent inhibitor of epithelial cell growth. Human colon cancer cell lines with high rates of microsatellite instability were found to harbor mutations in the type II TGF-beta receptor (RII) gene. Eight such examples, due to three different mutations, were identified. The mutations were clustered within small repeated sequences in the RII gene, were accompanied by the absence of cell surface RII receptors, and were usually associated with small amounts of RII transcript. RII mutation, by inducing the escape of cells from TGF-beta-mediated growth control, links DNA repair defects with a specific pathway of tumor progression.

Topics: Amino Acid Sequence; Animals; Colonic Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Disease Progression; DNA Repair; DNA, Neoplasm; DNA, Satellite; Frameshift Mutation; Humans; Mice; Molecular Sequence Data; Neoplasm Transplantation; Phenotype; Receptors, Transforming Growth Factor beta; Repetitive Sequences, Nucleic Acid; RNA, Messenger; Sequence Deletion; Transforming Growth Factor beta; Tumor Cells, Cultured