Genetic problems of hereditary polyposis of the large intestine. I. An analysis of the interrelation with intestinal cancer

An attempt has been made to estimate the correlation of oncological illnesses in the families within the limits of segregational and correlational analyses, considering the fact of accumulation in the families of probands with autosomal-dominant polyposes of colon of the cases of primary (without preceding polyposes) colon cancer. Significant correlation was found between the hereditary polyposes and primary colon cancer in the families studied. Based on these data, a hypothesis is discussed of the main gene and its modifications on the phenotypical version in the form of primary benign (polyposes) and malignant (cancer) pathology. No significant correlation was found between colon polyposes and cancer of stomach in the families.     

Age and origin of two common MLH1 mutations predisposing to hereditary colon cancer.

Two mutations in the DNA mismatch repair gene MLH1, referred to as mutations 1 and 2, are frequent among Finnish kindreds with hereditary nonpolyposis colorectal cancer (HNPCC). In order to assess the ages and origins of these mutations, we constructed a map of 15 microsatellite markers around MLH1 and used this information in haplotype analyses of 19 kindreds with mutation 1 and 6 kindreds with mutation 2. All kindreds with mutation 1 showed a single allele for the intragenic marker D3S1611 that was not observed on any unaffected chromosome. They also shared portions of a haplotype of 4-15 markers encompassing 2.0-19.0 cM around MLH1. All kindreds with mutation 2 shared another allele for D3S1611 and a conserved haplotype of 5-14 markers spanning 2.0-15.0 cM around MLH1. The degree of haplotype conservation was used to estimate the ages of these two mutations. While some recessive disease genes have been estimated to have existed and spread for as long as thousands of generations worldwide and hundreds of generations in the Finnish population, our analyses suggest that the spread of mutation 1 started 16-43 generations (400-1,075 years) ago and that of mutation 2 some 5-21 generations (125-525 years) ago. These datings are compatible with our genealogical results identifying a common ancestor born in the 16th and 18th century, respectively. Overall, our results indicate that all Finnish kindreds studied to date showing either mutation 1 or mutation 2 are due to single ancestral founding mutations relatively recent in origin in the population. Alternatively, the mutations arose elsewhere earlier and were introduced in Finland more recently.     

Genomic structure and DNA diagnosis of hereditary monogenic diseases in the Volga-Ural region

The review considers the main results of molecular analysis of the genes responsible for cystic fibrosis, phenylketonuria, Wilson-Konovalov disease, Duchenne-Becker progressive muscular dystrophy, myotonic dystrophy, Huntington's disease, and nonsyndromic hereditary hypoacusis in populations of the Volga-Ural region. The results were obtained in the past ten years within the framework of the Russian program Human Genome. The mutation spectra and frequencies of these genes were characterized in the major ethnic groups (Bashkirs, Tatars, Russians) of Bashkortostan. Several diseases were associated with particular alleles or haplotypes of polymorphic loci of relevant genes. The results were used to develop DNA diagnostic procedures optimal for the region and to establish the origin of the mutations involved.     

The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer

Germline mutations in two human mismatch repair (MMR) genes, hMSH2 and hMLH1, appear to account for approximately 70% of the common cancer susceptibility syndrome hereditary nonpolyposis colorectal cancer (HNPCC). Although the hMLH1 protein has been found to copurify with another MMR protein hPMS2 as a heterodimer, their function in MMR is unknown. In this study, we have identified the physical interaction regions of both hMLH1 with hPMS2. We then examined the effects of hMLH1 missense alterations found in HNPCC kindreds for their interaction with hPMS2. Four of these missense alterations (L574P, K616Delta, R659P, and A681T) displayed >95% reduction in binding to hPMS2. Two additional missense alterations (K618A and K618T) displayed a >85% reduction in binding to hPMS2, whereas three missense alterations (S44F, V506A, and E578G) displayed 25-65% reduction in binding to hPMS2. Interestingly, two HNPCC missense alterations (Q542L and L582V) contained within the consensus interaction region displayed no effect on interaction with hPMS2, suggesting that they may affect other functions of hMLH1. These data confirm that functional deficiencies in the interaction of hMLH1 with hPMS2 are associated with HNPCC as well as suggest that other unknown functional alteration of the human MutL homologues may lead to tumorigenesis in HNPCC kindreds.     

Effects of perioperative blood transfusion on the prognosis in hereditary and sporadic colon cancer

Abstract

We investigated the effects of perioperative blood transfusion in the prognosis of hereditary and sporadic colon cancer. There are 1075 colon cancer patients, including 936 sporadic colon cancer and 139 with hereditary colon cancer undergoing surgery at our hospital. All patients underwent 10 years of follow-up. In the sporadic group, mortality, local recurrence rate and distant metastases rate of transfused patients were significantly higher than non-transfused patients. The 10-year survival rates were significantly lower in patients receiving blood transfusions compared to non-transfused patients. In the hereditary group, mortality was higher in transfused patients compared to non-transfused patients.     

Genetic mapping of hereditary mixed polyposis syndrome to chromosome 6q.

Hereditary mixed polyposis syndrome (HMPS) is characterized by atypical juvenile polyps, colonic adenomas, and colorectal carcinomas. HMPS appears to be inherited in an autosomal dominant manner. Genetic linkage analysis has been performed on a large family with HMPS. Data did not support linkage to the APC locus or to any of the loci for hereditary nonpolyposis colorectal cancer. Evidence that the HMPS locus lies on chromosome 6q was, however, provided by significant two-point LOD scores for linkage between HMPS and the D6S283 locus. Analysis of recombinants and multipoint linkage analysis suggested that the HMPS locus lies in a 4-cM interval containing the D6S283 locus and flanked by markers D6S468 and D6S301.     

Genetic problems of hereditary polyposis of the large intestine. II. Characteristics of the population genetics

Based on the study carried out, we have suggested a populational-genetical model of hereditary polyposes with frequencies of some parameters, such as frequency of mutation, gene's (allele's) frequency, frequency of heterozygotes (general and for separate groups), fertility, fittnes and selection efficiency.     

Burden of monogenic hereditary pathologies of the residents of Ashkhabad in the Turkmen SSR]

The results of medico-genetic investigation of population of Ashkhabad city are presented involving 229 thousand individuals (118230 Turkomans, 94050 Russians and 16720 subjects of other nationalities). Aggravation values the ethnic groups studied are as follows: Turkomen--AD (autosome-dominant = 0.86 per 1000 subjects, AR (autosome-recessive) = 2.31 per 1000 subjects, attached X chromosomes = 0.52 per 1000 males; Russians--AD = 0.93 per 1000 subjects, AR = 0.84, attached X chromosomes = 0.17 per 1000 males; other nationalities AD = 0.81, AR = 1.43, attached X chromosomes = 0.27. Aggravation of the urban Turkomen population is more valid than that of rural people. Relationship between non-accidental inbreeding rate and aggravation with autosome-recessive pathology is shown for several ethnic subdivisions of the population studied.     

Adenomatous polyposis coli (APC) differentially regulates beta-catenin phosphorylation and ubiquitination in colon cancer cells

Most colorectal cancers have mutations of the adenomatous polyposis coli (APC) gene or the beta-catenin gene that stabilize beta-catenin and activate beta-catenin target genes, leading ultimately to cancer. The molecular mechanisms of APC function in beta-catenin degradation are not completely known. APC binds beta-catenin and is involved in the Axin complex, suggesting that APC regulates beta-catenin phosphorylation. Some evidence also suggests that APC regulates beta-catenin nuclear export. Here, we examine the effects of APC mutations on beta-catenin phosphorylation, ubiquitination, and degradation in the colon cancer cell lines SW480, DLD-1, and HT29, each of which contains a different APC truncation. Although the current models suggest that beta-catenin phosphorylation should be inhibited by APC mutations, we detected significant beta-catenin phosphorylation in these cells. However, beta-catenin ubiquitination and degradation were inhibited in SW480 but not in DLD-1 and HT29 cells. The ubiquitination ofbeta-catenin in SW480 cells can be rescued by exogenous expression of APC. The APC domains required for beta-catenin ubiquitination were analyzed. Our results suggest that APC regulates beta-catenin phosphorylation and ubiquitination by distinct domains and by separate molecular mechanisms.     

Possible relationship between Helicobacter pylori infection and cap polyposis of the colon

BACKGROUND: Cap polyposis is a rarely encountered disease characterized by multiple distinctive inflammatory colonic polyps located from the rectum to the distal colon. The etiology of this disease is still unknown, and no specific treatment has been established. AIM: We report three cases of cap polyposis that were cured following eradication therapy for Helicobacter pylori infection. METHODS AND RESULTS: Three women were referred to Shinshu University Hospital because of mucoid and/or bloody diarrhea. Laboratory data showed hypoproteinemia in all cases; markers of inflammation such as C-reactive protein were negative. Colonoscopy revealed multiple sessile polyps with mucus adherent on the apices of the mucosal folds in the rectum and/or the sigmoid colon. The intervening mucosa was normal. Microscopic examinations of biopsy specimens taken from sessile polyps revealed inflamed mucosa with elongated tortuous crypts attenuated towards the mucosal surface. A granulation tissue 'cap' was observed on the surface of the mucosa. Various treatments were unsuccessful, including administration of metronidazole or prednisolone, avoidance of straining at defecation, and surgical or endoscopic resection. All were diagnosed with H. pylori infection in the stomach. Helicobacter pylori was not detected in the biopsy specimens from the colonic inflammatory polyps by immunohistochemical study using polyclonal anti-H. pylori antibody. After successful eradication therapy the clinical symptoms improved. Disappearance of cap polyposis was confirmed by colonoscopy in all three cases. CONCLUSION: We speculate that H. pylori infection might play a role in the pathogenesis of cap polyposis.     

Genetics of colon cancer.

Strikingly rapid advances in the identification of genetic events that are important in colonic carcinogenesis have been made in the past several years. Specific inherited (adenomatous polyposis coli gene) and acquired (ras gene point mutations; c-myc gene amplification; allelic deletion at specific sites on chromosomes 5, 17, and 18) genetic abnormalities appear to be capable of mediating steps in the progression from normal to malignant colonic mucosa. Understanding these genetic factors and how they influence cellular function will have a profound effect on medical practice. High-risk populations will be (and are being) identified by genetic markers, thus allowing prevention and screening to be more precisely targeted to the population at risk; intervention strategies will be designed on the basis of the known cellular defects of neoplastic colonic mucosa; and new molecular preventive and therapeutic approaches can be developed.     

Epidemiology of monogenic hereditary diseases in Rostov oblast: Population dynamic factors determining the differentiation of the load of hereditary diseases in eight districts

Analysis of the diversity of monogenic hereditary diseases in eight raions (districts) of Rostov oblast (region) of Russia (Tsimlyansk, Volgodonskoi, Tselina, Egorlykskaya, Millerovo, Tarasovskaya, Rodionovo-Nesvetaiskaya, and Matveevo-Kurgan raions) has been summarized. The total sample size was 320925 subjects. The spectrum of hereditary diseases detected in the eight districts comprises 187 diseases, including 99 autosomal dominant (AD), 72 autosomal recessive (AR), and 16 X-linked diseases. The mean prevalence rate of each disease in the total population has been calculated. Accumulation of individual diseases in different regions of Rostov oblast has been calculated; the disease accumulation has been compared with that in some populations of Russia examined earlier. Cluster analysis using the data on the frequencies of genes of hereditary diseases has shown the gene geographic position of the Rostov oblast population among the following ethnic populations of Russia: Russians (Kostroma, Kirov, and Rostov oblasts and Krasnodar krai), Chuvashes (Chuvashia), Adygeans (Adygea), Maris (Marii El), and Udmurts (Udmurtia).     

Epidemiology of monogenic hereditary diseases in Rostov oblast: Population dynamic factors determining the differentiation of the load of hereditary diseases in eight districts

A genetic epidemiological study has been carried out in eight raions (districts) of Rostov oblast (region) of Russia: Tsimlyansk, Volgodonskoi, Tselina, Egorlykskaya, Millerovo, Tarasovskaya, Rodionovo-Nesvetaiskaya, and Matveevo-Kurgan raions. The population structure (the parameters of the isolation by distance model, ethnic assortative marriage, random inbreeding (F _ST), endogamy index, and ie) and the genetic demographic characteristics of the regional population (vital statistics, Crow’s index, and its components) have been analyzed. The total sample size was 320 925 subjects (including 114 106 and 206 816 urban and rural residents, respectively). The load of the main types of Mendelian diseases (autosomal dominant (AD), autosomal recessive (AR), and X-linked diseases) has been calculated for the total sample from eight districts and separately for the urban and rural populations. Substantial differences between individual districts in the AD and AR genetic loads have been found, especially upon separation into urban and rural samples. The results of correlation analysis suggest that migration and genetic drift are the main factors of genetic differentiation of populations with respect to the prevalence of hereditary diseases.     

DHPLC mutation analysis of the hereditary nonpolyposis colon cancer (HNPCC) genes hMLH1 and hMSH2

Denaturing high-performance liquid chromatography (DHPLC) is an efficient method for detection of mutations involving a single or few numbers of nucleotides, and it has been successfully used for mutation detection in disease-related genes. Colorectal cancer is one of the most common cancers, and mutations in the genes for hereditary nonpolyposis colon cancer (HNPCC), hMLH1 and hMSH2, also involve mainly point mutations. Sequence analysis is supposed to be a screening method with high sensitivity; however, it is time-consuming and expensive. We therefore decided to test sensitivity and reproducibility of DHPLC for 71 sequence variants in hMLH1 and hMSH2 initially found by sequence analysis in DNA samples of German HNPCC patients. DHPLC conditions of the PCR products were based on the melting pattern of the wild-type sequence of the corresponding PCR fragments. All but one of the 71 mutations was detected using DHPLC (sensitivity of 97%). Running time per sample averaged only 7 min, and the system is highly automated. Thus DHPLC is a rapid and sensitive method for the detection of hMLH1 and hMSH2 sequence variants.