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Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome caused by germline defects of mismatch repair (MMR) genes. Endometrial cancer is the most common extracolonic neoplasm in HNPCC and is the primary clinical manifestation of the syndrome in some families. The cumulative incidence of endometrial cancer among HNPCC mutation carriers is high, estimated to be from 22 to 43%. We hypothesized that women with double primary cancers of the colorectum and endometrium are likely to be members of HNPCC families. In order to determine how frequently HNPCC manifests in the context of double primary cancers, we examined alterations of two MMR genes, hMSH2 and hMLH1, in 40 unrelated women affected with double primary cancers. These cases were identified using hospital-based and population-based cancer registries in Ontario, Canada. MMR gene mutations were screened by single-strand conformation polymorphism analysis and confirmed by direct sequencing. Eighteen percent (seven of 40) were found to harbor mutations of one of the two MMR genes. Analysis of colorectal and/or endometrial tumors of mutation-negative probands found microsatellite instability in seven of 20 cases. Six of seven mutation-positive probands had strong family histories suggestive of HNPCC. First degree relatives of mutation-positive probands had a very high relative risk (RR) of colorectal cancer (RR = 8.1, CI 3. 5-15.9) and endometrial cancer (RR = 23.8, CI 6.4-61.0). The relative risk of mutation-negative cases was 2.8 (CI 1.7-4.5) for colorectal cancer and 5.4 (CI 2.0-11.7) for endometrial cancer. We recommend that all double primary patients with cancers at these sites should have a genetic evaluation, including molecular analysis for HNPCC where appropriate.
Hum Mol Genet 1999 May
PMID:Mismatch repair gene defects contribute to the genetic basis of double primary cancers of the colorectum and endometrium. 1019 71

Peutz-Jeghers syndrome (PJS) is a classic, but not widely known hereditary trait [1, 2]. Its clinical hallmarks are intestinal hamartomatous polyposis and melanin pigmentation of the skin and mucous membranes. In addition, PJS predisposes to cancer [3, 4]. The most common malignancies are small intestinal, colorectal, stomach and pancreatic adenocarcinomas. Other cancer types that probably occur in excess in PJS families include breast and uterine cervical cancer, as well as testicular and ovarian sex cord tumors. The relative risk of cancer may be as high as 18 times that of the general population, and the cancer patients' prognosis is reduced. Recently, the predisposing locus was mapped to 19p13.3 using a novel method [5]. Subsequently, the causative gene was shown to be LKB1 (a.k.a. STK11), a serine/threonine kinase of unknown function [6]. Although preliminary reports seem to suggest a minor role for LKB1 in sporadic tumorigenesis [7-12], further investigations are needed.
Cell Mol Life Sci 1999 May
PMID:The molecular basis and clinical aspects of Peutz-Jeghers syndrome. 1037 60

Inhaled nitric oxide (NO) is used to treat various cardiopulmonary disorders associated with pulmonary hypertension. The rationale is based on the fact that NO, given by inhalation, only dilates those pulmonary vessels that perfuse well-ventilated lung units. As a result, pulmonary gas exchange is improved while pulmonary vascular resistance is reduced and pulmonary blood flow is increased. Inhaled NO has been successfully applied to treat persistent pulmonary hypertension of the newborn, reducing the need for extracorporeal life support. Although pulmonary hypertension and altered vasoreactivity contribute to profound hypoxaemia in adult and paediatric acute respiratory distress syndrome (ARDS), the benefit of inhaled NO still remains to be established in patients with ARDS. ARDS is a complex response of the lung to direct or indirect insults, leading to pulmonary vasoconstriction and various inflammatory responses. Recent randomized trials suggest that inhaled NO only causes a transient improvement in oxygenation. Whether this effect is important in the long-term management of ARDS remains to be established. NO, measured in the exhaled breath, is an elegant and non-invasive means to monitor inflammation of the upper and lower respiratory tract. In the normal upper airways, the bulk of exhaled NO originates from the paranasal sinuses. Exhaled NO is increased in nasal allergy and decreased in cystic fibrosis, nasal polyposis and chronic sinusitis. That NO production is increased in asthmatic airways is also well established. However, several questions still need to be addressed, in particular evaluation of the sensitivity and specificity of the measurement techniques, and assessment of the bronchodilator action of endogenous NO.
Cell Mol Life Sci 1999 Jul
PMID:Inhaled and exhaled nitric oxide. 1044 91

DNA repair genes and microsatellite instability (MSI) are relatively recently described molecular events that have been associated particularly with colorectal cancers in the setting of hereditary non-polyposis colorectal cancer or the Lynch syndromes. Several other gastrointestinal (and other) malignancies have been analysed for abnormalities in DNA repair genes and MSI. Dietary and environmental factors have been implicated strongly in the aetiology of oesophageal cancer. However, the effect of this on the genetic profile, especially the DNA repair system and resultant MSI, is largely unknown. The purpose of this review is to provide a brief background of the dietary and environmental factors in oesophageal carcinogenesis and to discuss the role of the repair genes and MSI in the molecular pathogenesis of this malignancy. Several studies indicate that MSI (range, 3-40%) and loss of heterozygosity (LOH) (range, 3-64%) in the DNA repair genes are uncommon in carcinogenesis of the oesophagus. Most data are at the lower end of the ranges and this, together with the lack of uniform criteria for the assessment of MSI, accounts for the higher figures obtained in some studies. The rates of detection of MSI do not approach that of other gastrointestinal malignancies, such as gastric (up to 23%) and colorectal (up to 31%) carcinomas.
Mol Pathol 1999 Jun
PMID:DNA repair gene status in oesophageal cancer. 1062 32

Determinants of instability at a given microsatellite repeat merits investigation in view of relevance to understanding evolution of mutations at such sequences in human populations. The microsatellite D2S123 was studied as a paradigm CA repeat marker. Furthermore, this marker is one of a recommended panel used in molecular screening for hereditary non-polyposis colorectal cancer (HNPCC). In this investigation we show that the mutation rate at the D2S123 locus is markedly influenced by intra-allelic sequence variation within the repetitive tract itself. We employed a novel approach to characterize the nature of instability at D2S123, by utilizing cells derived from a non-tumour lineage, which harbour a dominant negative mismatch repair (MMR) mutation and a mutator phenotype. Individual alleles were typed using a semi-quantitative small pool PCR technique and this demonstrated substantial allele-these specific bias in susceptibility to mutation at the D2S123 locus. In support of these in vitro data, bias in allele mutation rate was also observed in tumours from 41 HNPCC patients, which was dependent on constitutional genotype. Sequencing of cell line and patient DNAs revealed that short alleles are significantly more susceptible to mutation due to the presence of uninterrupted CA repeats. Long D2S123 alleles are intrinsically more stable because of a TA interspersion within the repetitive tract. In addition to extending understanding of mutation at CA repeat dinucleotide tracts, these findings have considerable relevance both to screening programmes and to correlation of microsatellite instability (MSI) with colon cancer survival. The manifestation of tumour MSI may be substantially influenced by constitutional genotype.
Hum Mol Genet 2000 Nov 01
PMID:Sequence interruptions confer differential stability at microsatellite alleles in mismatch repair-deficient cells. 1106 29

Hereditary non-polyposis colon cancer (HNPCC), the most common form of hereditary colon cancer, is a syndrome of deficient DNA mismatch repair (MMR). Five, possibly six, human MMR genes have been identified that, when mutated in the germline, cause susceptibility to this syndrome. To date, more than 300 different predisposing mutations are known, mainly affecting the MMR genes MLH1 ( approximately 50%), MSH2 ( approximately 40%) and MSH6 ( approximately 10%). Genetically predisposed individuals carry a defective copy of an MMR gene in every cell. Somatic inactivation of the remaining wild-type copy in a target tissue, typically colon, gives rise to a profound repair defect, progressive accumulation of mutations and cancer. Instability at short tandem repeat sequences, microsatellites, is a typical manifestation of MMR deficiency and apart from HNPCC tumors, occurs in approximately 15% of sporadic colon and other tumors. The majority of the latter cases are attributable to one particular MMR gene, MLH1, and unlike HNPCC, an epigenetic rather than a genetic mechanism plays an important role in the inactivation of this gene. The present review provides an update of the genetics of HNPCC and more generally, of cancer development driven by deficient MMR. Recent discoveries suggest that apart from post-replication repair, MMR proteins have several other functions that are highly relevant to carcinogenesis. Knowledge of the complex interplay between the MMR system and other cellular pathways allows us to better understand the phenotypic manifestations of HNPCC and other cancers with deficient MMR.
Hum Mol Genet 2001 Apr
PMID:Deficient DNA mismatch repair: a common etiologic factor for colon cancer. 1125 6

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant inherited disease caused by defects in the process of DNA mismatch repair (MMR), and mutations in the hMLH1 or hMSH2 genes are responsible for the majority of HNPCC. In addition to clear loss-of-function mutations conferred by nonsense or frameshift alterations in the coding sequence or by splice variants, genetic screening has revealed a large number of missense codons with less obvious functional consequences. The ability to discriminate between a loss-of-function mutation and a silent polymorphism is important for genetic testing for inherited diseases like HNPCC where the opportunity exists for early diagnosis and preventive intervention. In this study, quantitative in vivo DNA MMR assays in the yeast Saccharomyces cerevisiae were performed to determine the functional significance of amino acid replacements observed in the human population. Missense codons previously observed in human genes were introduced at the homologous residue in the yeast MLH1 or MSH2 genes. This study also demonstrated feasibility of constructing genes that encode functional hybrid human-yeast MLH1 proteins. Three classes of missense codons were found: (i) complete loss of function, i.e. mutations; (ii) variants indistinguishable from wild-type protein, i.e. silent polymorphisms; and (iii) functional variants which support MMR at reduced efficiency, i.e. efficiency polymorphisms. There was a good correlation between the functional results in yeast and available human clinical data regarding penetrance of the missense codon. The results reported here raise the intriguing possibility that differences in the efficiency of DNA MMR exist between individuals in the human population due to common polymorphisms.
Hum Mol Genet 2001 Sep 01
PMID:Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae. 1155 25

LKB1 is a serine/threonine kinase which is inactivated by mutation in the Peutz-Jeghers polyposis and cancer predisposition syndrome (PJS). We have identified a novel leucine-rich repeat containing protein, LIP1, that interacts with LKB1. The LIP1 gene consists of 25 exons, maps to human chromosome 2q36 and encodes a protein of 121 kDa. LIP1 appears to be a cytoplasmically located protein whereas we and others have shown previously that LKB1 is predominantly nuclear, with only a small proportion of cells showing strong cytoplasmic expression. However, when LKB1 and LIP1 are co-expressed, the proportion of cytoplasmic LKB1 dramatically increases, suggesting that LIP1 may regulate LKB1 function by controlling its subcellular localization. Ectopic expression of both LKB1 and LIP1 in Xenopus embryos induces a secondary body axis, providing further evidence for a functional link between the two proteins. This phenotype resembles the effects of ectopic expression of TGFbeta superfamily members and their downstream effectors. A possible role for LIP1 and LKB1 in TGFbeta signalling is supported by the observation that LIP1 interacts with the TGFbeta-regulated transcription factor SMAD4, forming a LKB1-LIP1-SMAD4 ternary complex. SMAD4 mutations give rise to juvenile polyposis syndrome, which is clinically similar to PJS. Our data suggest an unsuspected mechanistic link between these two syndromes.
Hum Mol Genet 2001 Dec 01
PMID:LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1. 1174 30

Germline PTEN mutations cause Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR), two hamartoma-tumor syndromes with an increased risk of breast, thyroid and endometrial cancers. Somatic genetic and epigenetic inactivation of PTEN is involved in as high as 93% of sporadic endometrial carcinomas (EC), irrespective of microsatellite status, and can occur in the earliest precancers. EC is the most frequent extra-colonic cancer in patients with hereditary non-polyposis colon cancer syndrome (HNPCC), characterized by germline mutations in the mismatch repair (MMR) genes and by microsatellite instability (MSI) in component tumors. To determine whether PTEN is involved in the pathogenesis of EC arising in HNPCC cases, and whether PTEN inactivation precedes MMR deficiency, we obtained 41 ECs from 29 MLH1 or MSH2 mutation positive HNPCC families and subjected them to PTEN expression and mutation analysis. Immunohistochemical analysis revealed 68% (28/41) of the HNPCC-related ECs with absent or weak PTEN expression. The remaining 27% (11/41) of tumors had normal expression and 5% (2/41) with mixed populations showing weak/absent as well as normal expression. Mutation analysis of 20 aberrant PTEN-expressing tumors revealed that 17 (85%) harbored 18 somatic PTEN mutations. All mutations were frameshift, 10 (56%) of which involved the 6(A) tracts in exon 7 or 8. These results suggest that PTEN plays a significant pathogenic role in both HNPCC and sporadic endometrial carcinogenesis, unlike the scenarios for colorectal cancer. Furthermore, we have shown that somatic PTEN mutation, especially frameshift, is a consequence of profound MMR deficiency in HNPCC-related ECs. In contrast, among 60 previously reported MSI+ sporadic ECs with 70 somatic mutations in PTEN, 39 (56%) were frameshift, of which only eight (21%) were affecting the 6(A) tracts in exon 7 or 8 (P = 0.01), suggesting that PTEN mutations may precede MMR deficiency.
Hum Mol Genet 2002 Feb 15
PMID:Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors. 1185 77

To date, five mismatch-repair (MMR) genes, MLH1, MSH2, MSH6, MSH3 and PMS2, are known to be involved in human MMR function. Two of those, MLH1 and MSH2, are further the most common susceptibility genes for hereditary non-polyposis colorectal cancer (HNPCC), while MSH3 and PMS2 are seldom (PMS2) or not at all (MSH3 ) reported to be involved in HNPCC. Despite the increasing number of MSH6 germline mutations, their pathogenicity remains questionable, because the mutations are mainly linked to putative HNPCC families lacking the typical clinical and molecular characteristics of the syndrome, such as early age at onset and high microsatellite instability (MSI). High MSI is a consequence of MMR defect, and the pathogenicity of germline mutations in HNPCC is thus linked to malfunction of MMR. To address the question of whether and how MSH6 mutations cause susceptibility to HNPCC, we studied heterodimerization of four MSH6 variants with MSH2, and the functionality of these MutSalpha complexes in an in vitro MMR assay. All mutations occurred in putative HNPCC patients. Irrespective of the type or the site of the amino acid substitutions, all the variants repaired G.T mismatches to A.T as wild-type MSH6 protein. However, the MSH6 protein carrying a mutation in the MSH2/MSH6 interaction region was poorly expressed, suggesting problems in its stability. Our results are clinically relevant, since they demonstrate that under the stable in vitro conditions, when the amounts of the proteins are adequate for repair, the tested MSH6 mutations do not affect repair function. Consequently, while the typical HNPCC syndrome is associated with problems in repair reaction, the pathogenicity of mutations in putative HNPCC families may be linked to other biochemical events.
Hum Mol Genet 2002 May 15
PMID:Functional analysis of MSH6 mutations linked to kindreds with putative hereditary non-polyposis colorectal cancer syndrome. 1201 11


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