National Cancer Institute®
Last Modified: April 1, 2002
UI - 11484291
AU - Yar'mov N; Gachev N
TI - [Colorectal carcinoma and molecular genetics]
SO - Khirurgiia (Sofiia) 2000;56(2):50-2
In the last few years, problems relating to genetic determination of colorectal carcinoma are comprehensively discussed by a number of authors. The new elaborations concerning the familial polypoid and carcinoid syndromes discovered, as well as molecular researches along this line answer a great number of questions posed in connection with substantiating the old idea about many-staged cancerigenesis. As much as 94 per cent of colorectal carcinoma cases are assigned to the sporadic cancer diagnosis category. Familial polyposis accounts for 1 per cent of all neoplasms of the colon, while the remainder 5 per cent make part of diverse familial carcinoid syndromes. Most of the data on genetic etiology of colorectal carcinoma so far elucidated are presented in a summed up fashion.
UI - 11852407
AU - Terdiman J; Gum Jr J; Conrad P; Miller G; Weinberg V; Crawley S; Levin
TI - T; Reeves C; Schmitt A; Hepburn M; Sleisenger M; Kim Y [Search for microsatellite instability in colorectal cancer: an effective way to detect HNPCC?]
SO - Gastroenterol Clin Biol 2001 Oct;25(10):929-31
AD - Federation Transversale de Cancerologie, CHU de Toulouse et Institut, Claudius-Regaud, Tououse, France.
UI - 11899542
AU - Krutilkova V; Havlovicova M; Goetz P
TI - [Specialized genetic counseling in pediatric and adult oncology patients]
SO - Cas Lek Cesk 2002;141(1):23-7
AD - Ustav biologie a lekarske genetiky 2. LF UK a FNM, Praha. email@example.com
Five to ten percent of oncological diseases exhibit monogenic mode of inheritance. They occur as a consequence of the germline mutations of tumor suppressor genes and of the genes engaged in reparative processes. Most common monogenically determined oncological diseases are: AD form of breast and ovarian cancer, hereditary nonpolyposis colorectal cancer (HNPCC, Lynch sy.) and familiar adenomatous polyposis (FAP). The aim of the genetic investigation is to evaluate whether the index family deals with the hereditary form of tumor predisposition, than, if possible, to perform DNA analysis in the family and to propose preventive screening program (methods) for the probands in risk.
UI - 11870161
AU - Scartozzi M; Bianchi F; Rosati S; Galizia E; Antolini A; Loretelli C;
TI - Piga A; Bearzi I; Cellerino R; Porfiri E Mutations of hMLH1 and hMSH2 in patients with suspected hereditary nonpolyposis colorectal cancer: correlation with microsatellite instability and abnormalities of mismatch repair protein expression.
SO - J Clin Oncol 2002 Mar 1;20(5):1203-8
AD - Department of Clinica di Oncologia Medica, University of Ancona, Ancona, Italy.
PURPOSE: The relationship between germ-line mutations of hMSH2 and hMLH1, microsatellite instability (MSI), and loss of DNA mismatch repair (MMR) gene expression were studied to formulate an effective selection protocol for patients with suspected hereditary nonpolyposis colorectal cancer who should be offered genetic testing. PATIENTS AND METHODS: Patients eligible for germ-line analysis of hMLH1 and hMSH2 were selected. Tumor specimens were obtained to assess MSI and loss of MMR gene expression. RESULTS: Among 37 patients who participated in the study, two hMSH2 and two hMLH1 missense mutations (11%) were detected, none of which was found in a panel of 60 healthy volunteers. High MSI was found in five tumors (19%) and low MSI in 10 tumors (39%); 12 tumors (46%) were microsatellite stable. Four tumors demonstrated loss of hMLH1, and three tumors demonstrated loss of hMSH2 protein expression. CONCLUSION: No relationship was found between MMR gene mutations and MSI; low or no MSI was found in the four patients with germ-line mutations, and none of the five patients with high MSI demonstrated abnormalities of MMR genes. On the contrary, loss of hMLH1 or hMSH2 expression was found in the tumors from three of the four patients demonstrating germ-line mutations. These data suggest that germ-line mutations of the MMR gene can occur in people with MSI-negative tumors. Sensitive clinical criteria and the study of MMR gene expression may be useful to identify this subset of patients.
UI - 11920532
AU - Dove-Edwin I; Boks D; Goff S; Kenter GG; Carpenter R; Vasen HF; Thomas
TI - HJ The outcome of endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma.
SO - Cancer 2002 Mar 15;94(6):1708-12
AD - Imperial Cancer Research Fund Family Cancer Clinic, St Mark's Hospital, London, UK.
BACKGROUND: Endometrial carcinoma is the most common extracolonic malignancy associated with hereditary nonpolyposis colorectal carcinoma syndrome (HNPCC). The risk of endometrial carcinoma in HNPCC mutation carriers is approximately ten times that of the general population, and endometrial ultrasound surveillance to detect early cancer in asymptomatic individuals is recommended by the International Collaborative Group on HNPCC. There is little, if any, published data addressing the effectiveness of surveillance in HNPCC and familial colorectal carcinoma. METHODS: The outcomes of endometrial carcinoma surveillance scans were collected from the St Mark's Hospital Imperial Cancer Research Fund Family Cancer Clinic in the UK and the Netherlands Foundation for the Detection of Hereditary Tumors. Two hundred ninety two women from HNPCC (171) or HNPCC-like (98) families between the ages of 25-65 years were offered pelvic ultrasound surveillance scans for a period of up to 13 years. RESULTS: Results were available from 269 women. The study period included a total of 825.7 years of risk. Two cases of endometrial carcinoma were reported. Neither case was detected by surveillance scanning. Both cases presented at an early stage with symptoms and were subsequently cured. CONCLUSIONS: Endometrial carcinoma surveillance in hereditary colorectal carcinoma may not offer obvious clinical benefits. Copyright 2002 American Cancer Society.
UI - 11778159
AU - Wullen B; Muhlhofer A; Zoller WG
TI - [Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer]
SO - Z Gastroenterol 2001 Nov;39(11):981-4
AD - Zentrum fur Innere Medizin, Klinik fur Allgemeine Innere Medizin, Stuttgart.
UI - 11920458
AU - Furukawa T; Konishi F; Shitoh K; Kojima M; Nagai H; Tsukamoto T
TI - Evaluation of screening strategy for detecting hereditary nonpolyposis colorectal carcinoma.
SO - Cancer 2002 Feb 15;94(4):911-20
AD - Department of Surgery, Jichi Medical School, Kawachi-gun, Tochigi, Japan. firstname.lastname@example.org
BACKGROUND: The Amsterdam criteria are used worldwide for the clinical diagnosis of hereditary nonpolyposis colorectal carcinoma (HNPCC). In Japan, clinical criteria (JCC) have been proposed to identify as many HNPCC cases as possible, but the suitability of the JCC remains uncertain. In this article, the authors evaluate retrospectively whether the JCC are adequate to diagnose HNPCC compared with the Bethesda guidelines (BG) and also investigated useful screening methods for HNPCC. METHODS: The authors studied 452 colorectal carcinoma cases, of which 69 cases fulfilled the JCC (A, 12; B, 57) and 106 fulfilled the BG. Microsatellite instability (MSI) was examined for 452 cases. TGF beta RII, immunohistochemical staining, and germline mutations of hMLH1 and hMSH2 were analyzed in high-frequency MSI cases. RESULTS: High-frequency MSI was found in 21.7% (98 of 452). Germline mutations were detected in eight cases (hMLH1, three, hMSH2; five). Six cases fulfilled the JCC (A, four; B, two), and six fulfilled the BG. The germline mutation rate was significantly higher in the JCCA than in non-JCCA cases (33.3% vs. 0.91%; P < 0.001) and in cases with an age at onset younger than 50 years than older than 50 years (9.3% vs. 0.27%, P < 0.001). All germline mutation carriers had the TGF beta RII mutation. Immunohistochemically, a decreased nuclear staining was found in 57.3% (47 of 82) for hMLH1 and in 18.3% (15 of 82) for hMSH2. The frequency of predicted germline mutations was higher in cases with decreased hMSH2 than hMLH1 (33.3% vs. 6.4%; P = 0.016). CONCLUSIONS: The JCCA are suitable for selecting cases to analyze for gene mutations, but the JCCB are not useful for the clinical setting. The authors suggest that an age at onset younger than 50 years is also important for screening. Analyzing TGF beta RII mutations and immunohistochemical staining of hMLH1 or hMSH2 for cases with MSI phenotype are useful for selecting cases who should be tested for germline mutations. Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10332
UI - 11579115
AU - Percesepe A; Borghi F; Menigatti M; Losi L; Foroni M; Di Gregorio C;
TI - Rossi G; Pedroni M; Sala E; Vaccina F; Roncucci L; Benatti P; Viel A; Genuardi M; Marra G; Kristo P; Peltomaki P; Ponz de Leon M Molecular screening for hereditary nonpolyposis colorectal cancer: a prospective, population-based study.
SO - J Clin Oncol 2001 Oct 1;19(19):3944-50
AD - Department of Internal Medicine, University of Modena, Modena, Italy. email@example.com
PURPOSE: Germline mutations in mismatch repair genes predispose to hereditary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinical investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland found an incidence of 2% to 2.7% of mutation carriers for the disease. The aim of the present report is to establish the frequency of the disease in a high-incidence area for colon cancer. PATIENTS AND METHODS: Through the data of the local CRC registry, we prospectively collected all cases of CRC from January 1, 1996, through December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the incident cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleotide markers. MSI cases were subjected to MSH2 and MLH1 germline mutation analysis and immunohistochemistry; the methylation of the promoter region was studied for MLH1. RESULTS: Twenty-eight cases (8.3% of the total) showed MSI. MSI cases differed significantly from microsatellite-stable (MSS) cases for their proximal location (P <.01), high mucinous component (P <.01), and poor differentiation (P =.002). Of MSI cases studied (n = 12), only one with a family history compatible with HNPCC had a germline mutation (in MSH2). Five other patients with a family history of HNPCC (two with MSI and three with MSS tumors) did not show germline mutations. CONCLUSION: We conclude that the incidence of molecularly confirmed HNPCC (one [0.3%] of 336) in a high-incidence area for CRC is lower than in previous biomolecular and clinical estimates.
UI - 11896123
AU - Andermann A; Thiffault I; Wong N; Gordon P; MacNamara E; Chong G;
TI - Foulkes W Multimodal molecular screening is required to improve the sensitivity of MLH1 and MSH2 mutation analysis.
SO - J Clin Oncol 2002 Mar 15;20(6):1705-7
UI - 11920650
AU - Caldes T; Godino J; de la Hoya M; Garcia Carbonero I; Perez Segura P;
TI - Eng C; Benito M; Diaz-Rubio E Prevalence of germline mutations of MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer families from Spain.
SO - Int J Cancer 2002 Apr 10;98(5):774-9
AD - Laboratory of Molecular Oncology, San Carlos University Hospital, Madrid, Spain. firstname.lastname@example.org
HNPCC is an autosomal dominantly inherited cancer-susceptibility syndrome that confers an increased risk for colorectal cancer and endometrial cancer at a young age. It also entails an increased risk of a variety of other tumors, such as ovarian, gastric, uroepithelial and biliary tract cancers. The underlying pathogenic mutation lies in 1 of the 5 known DNA MMR genes (MSH2, MLH1, PMS1, PMS2 and MSH6). We screened a total of 140 individuals from 56 Spanish families with suspected HNPCC for mutations in the DNA mismatch repair genes MLH1 and MSH2, using DGGE and direct DNA sequencing. Families were selected on the basis of a history of HNPCC-related tumors or the occurrence of other associated tumors in members besides the index case affected with colorectal cancer. We detected 14 definite pathogenic germline mutations, 9 in MLH1 and 5 in MSH2 in 13 unrelated families selected by the Amsterdam criteria and Bethesda guidelines (1 family carries 2 mutations) and 3 missense mutations in 3 unrelated families selected by the Amsterdam criteria. Among the 17 germline mutations noted in the Spanish cohort, 10 are novel, 7 in MLH1 and 3 in MSH2, perhaps demonstrating different mutational spectra in the Spanish population, where no founder mutation has been identified. Based on our results, we suggest that in the Spanish population not only HNPCC families fulfilling the Amsterdam criteria but also those following Bethesda guidelines should undergo genetic testing for MSH2 and MLH1 mutations. Copyright 2002 Wiley-Liss, Inc.
UI - 8072530
AU - Nicolaides NC; Papadopoulos N; Liu B; Wei YF; Carter KC; Ruben SM; Rosen
TI - CA; Haseltine WA; Fleischmann RD; Fraser CM; et al Mutations of two PMS homologues in hereditary nonpolyposis colon cancer.
SO - Nature 1994 Sep 1;371(6492):75-80
AD - Johns Hopkins Oncology Center, Baltimore, Maryland 21231.
Hereditary nonpolyposis colorectal cancer (HNPCC) is one of man's commonest hereditary diseases. Several studies have implicated a defect in DNA mismatch repair in the pathogenesis of this disease. In particular, hMSH2 and hMLH1 homologues of the bacterial DNA mismatch repair genes mutS and mutL, respectively, were shown to be mutated in a subset of HNPCC cases. Here we report the nucleotide sequence, chromosome localization and mutational analysis of hPMS1 and hPMS2, two additional homologues of the prokaryotic mutL gene. Both hPMS1 and hPMS2 were found to be mutated in the germline of HNPCC patients. This doubles the number of genes implicated in HNPCC and may help explain the relatively high incidence of this disease.
UI - 7616541
AU - Froggatt NJ; Koch J; Davies R; Evans DG; Clamp A; Quarrell OW;
TI - Weissenbach J; Hodgson SV; Ponder BA; Barton DE; et al Genetic linkage analysis in hereditary non-polyposis colon cancer syndrome.
SO - J Med Genet 1995 May;32(5):352-7
AD - Cambridge University Department of Pathology, Addenbrooke's Hospital, Cambridge, UK.
Hereditary Non-polyposis Colon Cancer Syndrome (HNPCC) is the most common cause of familial colorectal cancer. Molecular genetic studies of HNPCC have shown evidence of locus heterogeneity, and mutations in four genes (hMSH2, hMLH1, hPMS1, and hPMS2) which encode components of the mismatch enzyme repair system may cause HNPCC. To determine the extent and nature of locus heterogeneity in HNPCC, we performed genetic linkage studies in 14 HNPCC families from eastern and north-western England. Linkage to hMLH1 was excluded in six families, each of which were likely to be linked to hMSH2 (lod score > 1.0 in each family and total lod score for all six families = 7.64). Linkage to hMSH2 was excluded in three families, each of which were likely to be linked to hMLH1 (lod score > 1.0 in each family and total lod score at hMLH1 for all three families = 3.93). In the remaining five families linkage to hMSH2 or hMLH1 could not be excluded. These results confirm locus heterogeneity in HNPCC and suggest that, in the population studied, most large families with HNPCC will have mutations in hMSH2 or hMLH1. We did not detect any correlation between clinical phenotype and the genetic linkage results, but a Muir-Torre syndrome family excluded from linkage to hMLH1 was likely to be linked to hMSH2 and showed microsatellite instability in a tumour from an affected relative.
UI - 8586419
AU - Nicolaides NC; Carter KC; Shell BK; Papadopoulos N; Vogelstein B;
TI - Kinzler KW Genomic organization of the human PMS2 gene family.
SO - Genomics 1995 Nov 20;30(2):195-206
AD - Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
The hPMS2 gene (HGMW-approved symbol PMS2) encodes a mutL homolog that causes hereditary non-polyposis colon cancer (HNPCC) when inherited in mutant form. We have here characterized the genomic structure of the hPMS2 gene to facilitate its analysis in HNPCC kindreds. The hPMS2 genomic locus was found to encompass 16 kb and consist of 15 exons. During its analysis, we identified a family of hPMS2-related genes located on chromosome 7 at bands 7p12-p13, 7q11, and 7q22. Exons 1 through 5 of these homologs shared a high degree of identity with hPMS2. We present the sequence of seven novel genes that represent the hPMSR (hPMS2-related) gene family. The similarity and number of these genes made specific amplification of hPMS2 problematic, but knowledge of them aided the successful design of oligonucleotides for this purpose.
UI - 8666379
AU - Nicolaides NC; Kinzler KW; Vogelstein B
TI - Analysis of the 5' region of PMS2 reveals heterogeneous transcripts and a novel overlapping gene.
SO - Genomics 1995 Sep 20;29(2):329-34
AD - Howard Hughes Medical Institute, Baltimore, Maryland 21231, USA.
The PMS2 gene encodes a protein that is involved in DNA mismatch repair and is mutated in a subset of patients with hereditary nonpolyposis colon cancer (HNPCC). The previously published PMS2 cDNA sequence lacks an upstream in-frame stop codon preceding the presumptive initiating methionine. To evaluate the 5' terminus of the PMS2 coding region further, we isolated additional cDNA clones, RT-PCR products, and the corresponding 5' genomic segment of the PMS2 locus. The PMS2 gene transcripts were found to have heterogeneous but colinear 5' termini, one of which contained an in-frame termination codon preceding the initiating methionine. In addition, a novel gene encoding a 34.5-kDa polypeptide was found to initiate transcriptionally within PMS2 from the opposite strand.
UI - 8614807
AU - Mellon I; Rajpal DK; Koi M; Boland CR; Champe GN
TI - Transcription-coupled repair deficiency and mutations in human mismatch repair genes.
SO - Science 1996 Apr 26;272(5261):557-60
AD - Department of Pathology, Program in Toxicology, Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
Deficiencies in mismatch repair have been linked to a common cancer predisposition syndrome in humans, hereditary nonpolyposis colorectal cancer (HNPCC), and a subset of sporadic cancers. Here, several mismatch repair-deficient tumor cell lines and HNPCC-derived lymphoblastoid cell lines were found to be deficient in an additional DNA repair process termed transcription-coupled repair (TCR). The TCR defect was corrected in a mutant cell line whose mismatch repair deficiency had been corrected by chromosome transfer. Thus, the connection between excision repair and mismatch repair previously described in Escherichia coli extends to humans. These results imply that deficiencies in TCR and exposure to carcinogens present in the environment may contribute to the etiology of tumors associated with genetic defects in mismatch repair.
UI - 9000555
AU - Meyers M; Theodosiou M; Acharya S; Odegaard E; Wilson T; Lewis JE; Davis
TI - TW; Wilson-Van Patten C; Fishel R; Boothman DA Cell cycle regulation of the human DNA mismatch repair genes hMSH2, hMLH1, and hPMS2.
SO - Cancer Res 1997 Jan 15;57(2):206-8
AD - Department of Human Oncology, University of Wisconsin, Madison 53792, USA.
Hereditary nonpolyposis colorectal cancer is a cancer susceptibility syndrome that has been found to be caused by mutations in any of several genes involved in DNA mismatch repair, including hMSH2, hMLH1, or hPMS2. Recent reports have suggested that hMSH2 and hMLH1 have a role in the regulation of the cell cycle. To determine if these genes are cell cycle regulated, we examined their mRNA and protein levels throughout the cell cycle in IMR-90 normal human lung fibroblasts. We demonstrate that the levels of hMSH2 mRNA and protein do not change appreciably throughout the cell cycle. Although hMLH1 mRNA levels remained constant, there was a modest (approximately 50%) increase in its protein levels during late G1 and S phase. The levels of hPMS2 mRNA fluctuated (decreasing 50% in G1 and increasing 50% in S phase), whereas hPMS2 protein levels increased 50% in late G1 and S phase. Our data indicate that, at least in normal cells, the machinery responsible for the detection and repair of mismatched DNA bases is present throughout the cell cycle.
UI - 9062331
AU - Burke W; Petersen G; Lynch P; Botkin J; Daly M; Garber J; Kahn MJ;
TI - McTiernan A; Offit K; Thomson E; Varricchio C Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium.
SO - JAMA 1997 Mar 19;277(11):915-9
AD - Department of Medicine, University of Washington, Seattle 98105-6920, USA.
OBJECTIVE: To provide recommendations for cancer surveillance and risk reduction for individuals carrying mutations associated with hereditary nonpolyposis colon cancer (HNPCC). PARTICIPANTS: A task force with expertise in medical genetics, oncology, primary care, gastroenterology, and epidemiology convened by the Cancer Genetics Studies Consortium (CGSC), organized by the National Human Genome Research Institute (previously the National Center for Human Genome Research). EVIDENCE: Studies evaluating cancer risk, surveillance, and risk reduction in individuals genetically susceptible to colon cancer were identified using MEDLINE and bibliographies of articles thus identified. Indexing terms used were "genetics" in combination with "colon cancer," and "screening" in combination with "cancer family" and "HNPCC." For studies evaluating specific interventions, quality of evidence was assessed using criteria of the US Preventive Services Task Force. CONSENSUS PROCESS: The task force developed recommendations through discussions over a 14-month period. CONCLUSIONS: Efficacy of cancer surveillance or other measures to reduce risk in individuals who carry cancer-predisposing mutations is unknown. Based on observational studies, colonoscopy every 1 to 3 years starting at age 25 years is recommended for individuals known to have HNPCC-associated mutations. Endometrial cancer screening is also recommended, based on expert opinion concerning presumptive benefit. No recommendation is made for or against prophylactic surgery (ie, colectomy, hysterectomy); these surgeries are an option for mutation carriers, but evidence of benefit is lacking. It is recommended that individuals considering genetic testing be counseled regarding the unknown efficacy of measures to reduce risk and that care for individuals with cancer-predisposing mutations be provided whenever possible within the context of research protocols designed to evaluate clinical outcomes.
UI - 9060003
AU - Lothe RA
TI - Microsatellite instability in human solid tumors.
SO - Mol Med Today 1997 Feb;3(2):61-8
AD - Department of Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Montebello, Oslo, Norway. email@example.com
A genome-wide instability has been found in almost all analyzed malignant tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC), and in a subgroup of sporadic (non-inherited) cancers of the same type. This mutator phenotype was initially seen as novel alleles at microsatellite loci (a family of repetitive DNA sequences) and was shown to be caused by mutations in the highly conserved mismatch repair genes. Mutations have been found in each of four of these human genes: hMSH2, hMLH1, hPMS1 and hPMS2, in the germline of HNPCC patients and in their tumors, as well as in sporadic tumors. These recent discoveries provide new molecular diagnostic tools for the detection of patients at high risk of developing carcinomas of the large bowel and other HNPCC-related tumors. Ongoing international research is progressively solving many of the unanswered questions at the genotypic and phenotypic levels of this newly identified mechanism in carcinogenesis.
UI - 9111864
AU - Peltomaki P; de la Chapelle A
TI - Mutations predisposing to hereditary nonpolyposis colorectal cancer.
SO - Adv Cancer Res 1997;71():93-119
AD - Department of Medical Genetics, Haartman Institute, University of Helsinki, Finland.
Since 1993 four genes have been identified that, when mutated, confer predisposition to a form of hereditary colon cancer (hereditary nonpolyposis colorectal cancer [HNPCC]). These genes belong to the Mut-related family of DNA mismatch repair genes whose protein products are responsible for the recognition and correction of errors that arise during DNA replication. Mutational inactivation of both copies of a DNA mismatch repair gene results in a profound repair defect demonstrable by biochemical assays, and in vivo this defect is presumed to lead to progressive accumulation of secondary mutations throughout the genome, some of which affect important growth-regulatory genes and, hence, give rise to cancer. To date, more than 70 different germline mutations have been detected in DNA mismatch repair genes and shown to be associated with HNPCC. Current evidence suggests that two genes, MSH2 and MLH1, account for roughly equal proportions of HNPCC kindreds, together being responsible for a majority of these families, but striking interethnic differences occur. Most mutations lead to truncated protein products. Mutation screening is quite demanding in HNPCC since, with a few exceptions, the predisposing mutations typically vary from kindred to kindred and individual mutations are scattered throughout the genes. Knowledge of the predisposing mutations allows genotype-phenotype correlations and forms the basis for further studies clarifying the pathogenesis of this disorder. In at-risk individuals, it allows predictive testing for cancer susceptibility and, consequently, appropriate clinical management of mutation carriers and noncarriers.
UI - 9259192
AU - Papadopoulos N; Lindblom A
TI - Molecular basis of HNPCC: mutations of MMR genes.
SO - Hum Mutat 1997;10(2):89-99
AD - Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
Hereditary nonpolyposis colorectal cancer (HNPCC) is inherited as a dominant disorder caused by germline defects in one of at least four mismatch repair (MMR) genes. Two of these genes, hMSH2 and hMLH1, account for the vast majority of the germline mutations in HNPCC kindreds, whereas hPMS1 and hPMS2 are mutated in only few families. MMR genes also are susceptible to somatic mutations in sporadic tumors. The mutational spectrum of the MMR genes shows no predominant type of mutation. Furthermore, the mutations are spread throughout the length of the genes, with no significant hot spots. Identification of MMR genes as the cause of HNPCC made presymptomatic diagnosis a reality. However, the presence of multiple genes and the heterogeneity of mutations present challenges to the development of diagnostic tests for this disease.
UI - 9322509
AU - Peltomaki P; Vasen HF
TI - Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer.
SO - Gastroenterology 1997 Oct;113(4):1146-58
AD - Department of Medical Genetics, Haartman Institute, Helsinki, Finland. Paivi.Peltomaki@helsinki.fi
BACKGROUND & AIMS: Germline mutations in four DNA mismatch repair genes are known to cause susceptibility to hereditary nonpolyposis colorectal cancer (HNPCC). The rapidly increasing information about these mutations needs to be collected and appropriately stored to facilitate further studies on the biological and clinical significance of the findings. METHODS: The International Collaborative Group on HNPCC has established a database of DNA mismatch repair gene mutations and polymorphisms. In this report, 126 predisposing mutations were analyzed. RESULTS: A majority of the mutations affected either the Mut L homologue (MLH) 1 (n = 75) or the Mut S homologue (MSH) 2 (n = 48) and were quite evenly distributed, with some clustering in MSH2 exon 12 and MLH1 exon 16. Most MSH2 mutations consisted of frameshift (60%) or nonsense changes (23%), whereas MLH1 was mainly affected by frameshift (40%) or missense alterations (31%). Although most mutations were unique, a few common recurring mutations were identified. Of the families studied (n = 202), 82% met the Amsterdam criteria and 15% did not; the general mutation profile was similar in both groups. CONCLUSIONS: The construction of mutation profiles will facilitate the development of diagnostic strategies in HNPCC.
UI - 9365839
AU - Moliaka YK; Cella M; Chudina AP; Kolesnikova TN; Terracciano L; Cathomas
TI - G; Bochkov NP; Buerstedde JM Mechanisms underlying mismatch repair deficiencies in normal cells.
SO - Genes Chromosomes Cancer 1997 Nov;20(3):305-9
AD - Department of Medical Genetics, Sechenov Moscow Medical Academy, Moscow, Russia.
Hereditary nonpolyposis colon cancer (HNPCC) is an autosomal dominantly inherited cancer predisposition which is linked to heterozygous mutations in mismatch repair genes. HNPCC tumour cells, in which the remaining wild-type copy of the mismatch repair gene is inactivated, display instability of microsatellite markers reflecting a defect in mismatch repair. Recently, patients carrying either one of two distinct germline mutations in the MLH1 and PMS2 genes were reported to accumulate somatic mutations of microsatellites in untransformed cells. One of the mechanisms that might account for this phenomenon was a dominant negative effect of the mutant allele. To evaluate this possibility, we examined a different family carrying one of the mutations (deletion of codon 618K in the MLH1 gene) which has been suspected to induce genetic instability in untransformed cells. No mutations in dinucleotide repeat markers were observed in a large number of lymphoblast clones derived from a carrier. Evidence for the deletion of the wild-type allele in two different tumours suggested that the inactivation of both gene copies was required for tumour initiation. These results indicate that the MLH1 618K deletion mutation alone does not necessarily cause marked mismatch repair deficiency in the presence of a wild-type allele.
UI - 9419392
AU - Lynch HT; Lemon SJ; Karr B; Franklin B; Lynch JF; Watson P; Tinley S;
TI - Lerman C; Carter C Etiology, natural history, management and molecular genetics of hereditary nonpolyposis colorectal cancer (Lynch syndromes): genetic counseling implications.
SO - Cancer Epidemiol Biomarkers Prev 1997 Dec;6(12):987-91
AD - Department of Preventive Medicine, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
We estimate that 5-10% of virtually all forms of cancer are due to a primary hereditary etiology. However, a hereditary cancer diagnosis is often missed because the family history of cancer is given short shrift in medical practice. Hereditary nonpolyposis colorectal cancer (HNPCC) certainly fits this estimate, although some studies suggest that a minimum of 2% with a range as high as 10% of the total colorectal cancer burden is due to HNPCC. Mutations in one of the four mismatch repair genes, i.e., hMSH2, hMLH1, hPMS1, and hPMS2, account for about 70% of HNPCC kindreds. Other germ-line mutations are likely to be identified to account for the remainder of HNPCC patients. By far the most common HNPCC mutations involve hMSH2 and hMLH1, with hPMS1 and hPMS2 accounting for only about 3% of such families. Prior to these molecular genetic discoveries, the genetic counselor could only provide the patient with an estimate of a 50% likelihood of manifesting HNPCC based on the counselee having one or more first-degree relatives manifesting syndrome cancers in their direct genetic lineage. Because DNA testing has become available in families with known mutations, we have provided pretest group education in the form of a family information service with intensive education about the natural history, genetic risk, surveillance, and options for management of HNPCC, as well as discussion of the potential for fear, anxiety, apprehension, and insurance or employer discrimination that might impact on this DNA testing. Following informed consent, these relatives were then counseled on a one-to-one basis. Using DNA-based genetic counseling involving hMSH2 or hMLH1, we have provided this service to four extended HNPCC kindreds. Details of this genetic counseling experience on these four kindreds will be discussed.
UI - 9445183
AU - Senba S; Konishi F; Okamoto T; Kashiwagi H; Kanazawa K; Miyaki M;
TI - Konishi M; Tsukamoto T Clinicopathologic and genetic features of nonfamilial colorectal carcinomas with DNA replication errors.
SO - Cancer 1998 Jan 15;82(2):279-85
AD - Department of Surgery, Jichi Medical School, Tochigi, Japan.
BACKGROUND. DNA replication errors (RERs) are closely associated with hereditary nonpolyposis colorectal carcinoma (HNPCC). Recently, alterations in DNA mismatch repair genes, including hMSH2, hMLH1, and hPMS2, have been implicated in the pathogenesis of HNPCC. Several studies have demonstrated RER in 13-17% of nonfamilial colorectal carcinomas. It is unclear, however, as to whether or not these RER positive nonfamilial colorectal carcinomas are incomplete forms of HNPCC or are caused by incidental alterations of DNA mismatch repair genes. Consequently, the authors studied the characteristics of RER positive nonfamilial colorectal carcinomas, placing particular emphasis on hMSH2 and hMLH1 gene mutations. METHODS. Fresh or frozen samples of 103 nonfamilial colorectal carcinomas were examined for RERs using the polymerase chain reaction (PCR) and specific microsatellite primers. The authors also identified mutations of the hMSH2 and hMLH1 genes in RER positive samples by a PCR single strand conformational polymorphism analysis followed by direct nucleotide sequencing. RESULTS. The incidence of RER was 15.7% (17/103) in nonfamilial colorectal carcinomas, and only 1 case, which was found in the ascending colon, showed a somatic mutation at exon 12 in the hMSH2 gene. Neither germline nor somatic mutations of the hMSH2 or hMLH1 genes could be found in any of the remaining RER positive tumors. RER positive nonfamilial carcinomas tended to be located more frequently in the right colon. There was no increased prevalence in young patients, and the clinicopathologic characteristics of HNPCC were absent in the patients with RER positive nonfamilial colorectal carcinoma. CONCLUSIONS. Based on these findings, the carcinogenesis of RER positive nonfamilial colorectal carcinoma is considered different from that of HNPCC.
UI - 9683794
AU - Viel A; Novella E; Genuardi M; Capozzi E; Fornasarig M; Pedroni M;
TI - Santarosa M; De Leon MP; Della Puppa L; Anti M; Boiocchi M Lack of PMS2 gene-truncating mutations in patients with hereditary colorectal cancer.
SO - Int J Oncol 1998 Sep;13(3):565-9
AD - Division of Experimental Oncology 1, Centro di Riferimento Oncologico, 33081 Aviano (PN), Italy.
Hereditary non-polyposis colorectal cancer (HNPCC) is a genetically heterogeneous disease for which PMS2 gene, a member of the human PMS gene family, is believed to have a marginal role. To better define the contribution of PMS2 to hereditary colorectal cancer, we investigated this gene in 22 unrelated Italian patients that, despite a positive family history and/or early onset and development of tumors with microsatellite instability (MSI), did not carry constitutional mutations of MLH1 and MSH2 genes. No mutations with clear-cut pathogenetic significance were detected in the coding regions of PMS2 gene, but only 8 polymorphisms (7 common and 1 rare, 3 silent and 5 missense) and 3 unique molecular variants (2 missense substitutions and one 3-nucleotide deletion) were seen. Lack of PMS2 truncating mutations in our study does not disagree with its supposed marginal involvement in hereditary colorectal cancer, but at the same time points out the need to investigate the phenotypic molecular and clinical characteristics more specifically associated with PMS2 mutations.
UI - 10480359
AU - Wang Q; Lasset C; Desseigne F; Saurin JC; Maugard C; Navarro C; Ruano E;
TI - Descos L; Trillet-Lenoir V; Bosset JF; Puisieux A Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer.
SO - Hum Genet 1999 Jul-Aug;105(1-2):79-85
AD - Departement d'Oncologie Fondamentale et Appliquee, INSERM Unite 453, Centre Leon Berard, Lyon, France.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a syndrome characterized by familial predisposition to colorectal carcinoma and extracolonic cancers of the gastrointestinal, urological, and female reproductive tracts. This dominant disorder is caused by germline defects in one of at least five DNA mismatch repair (MMR) genes: hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 (GTBP). Germline mutations of hMSH2 and hMLH1 are also frequently identified in families not fulfilling all the Amsterdam criteria, thereby demonstrating that the involvement of these genes is not confined to typical HNPCC. To evaluate the respective involvement of the various MMR genes in typical and incomplete HNPCC syndromes, we have performed an analysis of the hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in a large series of French kindreds (n=75) with colorectal tumors and/or aggregation of extracolonic cancers belonging to the HNPCC spectrum. Mutational analysis has been performed in all families, without preselection for the tumor phenotype. We have detected 26 pathogenic germline mutations of the hMLH1 and hMSH2 genes and several novel variants of the hPMS1, hPMS2, and hMSH6 genes. Our data confirm that, regardless of the type of families and the tumor phenotype, hPMS1, hPMS2, and hMSH6 germline mutations are rare in familial aggregation of colorectal cancers. Furthermore, they suggest that the presence of multiple primary malignancies in a single individual and the observation of extracolonic tumors in relatives of a colorectal cancer patient should be included among the guidelines for referring patients for genetic testing.
UI - 10470121
AU - Johannsdottir JT; Bergthorsson JT; Gretarsdottir S; Kristjansson AK;
TI - Ragnarsson G; Jonasson JG; Egilsson V; Ingvarsson S Replication error in colorectal carcinoma: association with loss of heterozygosity at mismatch repair loci and clinicopathological variables.
SO - Anticancer Res 1999 May-Jun;19(3A):1821-6
AD - Department of Pathology, National University Hospital, Reykjavik, Iceland.
Instability of microsatellite DNA or replication error (RER) is characteristic of tumours caused by mismatch repair (MMR) deficiency. Germline mutations in MMR genes are associated with Hereditary non-polyposis colorectal carcinoma (HNPCC) and somatic mutations in these genes are also found in a substantial fraction of colorectal cancers (CRC). In this study we concurrently screened colorectal tumours for the RER phenotype and loss of heterozygosity (LOH) at MMR gene loci. The RER phenotype was evident in 47/197 (24%) tumours. RER was more commonly detected in young patients (< 50 years) and in tumours located in the proximal colon. RER was positively associated with LOH at the hMSH2/hMSH6 loci on chromosome 2p, where LOH was observed in 46% of the RER+ tumours. LOH at hMLH1 and hPMS1 loci was more frequent in the younger patients (< 50 years). RER was not associated with clinicopathological parameters, such as Duke's stage and tumour differentiation (grade). The RER phenotype was associated with better overall survival, but there was a trend towards significance when multivariate analysis was used. This indicates that loss of MMR genes generate a less aggressive phenotype, and raises the question about RER being a useful indicator of prognosis for CRC patients.
UI - 10822375
AU - Ma AH; Xia L; Littman SJ; Swinler S; Lader G; Polinkovsky A; Olechnowicz
TI - J; Kasturi L; Lutterbaugh J; Modrich P; Veigl ML; Markowitz SD; Sedwick WD Somatic mutation of hPMS2 as a possible cause of sporadic human colon cancer with microsatellite instability.
SO - Oncogene 2000 Apr 27;19(18):2249-56
AD - Ireland Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, OH 44106, USA.
Inactivation of DNA-mismatch repair underlies the genesis of microsatellite unstable (MSI) colon cancers. hPMS2 is one of several genes encoding components of the DNA-mismatch repair complex, and germline hPMS2 mutations have been found in a few kindreds with hereditary nonpolyposis colorectal carcinoma (HNPCC), in whom hereditary MSI colon cancers develop. However, mice bearing null hPMS2 genes do not develop colon cancers and hPMS2 mutations in sporadic human colon cancers have not been described. Here we report that in Vaco481 colon cancer the hPMS2 gene is inactivated by somatic mutations of both hPMS2 alleles. The cell line derived from this tumor is functionally deficient in DNA mismatch repair. This deficiency can be biochemically complemented by addition of a purified hMLH1-hPMS2 (hMutLalpha) complex. The hPMS2 deficient Vaco481 cancer cell line demonstrates microsatellite instability, an elevated HPRT gene mutation rate, and resistance to the cytotoxicity of the alkylator MNNG. We conclude that somatic inactivation of hPMS2 can play a role in development of sporadic MSI colon cancer expressing the full range of cancer phenotypes associated with inactivation of the mismatch repair system.
UI - 11358834
AU - Chen Y; Wang J; Fraig MM; Metcalf J; Turner WR; Bissada NK; Watson DK;
TI - Schweinfest CW Defects of DNA mismatch repair in human prostate cancer.
SO - Cancer Res 2001 May 15;61(10):4112-21
AD - Laboratory of Cancer Genomics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Loss of mismatch repair (MMR) function leads to the accumulation of errors that normally occur during DNA replication, resulting in genetic instability. Germ-line mutations of MMR genes in the patients with hereditary nonpolyposis colorectal cancer lead to inactivation of MMR protein functions, and the defects of MMR are well correlated to the high rate of microsatellite instability in their tumors. Previous studies (T. Uchida, et al. Oncogene, 10: 1019-1022, 1995; S. Egawa, et al. Cancer RES:, 55: 2418-2421, 1995; J. M. Cunningham, et al. Cancer RES:, 56: 4475-4482, 1996; X. Gao, et al. Oncogene, 9: 2999-3003, 1994; H. Rohrbach, et al. Prostate, 40: 20-27, 1999) have shown that genetic instability (chromosomal and microsatellite instability) is detectable in human prostate cancer. To elucidate the role of MMR genes in the tumorigenesis of prostate cancer, we evaluated the expression of these genes in human cancer cell lines and in tumor specimens. Using Western blot analysis, we detected loss among MSH2, MLH1, PMS2, and PMS1 proteins in DU145, LNCaP, p69SV40T, M2182, and M12 cells. In addition, genomic instability in the prostate cell lines including DU145, PC3, LNCaP, p67SV40T, M2182, and M12 was detected by a microsatellite mutation assay. Significantly, immunohistochemical analysis of prostatic tissue revealed the reduction or absence of MMR protein expression in the epithelium of prostate tumor foci compared with normal adjacent prostate tissue. In contrast to hereditary nonpolyposis colorectal cancer, characterized by defects predominantly in MLH1 and MSH2, the samples we examined showed more tumor foci with loss of PMS1 and PMS2. PMS1, which is only expressed in the basal cells in normal glands, is conspicuously absent in most prostate cancer. From these results, we conclude that there are defects of MMR genes in human prostate cancer.
UI - 11429708
AU - Jager AC; Rasmussen M; Bisgaard HC; Singh KK; Nielsen FC; Rasmussen LJ
TI - HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence assembly of hMutLalpha and hMLH1-hEXO1 complexes.
SO - Oncogene 2001 Jun 14;20(27):3590-5
AD - Department of Clinical Biochemistry, Rigshospitalet, DK-2100 Copenhagen, Denmark.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a common inherited form of neoplasia caused by germline mutations in DNA mismatch repair (MMR) genes. MMR proteins have been reported to associate with several proteins, including the human exonuclease 1 (hEXO1). We report here novel HNPCC-hMLH1 mutant proteins (T117M, Q426X and 1813insA) in Danish HNPCC patients. We demonstrate that these mutant HNPCC-hMLH1 proteins are unable to form complexes with hEXO1 and hPMS2 in vivo. The results indicate that mutations found in HNPCC gene carriers disrupt hMLH1-hEXO1 complex formation and hMutLalpha heterodimer assembly essential for MMR activity.
UI - 11546830
AU - Liu T; Chen J; Salahshor S; Kuismanen S; Holmberg E; Gronberg H;
TI - Peltomaki P; Lindblom A Screening families with endometrial and colorectal cancers for germline mutations.
SO - J Med Genet 2001 Sep;38(9):E29