National Cancer Institute®
Last Modified: September 1, 2002
UI - 12132870
AU - Kim JC; Kim HC; Roh SA; Koo KH; Lee DH; Yu CS; Lee JH; Kim TW; Lee HL;
TI - Beck NE; Bodmer WF hMLH1 and hMSH2 mutations in families with familial clustering of gastric cancer and hereditary non-polyposis colorectal cancer.
SO - Cancer Detect Prev 2001;25(6):503-10
AD - Department of Surgery, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Seoul, Korea.
The pattern of hMLHI and hMSH2 mutations was assessed to identify the genetic correlation between hereditary gastric and colorectal cancers. Four disease groups and their healthy family members were assembled according to the presentation of gastric cancer: FG, familial clustering of gastric cancer (n = 32); CG, family with one or more colorectal and gastric cancers in first-degree relatives (n = 22); HS, seven HNPCC families corresponding to the Amsterdam criteria (AMS+) and 12 suspected HNPCC families which did not satisfy one of the criteria (AMS-), but no gastric cancer among first- and second-degree relatives (n = 19); and SG, sporadic gastric cancer (n = 33). In the CG group, three were included in AMS + and six in AMS- criteria. Peripheral blood was obtained from them to detect hMLHI and hMLH2 mutations using PCR-SSCP analysis and direct sequencing. The incidence of mutations was 9.4% in the FG group, 54.5% in the CG group, 31.6% in the HS group, and none in the SG group. The incidence, type, and number of the mutation were not different between the CG and HS groups. Thirty-four different mutations included 19 in hMLH1 and 15 in hMSH2. Gastric cancer was the most common extracolonic malignancy in HNPCC and suspected HNPCC families (9/28, 32.1%). The hMLH1 or hMSH2 mutation occurred in seven of 10 families with AMS+, whereas it occurred in four of 18 with AMS- (70% vs. 22.2%, P = .013). Five mutations in the hMLH1 and six mutations in the hMSH2 were exclusively found in families with gastric cancer. All three mutations in the FG group were in hMLHI and there was no mutation in their healthy family members. This study demonstrates that some familial clustering type of gastric cancer appears to be associated with hMLHI mutations thereby indicating a difference from the hereditary gastric cancer studies previously reported. In addition, hMLHI and hMSH2 mutations may impact the gastric cancer carcinogenesis in HNPCC or suspected HNPCC.
UI - 12095971
AU - Rossi BM; Lopes A; Oliveira Ferreira F; Nakagawa WT; Napoli Ferreira CC;
TI - Casali Da Rocha JC; Simpson CC; Simpson AJ hMLH1 and hMSH2 gene mutation in Brazilian families with suspected hereditary nonpolyposis colorectal cancer.
SO - Ann Surg Oncol 2002 Jul;9(6):555-61
AD - Department of Pelvic Surgery, the Hospital do Cancer A. C. Camargo, Fundacao Antonio Prudente, Sao Paulo, Brazil.
BACKGROUND: The aim of this study was to search for mutations in the human mutS homolog 2 (hMSH2) and human mutL homolog 1 (hMLH1) genes in 25 unrelated Brazilian kindreds with suspected hereditary nonpolyposis colorectal cancer (HNPCC). METHODS: The families were grouped according to the following clinical criteria: Amsterdam I or II; familial colorectal cancer (CRC); an early age of onset of CRC in the proband only; or with at least one or two relatives who had HNPCC-related cancers; CRC in the proband only. All patients were studied with direct sequencing. RESULTS: Ten mutations were detected (10 of 25 [40%]); of nine different mutations, seven were novel. The hMLH1 gene had a higher mutation detection rate than hMSH2 (8 of 25 [32%] vs. 2 of 25 [8%]). Only 3 of these 10 families fulfilled the Amsterdam criteria. Two different polymorphisms were detected in the hMLH1 gene and four in the hMSH2 gene. CONCLUSIONS: The hMLH1 gene had a higher mutation detection rate than hMSH2. The physician who deals with CRC must take into consideration the heredity issue with patients who present with an early age of onset or a familial history of CRC- or HNPCC-related cancers, including gastric cancer, even if they do not fulfill the former Amsterdam criteria.
UI - 12210035
AU - Neibergs HL; Hein DW; Spratt JS
TI - Genetic profiling of colon cancer.
SO - J Surg Oncol 2002 Aug;80(4):204-13
AD - Norton Hereditary Cancer Institute, Louisville, Kentucky, USA.
UI - 9240418
AU - Akiyama Y; Tsubouchi N; Yuasa Y
TI - Frequent somatic mutations of hMSH3 with reference to microsatellite instability in hereditary nonpolyposis colorectal cancers.
SO - Biochem Biophys Res Commun 1997 Jul 18;236(2):248-52
AD - Department of Hygiene and Oncology, Tokyo Medical and Dental University School of Medicine, Bunkyo-ku, Japan.
hMSH3 is one of the human DNA mismatch repair genes but has not yet been reported to be associated with hereditary nonpolyposis colorectal cancer. Recently, somatic mutation at a polyadenine tract, i.e., (A)8, in hMSH3 was reported in cancers with microsatellite instability (MI). To clarify the tumorigenetic role of hMSH3, we screened for somatic mutations at the hMSH3 (A)8 repeat in 29 tumors from 23 hereditary nonpolyposis colorectal cancer patients. One or two A deletions in the (A)8 repeat were found in 11 (57.9%) of the 19 MI-positive tumors but not in 10 MI-negative ones, indicating secondary mutations after germline mutations of other mismatch repair genes. Moreover, the MI frequency of three or more nucleotide repeats was higher in hMSH3 (A)8-mutated tumor cells than in nonmutated ones (p<0.05). These data suggest that a mutation of a mismatch repair gene enhances the frequency of another mismatch repair gene mutation, such as of hMSH3, resulting in severe MI.
UI - 9401011
AU - Yin J; Kong D; Wang S; Zou TT; Souza RF; Smolinski KN; Lynch PM;
TI - Hamilton SR; Sugimura H; Powell SM; Young J; Abraham JM; Meltzer SJ Mutation of hMSH3 and hMSH6 mismatch repair genes in genetically unstable human colorectal and gastric carcinomas.
SO - Hum Mutat 1997;10(6):474-8
AD - Department of Medicine, University of Maryland School of Medicine and Baltimore VA Hospital, USA.
Mutations within microsatellite sequences, consisting of additions or deletions of repeat units, are known as the replication/repair error positive (RER+) phenotype or micorsatellite instability (MI). Microsatellite instability has been demonstrated in hereditary and sporadic colorectal carcinomas and is usually observed in noncoding regions of genomic DNA. However, relatively few coding region targets of MI have been identified thus far. Using PCR, we amplified regions encompassing (A)8 and (C)8 microsatellite tracts within hMSH3 and hMSH6 from 31 RER+ sporadic colorectal tumors, 8 hereditary colon cancers, 23 RER+ gastric carcinomas, and 32 RER- gastric tumors. Mutations were found in 11 (36%) of 31 sporadic colon carcinomas, 4 (50%) of 8 hereditary colorectal cancers, and 5 (22%) of 23 RER+ gastric carcinomas, but in only 2 (6%) of 32 RER- gastric carcinomas. These frameshift mutations cause premature stop codons downstream that are predicted to abolish normal protein function. Our results and those of others suggest that DNA mismatch repair genes, such as hMSH3 and hMSH6, are targets for the mutagenic activity of upstream mismatch repair gene mutations and that this enhanced genomic instability may accelerate the accumulation of mutations in RER+ tumors.
UI - 9590282
AU - Lu SL; Kawabata M; Imamura T; Akiyama Y; Nomizu T; Miyazono K; Yuasa Y
TI - HNPCC associated with germline mutation in the TGF-beta type II receptor gene.
SO - Nat Genet 1998 May;19(1):17-8
UI - 9774676
AU - Guerrette S; Wilson T; Gradia S; Fishel R
TI - Interactions of human hMSH2 with hMSH3 and hMSH2 with hMSH6: examination of mutations found in hereditary nonpolyposis colorectal cancer.
SO - Mol Cell Biol 1998 Nov;18(11):6616-23
AD - Genetics and Molecular Biology Program, Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Mutations in the human mismatch repair protein hMSH2 have been found to cosegregate with hereditary nonpolyposis colorectal cancer (HNPCC). Previous biochemical and physical studies have shown that hMSH2 forms specific mispair binding complexes with hMSH3 and hMSH6. We have further characterized these protein interactions by mapping the contact regions within the hMSH2-hMSH3 and the hMSH2-hMSH6 heterodimers. We demonstrate that there are at least two distinct interaction regions of hMSH2 with hMSH3 and hMSH2 with hMSH6. Interestingly, the interaction regions of hMSH2 with either hMSH3 or hMSH6 are identical and there is a coordinated linear orientation of these regions. We examined several missense alterations of hMSH2 found in HNPCC kindreds that are contained within the consensus interaction regions. None of these missense mutations displayed a defect in protein-protein interaction. These data support the notion that these HNPCC-associated mutations may affect some other function of the heterodimeric complexes than simply the static interaction of hMSH2 with hMSH3 or hMSH2 with hMSH6.
UI - 9852252
AU - Whitehouse A; Meredith DM; Markham AF
TI - DNA mismatch repair genes and their association with colorectal cancer (Review).
SO - Int J Mol Med 1998 Feb;1(2):469-74
AD - Molecular Medicine Unit, University of Leeds, Clinical Sciences Building, St. James's University Hospital, Leeds LS9 7TF, UK.
Mismatch repair genes are involved in increasing the fidelity of replication by specific repair of DNA polymerase incorporation errors. In Escherichia coli, the best studied mismatch repair (MMR) pathway is the methyl-directed long patch repair system which is mediated by three gene products; MutS, MutL and MutH. These are conserved in higher eukaryotes. Mutations in human homologues of these proteins have been shown to be implicated in hereditary non-polyposis colorectal cancer (HNPCC). Alterations in the coding regions of MMR genes result in a mutator phenotype with marked instability of microsatellite sequences, indicative of a deficiency in DNA repair.
UI - 10545954
AU - de Wind N; Dekker M; Claij N; Jansen L; van Klink Y; Radman M; Riggins
TI - G; van der Valk M; van't Wout K; te Riele H HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions.
SO - Nat Genet 1999 Nov;23(3):359-62
AD - Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Cancer predisposition in hereditary non-polyposis colon cancer (HNPCC) is caused by defects in DNA mismatch repair (MMR). Mismatch recognition is attributed to two heterodimeric protein complexes: MutSalpha (refs 2, 3, 4, 5), a dimer of MutS homologues MSH2 and MSH6; and MutSbeta (refs 2,7), a dimer of MSH2 and MSH3. These complexes have specific and redundant mismatch recognition capacity. Whereas MSH2 deficiency ablates the activity of both dimers, causing strong cancer predisposition in mice and men, loss of MSH3 or MSH6 (also known as GTBP) function causes a partial MMR defect. This may explain the rarity of MSH6 and absence of MSH3 germline mutations in HNPCC families. To test this, we have inactivated the mouse genes Msh3 (formerly Rep3 ) and Msh6 (formerly Gtmbp). Msh6-deficient mice were prone to cancer; most animals developed lymphomas or epithelial tumours originating from the skin and uterus but only rarely from the intestine. Msh3 deficiency did not cause cancer predisposition, but in an Msh6 -deficient background, loss of Msh3 accelerated intestinal tumorigenesis. Lymphomagenesis was not affected. Furthermore, mismatch-directed anti-recombination and sensitivity to methylating agents required Msh2 and Msh6, but not Msh3. Thus, loss of MMR functions specific to Msh2/Msh6 is sufficient for lymphoma development in mice, whereas predisposition to intestinal cancer requires loss of function of both Msh2/Msh6 and Msh2/Msh3.
UI - 10601558
AU - Johannsdottir JT; Jonasson JG; Bergthorsson JT; Amundadottir LT;
TI - Magnusson J; Egilsson V; Ingvarsson S The effect of mismatch repair deficiency on tumourigenesis; microsatellite instability affecting genes containing short repeated sequences.
SO - Int J Oncol 2000 Jan;16(1):133-9
AD - Department of Pathology, National University Hospital, Reykjavik, Iceland.
We have investigated microsatellite instability (MSI) in colorectal, gastric, endometrial and ovarian cancer as a result of mismatch repair (MMR) deficiency. We detected frameshift mutations in several genes that carry short repeated sequences and are important in cell fidelity and growth control; hMSH3, hMSH6, BAX, IGFIIR, TGFbetaIIR, E2F4 and BRCA2. Accumulation of mutations was heterogeneous and mainly restricted to tumours showing MSI at several loci (MSI-H). Both insertions and deletions were evident and occasional intratumour heterogeneity was evident with more than one different additional allele in the tumour. Most MSI-H tumours had acquired mutations in more than one gene and longer repeated sequences were more frequently targets for mutations. The TGFbetaIIR gene was mutated in 62%, the hMSH3 gene in 43%, the E2F4 gene in 35%, the hMSH6 in 32%, the BAX gene in 32%, the IGFIIR gene in 26%, and the BRCA2 gene in 2% of the MSI-H tumours. Homozygous mutations or mutation of both alleles were evident in all genes except BRCA2, in total 23/105 mutated cases, varying from 7% for BAX to 50% for E2F4. E2F4 mutations were exclusively found in colon tumours and E2F4 polymorphisms was found in 8% of cases. No difference in mutation prevalence was noted between cancer types apart from TGFbetaIIR mutations, which were frequently found in colon and gastric tumours but not in endometrial tumours, suggesting that endometrial tumours progress by a different route where TGFbetaIIR mutations are less favourable.
UI - 10719374
AU - Percesepe A; Pedroni M; Sala E; Menigatti M; Borghi F; Losi L; Viel A;
TI - Genuardi M; Benatti P; Roncucci L; Peltomaki P; Ponz de Leon M Genomic instability and target gene mutations in colon cancers with different degrees of allelic shifts.
SO - Genes Chromosomes Cancer 2000 Apr;27(4):424-9
AD - Department of Internal Medicine, University of Modena, Modena, Italy. email@example.com
Two grades (high and low) of microsatellite instability (MSI) are known, depending on the number of mutated markers and the amount of allelic shifts. Forty-two colorectal tumors, previously found to have high-degree MSI at dinucleotidic repeat loci, were revisited with BAT26, a mononucleotide marker, and the number of shifted bases were counted. Seven tumors, all with local stages at diagnosis, had < or =6-bp deletions and consistently displayed shorter shifts also with other intronic mononucleotide markers. Analysis of mononucleotide tracts in the coding regions of MSH3, MSH6, BAX, and TGFbetaRII in the groups with large (>6 bp) and short (< or =6 bp) allelic shifts showed specific patterns of involvement for the individual genes: TGFbetaRII displayed a uniformly high rate of mutations, while MSH3, MSH6, and BAX were less frequently altered in tumors with short shifts. Our findings suggest that microsatellite instability arises gradually, evenly involving loci with similar features of length and repetition. However, target genes have a specific timing of mutation in this process: TGFbetaRII is involved in the early phases, while BAX and MSH6 are frequently associated with big size shifts and tumors with more advanced stages. Copyright 2000 Wiley-Liss, Inc.
UI - 10965759
AU - Baba S
TI - [Genetic abnormality of hereditary nonpolyposis colorectal cancer and implication of clinical application]
SO - Nippon Shokakibyo Gakkai Zasshi 2000 Aug;97(8):1017-24
AD - Hamamatsu University School of Medicine.
UI - 11245474
AU - Huang J; Kuismanen SA; Liu T; Chadwick RB; Johnson CK; Stevens MW;
TI - Richards SK; Meek JE; Gao X; Wright FA; Mecklin JP; Jarvinen HJ; Gronberg H; Bisgaard ML; Lindblom A; Peltomaki P MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer.
SO - Cancer Res 2001 Feb 15;61(4):1619-23
AD - Division of Human Cancer Genetics, Ohio State University, Columbus 43210, USA.
A set of 90 nonpolypotic colon cancer families in which germ-line mutations of MSH2 and MLH1 had been excluded were screened for mutations in two additional DNA mismatch repair genes, MSH6 and MSH3. Kindreds fulfilling and not fulfilling the Amsterdam I criteria, showing early and late onset colorectal (and other) cancers, and having microsatellite stable and unstable tumors were included. Two partly parallel approaches were used: genetic linkage analysis (19 large families) and the protein truncation test (85, mostly smaller, families). Whereas MSH3 was not involved in any family, a large Amsterdam-positive, late-onset family showed a novel germ-line mutation in MSH6 (deletion of CT at nucleotide 3052 in exon 4). The mutation was identified through genetic linkage (multipoint lod score 2.4) and subsequent sequencing of MSH6. Furthermore, the entire MSH6 gene was sequenced exon by exon in families with frameshift mutations in the (C)8 tract in tumors, previously suggested as a predictor of MSH6 germ-line mutations; no mutations were found. We conclude that germ-line involvement of MSH6 and MSH3 is rare and that other genes are likely to account for a majority of MSH2-, MLH1-mutation negative families with nonpolypotic colon cancer.
UI - 11507051
AU - Mori Y; Yin J; Rashid A; Leggett BA; Young J; Simms L; Kuehl PM;
TI - Langenberg P; Meltzer SJ; Stine OC Instabilotyping: comprehensive identification of frameshift mutations caused by coding region microsatellite instability.
SO - Cancer Res 2001 Aug 15;61(16):6046-9
AD - Department of Medicine, University of Maryland School of Medicine, Baltimore V. A. Hospital, Baltimore, Maryland 21201, USA.
Coding region frameshift mutation caused by microsatellite instability (MSI) is one mechanism contributing to tumorigenesis in cancers with MSI in high frequency. Mutation of TGFBR2 is one example of this process. To identify additional examples, a large-scale genomic screen of coding region microsatellites was conducted. 1115 coding homopolymeric loci with six or more nucleotides were identified in an online genetic database. Mutational screening was performed at 152 of these loci in 46 colorectal tumors with MSI in high frequency. Nine loci were mutated in > or =20% of tumors, 10 loci in 10-20%, 24 loci in 5-10%, 43 loci in <5%, and 66 loci were not mutated in any tumors. The most frequently mutated novel loci were the activin type II receptor gene (58.1%), SEC63 (48.8%), AIM 2 (47.6%), a gene encoding a subunit of the NADH-ubiquinone oxidoreductase complex (27.9%), a homologue of mouse cordon-bleu (23.8%), and EBP1/PA2G4 (20.9%). This genome-wide approach identifies coding region MSI in genes or pathways not implicated previously in colorectal tumorigenesis, which may merit functional study or other additional analysis.
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
UI - 11950865
AU - Albuquerque C; Cravo M; Cruz C; Lage P; Chaves P; Fidalgo P; Suspiro A;
TI - Nobre Leitao C Genetic characterisation of patients with multiple colonic polyps.
SO - J Med Genet 2002 Apr;39(4):297-302
UI - 12063922
AU - Jonas J; Kruse R; Bahr R
TI - [Muir-Torre syndrome]
SO - Chirurg 2002 Apr;73(4):366-9
AD - Klinik fur Abdominal- und Thoraxchirurgie, Stadtisches Klinikum Karlsruhe, Moltkestrasse 90, 76133 Karlsruhe. AllgemeinChirurgie@Klinikum-Karlsruhe.de
The Muir-Torre syndrome (MTS) is an autosomal dominant disease defined by the coincidence of at least one sebaceous skin tumor and one internal malignancy. We describe an additional case and give a review of the literature. Over a period of 7 years, 19 skin tumors were excised in a 50 year old male patient. A total of 3 colonic carcinomas, one gastric carcinoma and one laryngeal carcinoma were operated successfully. The underlying defective mutation in the hMSH2 gene and the microsatellite instability were demonstrable. MTS is graded as a subgroup of hereditary non-polyposis colorectal cancer (HNPCC). In patients with MTS and with family members with known defective mutation, regular follow-up and search for new malignancies are mandatory.
UI - 12183410
AU - Nakagawa H; Yan H; Lockman J; Hampel H; Kinzler KW; Vogelstein B; De La
TI - Chapelle A Allele separation facilitates interpretation of potential splicing alterations and genomic rearrangements.
SO - Cancer Res 2002 Aug 15;62(16):4579-82
AD - Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Mutations that alter normal splice patterns and genomic rearrangements are common causes of hereditary diseases including hereditary nonpolyposis colorectal cancer. However, abnormal transcripts can be difficult to detect and interpret because splicing patterns are often heterogeneous even in normal cells. Standard techniques including sequencing and Southern hybridization fail to detect some genomic rearrangements. We show here that separation of alleles in somatic cell hybrids, through "conversion" technology, considerably facilitates the interpretation of abnormal splicing patterns and the detection of genomic rearrangements. We detected novel mutations in MLH1 in each of four hereditary nonpolyposis colorectal cancer patients. The genomic mutations were CAG>CAA predicting Q346Q; GAG>AAG predicting E102K; a>g at nucleotide 1559-2 at intron 13, and a tandem duplication involving exons 7-12. By separating the two alleles, we showed that one allele produced only abnormal transcript or no transcript whereas the other allele produced only normal transcript. These results allowed pathogenicity to be unambiguously assigned to the mutations and increased the sensitivity of genomic testing.
UI - 12124176
AU - Heinen CD; Wilson T; Mazurek A; Berardini M; Butz C; Fishel R
TI - HNPCC mutations in hMSH2 result in reduced hMSH2-hMSH6 molecular switch functions.
SO - Cancer Cell 2002 Jun;1(5):469-78
AD - Genetics and Molecular Biology Program, Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Mutations in the human mismatch repair (MMR) gene hMSH2 have been linked to approximately 40% of hereditary nonpolyposis colorectal cancers (HNPCC). While the consequences of deletion or truncating mutations of hMSH2 would appear clear, the detailed functional defects associated with missense alterations are unknown. We have examined the effect of seven single amino acid substitutions associated with HNPCC that cover the structural subdomains of the hMSH2 protein. We show that alterations which produced a known cancer-causing phenotype affected the mismatch-dependent molecular switch function of the biologically relevant hMSH2-hMSH6 heterodimer. Our observations demonstrate that amino acid substitutions within hMSH2 that are distant from known functional regions significantly alter biochemical activity and the ability of hMSH2-hMSH6 to form a sliding clamp.
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