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• W1977048390 abstract "A subset of hereditary and sporadic colorectal carcinomas is defined by microsatellite instability (MSI), but the spectra of gene mutations have not been characterized extensively. Thirty-nine hereditary nonpolyposis colorectal cancer syndrome carcinomas (HNPCCa) and 57 sporadic right-sided colonic carcinomas (SRSCCa) were evaluated. Of HNPCCa, 95% (37/39) were MSI-positive as contrasted with 31% (18/57) of SRSCCa (P < 0.000001), but instability tended to be more widespread in SRSCCa (P = 0.08). Absence of nuclear hMSH2 mismatch repair gene product by immunohistochemistry was associated with germline hMSH2 mutation (P = 0.0007). The prevalence of K-ras proto-oncogene mutations was similar in HNPCCa and SRSCCa (30% (11/37) and 30% (16/54)), but no HNPCCa from patients with germlinehMSH2 mutation had codon 13 mutation (P = 0.02), and two other HNPCCa had multiple K-ras mutations attributable to subclones. 18q allelic deletion and p53 gene product overexpression were inversely related to MSI (P = 0.0004 andP = 0.0001, respectively). Frameshift mutation of the transforming growth factor β type II receptor gene was frequent in all MSI-positive cancers (85%, 46/54), but mutation of the E2F-4 transcription factor gene was more common in HNPCCa of patients with germline hMSH2mutation than in those with germline hMLH1 mutation (100% (8/8) versus 40% (2/5),P = 0.04), and mutation of theBax proapoptotic gene was more frequent in HNPCCa than in MSI-positive SRSCCa (55% (17/31) versus 13% (2/15), P = 0.01). The most common combination of mutations occurred in only 23% (8/35) of evaluable MSI-positive cancers. Our findings suggest that the accumulation of specific genetic alterations in MSI-positive colorectal cancers is markedly heterogeneous, because the occurrence of some mutations (eg, ras,E2F-4, and Bax genes), but not others (eg, transforming growth factor β type II receptor gene), depends on the underlying basis of the mismatch repair deficiency. This genetic heterogeneity may contribute to the heterogeneous clinical and pathological features of MSI-positive cancers. A subset of hereditary and sporadic colorectal carcinomas is defined by microsatellite instability (MSI), but the spectra of gene mutations have not been characterized extensively. Thirty-nine hereditary nonpolyposis colorectal cancer syndrome carcinomas (HNPCCa) and 57 sporadic right-sided colonic carcinomas (SRSCCa) were evaluated. Of HNPCCa, 95% (37/39) were MSI-positive as contrasted with 31% (18/57) of SRSCCa (P < 0.000001), but instability tended to be more widespread in SRSCCa (P = 0.08). Absence of nuclear hMSH2 mismatch repair gene product by immunohistochemistry was associated with germline hMSH2 mutation (P = 0.0007). The prevalence of K-ras proto-oncogene mutations was similar in HNPCCa and SRSCCa (30% (11/37) and 30% (16/54)), but no HNPCCa from patients with germlinehMSH2 mutation had codon 13 mutation (P = 0.02), and two other HNPCCa had multiple K-ras mutations attributable to subclones. 18q allelic deletion and p53 gene product overexpression were inversely related to MSI (P = 0.0004 andP = 0.0001, respectively). Frameshift mutation of the transforming growth factor β type II receptor gene was frequent in all MSI-positive cancers (85%, 46/54), but mutation of the E2F-4 transcription factor gene was more common in HNPCCa of patients with germline hMSH2mutation than in those with germline hMLH1 mutation (100% (8/8) versus 40% (2/5),P = 0.04), and mutation of theBax proapoptotic gene was more frequent in HNPCCa than in MSI-positive SRSCCa (55% (17/31) versus 13% (2/15), P = 0.01). The most common combination of mutations occurred in only 23% (8/35) of evaluable MSI-positive cancers. Our findings suggest that the accumulation of specific genetic alterations in MSI-positive colorectal cancers is markedly heterogeneous, because the occurrence of some mutations (eg, ras,E2F-4, and Bax genes), but not others (eg, transforming growth factor β type II receptor gene), depends on the underlying basis of the mismatch repair deficiency. This genetic heterogeneity may contribute to the heterogeneous clinical and pathological features of MSI-positive cancers. The molecular genetics of colorectal carcinoma are among the best understood of the common human neoplasms (reviewed in 1Kinzler KW Vogelstein B Lessons from hereditary colorectal cancer.Cell. 1996; 87: 159-170Abstract Full Text Full Text PDF PubMed Scopus (4252) Google Scholar, 3Gryfe R Swallow C Bapat B Redston M Gallinger S Couture J Molecular biology of colorectal cancer.Curr Probl Cancer. 1997; 21: 233-300Abstract Full Text PDF PubMed Google Scholar). In most colorectal carcinomas, inactivation of the APC (adenomatous polyposis coli) gene initiates colorectal neoplasia leading to dysplasia, commonly in the form of an adenoma. In patients with familial adenomatous polyposis, germline inactivation of APC appears to be followed by its somatic inactivation in colorectal epithelium, typically leading to large numbers of adenomas. During progression through the adenoma-adenocarcinoma sequence, additional alterations accumulate in proto-oncogenes including ras and in tumor suppressor genes on chromosome 18q (DCC, Smad2, orSmad4, reviewed in 4Hartsough MT Mulder KM Transforming growth factor-β signaling in epithelial cells.Pharmacol Ther. 1997; 75: 21-41Crossref PubMed Scopus (110) Google Scholar, 6White RL Tumor suppressing pathways.Cell. 1998; 92: 591-592Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar) and 17p (p53). The alterations each appear to provide a selective growth advantage. These alterations are found in various combinations in usual colorectal carcinomas, and extensive allelic deletions and altered total DNA content by flow cytometry or related methods are frequent.About 15% of colorectal cancers are characterized by microsatellite instability (MSI), also termed DNA replication errors or ubiquitous somatic mutations (reviewed in Refs. 7 to 16). Inactivation of one of a group of genes whose products participate in postreplicative repair of nucleotide mismatches leads to insertions and deletions of nucleotides in intrinsically unstable repeated sequences (ie, microsatellites) throughout the genome because of defective repair of the slippage mistakes made by DNA polymerases. MSI-positive tumors thus accumulate numerous frameshift mutations but also have a mutator phenotype that increases both base substitution mutations and frameshift mutations in expressed genes. In patients with hereditary nonpolyposis colorectal cancer syndrome (HNPCC, Warthin-Lynch syndrome; reviewed in 17Lynch HT Smyrk T Lynch J An update of HNPCC (Lynch syndrome).Cancer Genet Cytogenet. 1997; 93: 84-99Abstract Full Text PDF PubMed Scopus (184) Google Scholar, 18Marra G Boland CR Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives.J Natl Cancer Inst. 1995; 87: 1114-1125Crossref PubMed Scopus (478) Google Scholar), germline mutation of hMSH2(human MutS homolog 2), hMLH1 (human MutL homolog 1),hPMS1 or hPMS2 (human postmeiotic segregation 1 and 2), or the GTBP (guanine/thymidine mismatch-binding protein)/hMSH6 gene predispose to tumorigenesis. In addition to germline and somatic alterations in these genes in HNPCC, somatic inactivation alone of mismatch repair genes have been identified as a cause of MSI in sporadic tumors. Loss of immunohistochemical expression of hMSH2 and hMLH1 gene products in MSI-positive tumors has been reported.19Leach FS Polyak K Burrell M Johnson KA Hill D Dunlop MG Wyllie AH Peltomaki P de la Chapelle A Hamilton SR Kinzler KW Vogelstein B Expression of the human mismatch repair gene hMSH2 in normal and neoplastic tissues.Cancer Res. 1996; 56: 235-240PubMed Google Scholar, 20Thibodeau SN French AJ Roche PC Cunningham JM Tester DJ Lindor NM Moslein G Baker SM Liskay RM Burgart LJ Honchel R Halling KC Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes.Cancer Res. 1996; 56: 4836-4840PubMed Google Scholar, 21Dietmaier W Wallinger S Bocker T Kullmann F Fishel R Ruschoff J Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression.Cancer Res. 1997; 57: 4749-4756PubMed Google Scholar, 22Kim H Piao Z Kim JW Choi JS Kim NK Lee JM Park JH Expression of hMSH2 and hMLH1 in colorectal carcinomas with microsatellite instability.Mod Pathol. 1998; 194: 3-10Google Scholar, 23Thibodeau SN French AJ Cunningham JM Tester D Burgart LJ Roche PC Mcdonnell SK Schaid DJ Vockley CW Michels VV Farr Jr, GH O'Connell MJ Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1.Cancer Res. 1998; 58: 1713-1718PubMed Google Scholar MSI-positive colorectal carcinomas in both the inherited and sporadic settings have unusual pathological manifestations, including right-sided predominance and high frequency of large size; poorly differentiated, medullary, or mucinous histopathological type; and prominent lymphoid inflammatory response.24Thibodeau SN Bren G Schaid D Microsatellite instability in cancer of the proximal colon.Science. 1993; 260: 816-819Crossref PubMed Scopus (2785) Google Scholar, 25Lothe RA Peltomaki P Meling GI Aaltonen LA Nystrom-Lahti M Pylkkanen L Heimdal K Andersen TI Moller P Rognum TO Fossa SD Haldorsen T Langmark F Brogger A de la Chapelle A Borresen A-L Genomic instability in colorectal cancer: relationship of clinicopathological variables and family history.Cancer Res. 1993; 53: 5849-5852PubMed Google Scholar, 26Kim H Jen J Vogelstein B Hamilton SR Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences.Am J Pathol. 1994; 145: 148-156PubMed Google Scholar, 27Ilyas M Tomlinson IPM Novel MR Hanby A Bodmer WF Talbot IC Clinico-pathological features and p53 expression in left-sided sporadic colorectal cancers with and without microsatellite instability.J Pathol. 1996; 179: 370-375Crossref PubMed Scopus (33) Google Scholar, 28Ruschoff J Dietmaier W Luttges J Seitz G Bocker T Zimgibl H Schlegel J Schackert HK Jauch KW Hofstaedter F Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics.Am J Pathol. 1997; 150: 1815-1825PubMed Google Scholar, 29Senba S Konishi F Okamoto T Kashiwagi H Kanazawa K Miyaki M Konishi M Tsukamoto T Clinicopathologic and genetic features of nonfamilial colorectal carcinomas with DNA replication errors.Cancer. 1998; 82: 279-285Crossref PubMed Scopus (70) Google Scholar, 30Forster S Sattler HP Hack M Romanakis K Rohde V Seitz G Wullich B Microsatellite instability in sporadic carcinomas of the proximal colon: association with diploid DNA content, negative protein expression of p53, and distinct histomorphologic features.Surgery. 1998; 123: 13-18Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 31Jass JR Do K-A Simms LA Iino H Wynter C Pillay SP Searle J Radford-Smith G Young J Leggett B Morphology of sporadic colorectal cancer with DNA replication errors.Gut. 1998; 42: 673-679Crossref PubMed Scopus (407) Google ScholarTumors with widespread MSI have extensive subtle alterations in repeated nucleotide sequences, including those within the coding regions of genes. Inactivation of the APC gene by subtle mutation is common in MSI-positive neoplasms,32Huang J Papadopoulos N McKinley AJ Farrington SM Curtis LJ Wyllie AH Zheng S Willson JKV Markowitz SD Morin P Kinzler KW Vogelstein B Dunlop MG APC mutations in colorectal tumors with mismatch repair deficiency.Proc Natl Acad Sci USA. 1996; 93: 9049-9054Crossref PubMed Scopus (293) Google Scholar although some studies have reported low rates of APCmutation.33Konishi M Kikuchi-Yanoshita R Tanaka K Muraoka M Onda A Okumura Y Kishi N Iwama T Mori T Koike M Ushio K Chiba M Nomizu S Konishi F Utsunomiya J Miyaki M Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer.Gastroenterology. 1996; 111: 307-317Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar, 34Olschwang S Hamelin R Laurent-Puig P Thuille B DeRycke Y Li Y-J Muzeau F Girodet J Salmon R-J Thomas G Alternative genetic pathways in colorectal carcinogenesis.Proc Natl Acad Sci USA. 1997; 94: 12122-12127Crossref PubMed Scopus (225) Google Scholar In clear contrast to usual colorectal cancer, mutations are frequent in MSI-positive tumors among mononucleotide or other small repeats within the gene for the transforming growth factor β type II receptor (TGFβ RII),33Konishi M Kikuchi-Yanoshita R Tanaka K Muraoka M Onda A Okumura Y Kishi N Iwama T Mori T Koike M Ushio K Chiba M Nomizu S Konishi F Utsunomiya J Miyaki M Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer.Gastroenterology. 1996; 111: 307-317Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar, 34Olschwang S Hamelin R Laurent-Puig P Thuille B DeRycke Y Li Y-J Muzeau F Girodet J Salmon R-J Thomas G Alternative genetic pathways in colorectal carcinogenesis.Proc Natl Acad Sci USA. 1997; 94: 12122-12127Crossref PubMed Scopus (225) Google Scholar, 35Markowitz S Wang J Myeroff L Parsons R Sun L-Z Lutterbaugh J Fan RS Aborowska E Kinzler KW Vogelstein B Brattain M Willson JKV Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability.Science. 1995; 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14: 255-257Crossref PubMed Scopus (438) Google Scholar, 49Ouyang H Shiwaku HO Hagiwara H Miura K Abe T Kato Y Ohtani H Shiiba K Souza RF Meltzer SJ Horii A The insulin-like growth factor II receptor gene is mutated in genetically unstable cancers of the endometrium, stomach, and colorectum.Cancer Res. 1997; 57: 1851-1854PubMed Google Scholar the hMSH3 andhMSH6 mismatch repair genes,47Ikeda M Orimo H Moriyama H Nakajima E Matsubara N Mibu R Tanaka N Shimada T Kimura A Shimizu K Close correlation between mutations of E2F4 and hMSH3 genes in colorectal cancers with microsatellite instability.Cancer Res. 1998; 58: 594-598PubMed Google Scholar, 50Yamamoto H Sawai H Perucho M Frameshift somatic mutations in gastrointestinal cancer of the microsatellite mutator phenotype.Cancer Res. 1997; 57: 4420-4426PubMed Google Scholar, 51Yin J Kong D Wang S Zou T-T Souza RF Smolinski KN Lynch PM 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.Hum Mutat. 1997; 10: 474-478Crossref PubMed Scopus (76) Google Scholar and theBax gene for a BCL-2-related protein50Yamamoto H Sawai H Perucho M Frameshift somatic mutations in gastrointestinal cancer of the microsatellite mutator phenotype.Cancer Res. 1997; 57: 4420-4426PubMed Google Scholar, 52Rampino N Yamamoto H Ionov Y Li Y Sawai H Reed JC Perucho M Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype.Science. 1997; 275: 967-969Crossref PubMed Scopus (1229) Google Scholar, 53Yagi OK Akiyama Y Nomizu T Iwama T Endo M Yuasa Y Proapoptotic gene BAX is frequently mutated in hereditary nonpolyposis colorectal cancers but not in adenomas.Gastroenterology. 1998; 114: 268-274Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 54Ouyang H Furukawa T Abe T Kato Y Horii A The BAX gene, the promoter of apoptosis, is mutated in genetically unstable cancers of the colorectum, stomach, and endometrium.Clin Cancer Res. 1998; 4: 1071-1074PubMed Google Scholar that promotes apoptosis (reviewed in 55Potten CS Wilson JW Booth C Regulation and significance of apoptosis in the stem cells of the gastrointestinal epithelium.Stem Cells. 1997; 15: 82-93Crossref PubMed Scopus (242) Google Scholar). Because of the high frequency of mutation in microsatellite sequences throughout the genome, it is not clear that the intragenic mutations are causally related to tumor progression, and many genes with repeat sequences do not show instability.54Ouyang H Furukawa T Abe T Kato Y Horii A The BAX gene, the promoter of apoptosis, is mutated in genetically unstable cancers of the colorectum, stomach, and endometrium.Clin Cancer Res. 1998; 4: 1071-1074PubMed Google Scholar, 56Simms LA Zou TT Young J Shi YQ Appel R Rhyu MG Sugimura H Chenevix-Trench G Souza RF Meltzer SJ Leggett BA Apparent protection from instability of repeat sequences in cancer-related genes in replication error positive gastrointestinal cancers.Oncogene. 1997; 14: 2613-2618Crossref PubMed Scopus (17) Google Scholar In addition, allelic losses are infrequent, and total DNA content of tumor cells is typically in the normal range. Little is known, however, about the pattern in MSI-positive tumors of accumulated alterations in the oncogenes and suppressor genes that are important in the progression of usual colorectal neoplasia, because only small numbers of MSI-positive tumors have been studied, and conflicting results have been reported. For example, ras proto-oncogene mutations in MSI-positive colorectal carcinomas were reported to occur at frequencies similar to microsatellite-stable (MSS) cancers in some series28Ruschoff J Dietmaier W Luttges J Seitz G Bocker T Zimgibl H Schlegel J Schackert HK Jauch KW Hofstaedter F Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics.Am J Pathol. 1997; 150: 1815-1825PubMed Google Scholar, 34Olschwang S Hamelin R Laurent-Puig P Thuille B DeRycke Y Li Y-J Muzeau F Girodet J Salmon R-J Thomas G Alternative genetic pathways in colorectal carcinogenesis.Proc Natl Acad Sci USA. 1997; 94: 12122-12127Crossref PubMed Scopus (225) Google Scholar, 40Tannergard P Liu T Weger A Nordenskjold M Lindblom A Tumorigenesis in colorectal tumors from patients with hereditary non-polyposis colorectal cancer.Hum Genet. 1997; 101: 51-55Crossref PubMed Scopus (69) Google Scholar, 57Aaltonen LA Peltomaki P Leach FS Sistonen P Pylkkanen L Mecklin JP Jarvinen H Powell SM Jen J Hamilton SR Petersen GM Kinzler KW Vogelstein B de la Chapelle A Clues to the pathogenesis of familial colorectal cancer.Science. 1993; 260: 812-816Crossref PubMed Scopus (2559) Google Scholar, 58Craanen ME Blok P Offerhaus GJ Tytgat GN Recent developments in hereditary nonpolyposis colorectal cancer.Scand J Gastroenterol. 1996; 218: 92-97Crossref Google Scholar but at low frequency in others.33Konishi M Kikuchi-Yanoshita R Tanaka K Muraoka M Onda A Okumura Y Kishi N Iwama T Mori T Koike M Ushio K Chiba M Nomizu S Konishi F Utsunomiya J Miyaki M Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer.Gastroenterology. 1996; 111: 307-317Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar, 43Iacopetta BJ Welch J Soong R House AK Zhou X-P Hamelin R Mutation of the transforming growth factor β type II receptor gene in right-sided colorectal cancer: relationship to clinicopathological features and genetic alterations.J Pathol. 1998; 184: 390-395Crossref PubMed Scopus (75) Google Scholar, 59Ionov Y Peinado MA Malkhosyan S Shibata D Perucho M Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis.Nature. 1993; 363: 558-561Crossref PubMed Scopus (2390) Google Scholar, 60Breivik J Lothe RA Meling GI Rognum TO Borresen-Dale AL Gaudernack G Different genetic pathways to proximal and distal colorectal cancer influenced by sex-related factors.Int J Cancer. 1997; 74: 664-669Crossref PubMed Scopus (176) Google Scholar, 61Losi L Ponz de Leon M Jiricny J Di Gregorio C Benatti P Percesepe A Fante R Roncucci L Pedroni M Benhattar J K-ras and p53 mutations in hereditary non-polyposis colorectal cancers.Int J Cancer. 1997; 74: 94-96Crossref PubMed Scopus (64) Google Scholar For p53 alterations, conflicting reports of similar27Ilyas M Tomlinson IPM Novel MR Hanby A Bodmer WF Talbot IC Clinico-pathological features and p53 expression in left-sided sporadic colorectal cancers with and without microsatellite instability.J Pathol. 1996; 179: 370-375Crossref PubMed Scopus (33) Google Scholar, 42Habano W Sugai T Nakamura S-I Mismatch repair deficiency leads to a unique mode of colorectal tumorigenesis characterized by intratumoral heterogeneity.Oncogene. 1998; 16: 1259-1265Crossref PubMed Scopus (26) Google Scholar, 57Aaltonen LA Peltomaki P Leach FS Sistonen P Pylkkanen L Mecklin JP Jarvinen H Powell SM Jen J Hamilton SR Petersen GM Kinzler KW Vogelstein B de la Chapelle A Clues to the pathogenesis of familial colorectal cancer.Science. 1993; 260: 812-816Crossref PubMed Scopus (2559) Google Scholar, 58Craanen ME Blok P Offerhaus GJ Tytgat GN Recent developments in hereditary nonpolyposis colorectal cancer.Scand J Gastroenterol. 1996; 218: 92-97Crossref Google Scholar or lower28Ruschoff J Dietmaier W Luttges J Seitz G Bocker T Zimgibl H Schlegel J Schackert HK Jauch KW Hofstaedter F Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics.Am J Pathol. 1997; 150: 1815-1825PubMed Google Scholar, 30Forster S Sattler HP Hack M Romanakis K Rohde V Seitz G Wullich B Microsatellite instability in sporadic carcinomas of the proximal colon: association with diploid DNA content, negative protein expression of p53, and distinct histomorphologic features.Surgery. 1998; 123: 13-18Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 33Konishi M Kikuchi-Yanoshita R Tanaka K Muraoka M Onda A Okumura Y Kishi N Iwama T Mori T Koike M Ushio K Chiba M Nomizu S Konishi F Utsunomiya J Miyaki M Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer.Gastroenterology. 1996; 111: 307-317Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar, 34Olschwang S Hamelin R Laurent-Puig P Thuille B DeRycke Y Li Y-J Muzeau F Girodet J Salmon R-J Thomas G Alternative genetic pathways in colorectal carcinogenesis.Proc Natl Acad Sci USA. 1997; 94: 12122-12127Crossref PubMed Scopus (225) Google Scholar, 43Iacopetta BJ Welch J Soong R House AK Zhou X-P Hamelin R Mutation of the transforming growth factor β type II receptor gene in right-sided colorectal cancer: relationship to clinicopathological features and genetic alterations.J Pathol. 1998; 184: 390-395Crossref PubMed Scopus (75) Google Scholar, 55Potten CS Wilson JW Booth C Regulation and significance of apoptosis in the stem cells of the gastrointestinal epithelium.Stem Cells. 1997; 15: 82-93Crossref PubMed Scopus (242) Google Scholar, 59Ionov Y Peinado MA Malkhosyan S Shibata D Perucho M Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis.Nature. 1993; 363: 558-561Crossref PubMed Scopus (2390) Google Scholar, 60Breivik J Lothe RA Meling GI Rognum TO Borresen-Dale AL Gaudernack G Different genetic pathways to proximal and distal colorectal cancer influenced by sex-related factors.Int J Cancer. 1997; 74: 664-669Crossref PubMed Scopus (176) Google Scholar, 61Losi L Ponz de Leon M Jiricny J Di Gregorio C Benatti P Percesepe A Fante R Roncucci L Pedroni M Benhattar J K-ras and p53 mutations in hereditary non-polyposis colorectal cancers.Int J Cancer. 1997; 74: 94-96Crossref PubMed Scopus (64) Google Scholar, 62Muta H Noguchi M Perucho M Ushio K Sugihara K Ochiai A Nawata H Hirohashi S Clinical implications of microsatellite instability in colorectal cancers.Cancer. 1996; 77: 265-270Crossref PubMed Scopus (55) Google Scholar, 63Cottu PH Muzeau F Estreicher A Flejou JF Iggo R Thomas G Hamelin R Inverse correlation between RER+ status and p53 mutation in colorectal cancer cell lines.Oncogene. 1996; 13: 2727-2730PubMed Google Scholar frequencies of abnormalities have also appeared. Furthermore, alterations such as loss of heterozygosity of chromosome 8p have been reported at different frequency in sporadic MSI-positive tumors than in HNPCC MSI-positive tumors,33Konishi M Kikuchi-Yanoshita R Tanaka K Muraoka M Onda A Okumura Y Kishi N Iwama T Mori T Koike M Ushio K Chiba M Nomizu S Konishi F Utsunomiya J Miyaki M Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer.Gastroenterology. 1996; 111: 307-317Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar and frequency of mutation of some genes (eg,E2F-4) differed with severity of MSI.46Souza RF Yin J Smolinski KN Zou TT Wang S Shi YQ Rhyu MG Cottrell J Abraham JM Biden K Simms L Leggett B Bova GS Frank T Powell SM Sugimura H Young J Harpaz N Shimizu K Matsubara N Meltzer SJ Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors.Cancer Res. 1997; 57: 2350-2353PubMed Google ScholarTo address these uncertainties about genetic alterations in MSI-positive tumors, we studied the spectra of mutations in a large series of colorectal carcinomas from patients with HNPCC or sporadic colonic cancer. We evaluated MSI status; immunohistochemical expression of hMSH2 and hMLH1 gene products; mutation of the Kirstenras proto-oncogene; allelic deletion of the long arm of chromosome 18q where the DCC, DPC4/Smad4, andJV-18/MADR2/Smad2 genes reside; overexpression of p53 gene product and mutation of the p53 gene; and mutations in nucleotide repeat sequences in the coding regions of the TGFβ RII,E2F-4, and Bax genes. The results have implications for the diagnosis and treatment of MSI-positive tumors as well as understanding of the biology of colorectal neoplasia.Materials and MethodsPatients and Tumor SpecimensWe studied 39 colorectal cancers from patients in 20 families, that met International Collaborative Group criteria for HNPCC64Vasen HFA Mecklin JP Kahn PM Lynch HT Hereditary non-polyposis colorectal cancer.Lancet. 1991; 338: 877Abstract Scopus (83) Google Scholar and/or had germline mutation of hMSH2 orhMLH1,65Wijnen J Khan PM Vasen H van der Klift H Mulder A van Leeuwen-Cornelisse I Bakker B Losekoot M Moller P Fodde R Hereditary nonp" @default.
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• W1977048390 date "1998-10-01" @default.
• W1977048390 modified "2023-10-11" @default.
• W1977048390 title "Accumulated Clonal Genetic Alterations in Familial and Sporadic Colorectal Carcinomas with Widespread Instability in Microsatellite Sequences" @default.
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