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• W1965219770 abstract "Some studies have shown an inverse relationship between microsatellite instability in colon cancer and mutations in p53 and K-ras, whereas others have not. We therefore evaluated these features in a population-based sample of 496 individuals with colon cancer. Microsatellite instability was determined by a panel of 10 tetranucleotide repeats, the Bethesda consensus panel of mono- and dinucleotide repeats, and coding mononucleotide repeats in transforming growth factor-beta receptor type II, hMSH3, BAX, hMSH6, and insulin-like growth factor receptor type II. Mutations in codons 12 and 13 in K-ras were evaluated by sequencing. p53 overexpression (as detected by immunohistochemistry) was used as an indicator of p53 mutation; this was evaluated in 275 of the tumors. K-ras mutations were present in 33.2% of tumors, p53 overexpression in 51.5%, and microsatellite instability (as determined by the Bethesda consensus panel) in 12.5%. K-ras mutations were significantly less common in unstable tumors than stable tumors (11.8%versus 36.9%, P < 0.001). p53 overexpression was significantly less common in unstable tumors than stable tumors (20.0% versus 55.7%, P < 0.001). These inverse relationships between microsatellite instability and ras gene mutations and p53 overexpression were shown to be independent of tumor site in logistic regression analyses. All other measures of instability also showed statistically significant inverse relationships independent of tumor site with alterations in ras and p53, and instability results determined by the panel of 10 tetranucleotide repeats were highly significantly related to those determined by the Bethesda consensus panel. Coding mononucleotide repeat mutations were significantly more common in unstable tumors than stable tumors (85.7% versus 1.0%, P < 0.001). We conclude that there is an inverse relationship between microsatellite instability and mutations in p53 and K-ras, and that the molecular profile of colon cancers with microsatellite instability is characterized by relatively infrequent mutations in K-ras and p53 and relatively frequent mutations in coding mononucleotide repeats. Some studies have shown an inverse relationship between microsatellite instability in colon cancer and mutations in p53 and K-ras, whereas others have not. We therefore evaluated these features in a population-based sample of 496 individuals with colon cancer. Microsatellite instability was determined by a panel of 10 tetranucleotide repeats, the Bethesda consensus panel of mono- and dinucleotide repeats, and coding mononucleotide repeats in transforming growth factor-beta receptor type II, hMSH3, BAX, hMSH6, and insulin-like growth factor receptor type II. Mutations in codons 12 and 13 in K-ras were evaluated by sequencing. p53 overexpression (as detected by immunohistochemistry) was used as an indicator of p53 mutation; this was evaluated in 275 of the tumors. K-ras mutations were present in 33.2% of tumors, p53 overexpression in 51.5%, and microsatellite instability (as determined by the Bethesda consensus panel) in 12.5%. K-ras mutations were significantly less common in unstable tumors than stable tumors (11.8%versus 36.9%, P < 0.001). p53 overexpression was significantly less common in unstable tumors than stable tumors (20.0% versus 55.7%, P < 0.001). These inverse relationships between microsatellite instability and ras gene mutations and p53 overexpression were shown to be independent of tumor site in logistic regression analyses. All other measures of instability also showed statistically significant inverse relationships independent of tumor site with alterations in ras and p53, and instability results determined by the panel of 10 tetranucleotide repeats were highly significantly related to those determined by the Bethesda consensus panel. Coding mononucleotide repeat mutations were significantly more common in unstable tumors than stable tumors (85.7% versus 1.0%, P < 0.001). We conclude that there is an inverse relationship between microsatellite instability and mutations in p53 and K-ras, and that the molecular profile of colon cancers with microsatellite instability is characterized by relatively infrequent mutations in K-ras and p53 and relatively frequent mutations in coding mononucleotide repeats. The relationship between microsatellite instability and mutations in p53 and K-ras in colon cancer is somewhat controversial. Some studies have shown an inverse relationship between instability and mutations in these genes, whereas other studies have not.1Fujiwara T Stolker JM Watanabe T Rashid A Longo P Eshleman J Booker S Lynch HT Jass JR Green JS Kim H Jen J Vogelstein B Hamilton SR Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences.Am J Pathol. 1998; 153: 1063-1078Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar Possible explanations for these inconsistent results include small studies with insufficient power to show a significant relationship, studies of different populations, and/or different methods for measuring microsatellite instability. In addition, most previous studies did not control for tumor site, a potentially confounding variable because of the high correlation between microsatellite instability and proximal tumor location.2Samowitz WS Slattery ML Kerber RA Microsatellite instability in human colonic cancer is not a useful clinical indicator of familial colorectal cancer.Gastroenterology. 1995; 109: 1765-1771Abstract Full Text PDF PubMed Scopus (90) Google Scholar The above concerns are addressed in the current study by evaluating microsatellite instability, K-ras, and p53 in a large, population-based sample of colon cancers from the state of Utah. Microsatellite instability is analyzed in several different ways: a panel of 10 tetranucleotide repeats used by us in previous studies,2Samowitz WS Slattery ML Kerber RA Microsatellite instability in human colonic cancer is not a useful clinical indicator of familial colorectal cancer.Gastroenterology. 1995; 109: 1765-1771Abstract Full Text PDF PubMed Scopus (90) Google Scholar, 3Samowitz WS Slattery ML Microsatellite instability in colorectal adenomas.Gastroenterology. 1997; 112: 1515-1519Abstract Full Text PDF PubMed Scopus (57) Google Scholar, 4Samowitz WS Slattery ML Transforming growth factor β receptor type 2 mutations and microsatellite instability in sporadic colorectal adenomas and carcinomas.Am J Pathol. 1997; 151: 33-35PubMed Google Scholar the Bethesda consensus panel generated by a National Cancer Institute workshop on microsatellite instability,5Boland CR Thibodeau SN Hamilton SR Sidransky D Eshleman JR Burt RW Meltzer SJ Rodriguez-Bigas MA Fodde R Ranzani N Srivastava S A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.Cancer Res. 1998; 58: 5248-5257PubMed Google Scholar and mononucleotide repeats within the coding regions of transforming growth factor-β receptor type II (TGFβRII), BAX, hMSH3, hMSH6, and the insulin-like growth factor type II receptor (IGFIIR).6Samowitz WS Slattery ML Regional reproducibility of microsatellite instability in sporadic colorectal cancer.Genes Chromosom Cancer. 1999; 26: 106-114Crossref PubMed Scopus (39) Google Scholar We also determine whether relationships between microsatellite instability and alterations in ras and p53 are independent of tumor site (and other variables) in logistic regression analyses. Molecular analysis of colon cancer samples from 496 individuals was performed. These individuals represent the Utah portion of a population-based case-control study of the etiology of colon cancer7Slattery ML Potter JD Caan BJ Edwards SL Coates A Ma K-N Berry TD Energy balance and colon cancer: beyond physical activity.Cancer Res. 1997; 57: 75-80PubMed Google Scholar and includes 154 individuals previously evaluated in a study of microsatellite instability and family history.2Samowitz WS Slattery ML Kerber RA Microsatellite instability in human colonic cancer is not a useful clinical indicator of familial colorectal cancer.Gastroenterology. 1995; 109: 1765-1771Abstract Full Text PDF PubMed Scopus (90) Google Scholar Study participants were from an eight county area in Utah (Davis, Salt Lake, Utah, Weber, Wasatch, Tooele, Morgan, and Summit counties). Eligibility criteria included diagnosis with first-primary incident colon cancer (ICD-O second edition codes 18.0, 18.2 to 18.9) between October 1, 1991, and September 30, 1994, age between 30 and 79 years at time of diagnosis, and mentally competent to complete the interview. Individuals with adenomatous polyposis coli or inflammatory bowel disease were excluded from the study. Individuals with hereditary nonpolyposis colon cancer were not specifically excluded, but such individuals should comprise only a small fraction of those with colon cancer at the population level;8Aaltonen LA Salovaara R Kristo P Canzian F Hemminki A Peltomaki P Chadwick RB Kaariainen H Eskelinen M Jarvinen H Mecklin J-P de la Chapelle A Incidence of hereditary nonpolyposis colorectal cancer and feasibility of molecular screening for the disease.N Engl J Med. 1998; 338: 1481-1487Crossref PubMed Scopus (989) Google Scholar this study sample therefore consists mostly of individuals with sporadic colon cancer. The 496 individuals represent 85.8% (496 of 578) of those diagnosed with colon cancer in the state of Utah between October, 1991, and October, 1994, again underscoring the population-based nature of this study. Colon cancer tissue was microdissected and DNA extracted from formalin-fixed paraffin-embedded tissue blocks as described previously.9Spirio LN Samowitz WS Robertson J Robertson M Burt RW Leppert MF White R Alleles of APC modulate the frequency and classes of mutations that lead to colon polyps.Nat Genet. 1998; 20: 385-388Crossref PubMed Scopus (126) Google Scholar The respective normal DNA from each individual was extracted from peripheral blood (222 cases) or from paraffin blocks of normal colonic mucosa (274 cases). Each tumor was evaluated for microsatellite instability with a panel of 10 tetranucleotide repeats2Samowitz WS Slattery ML Kerber RA Microsatellite instability in human colonic cancer is not a useful clinical indicator of familial colorectal cancer.Gastroenterology. 1995; 109: 1765-1771Abstract Full Text PDF PubMed Scopus (90) Google Scholar and with the Bethesda consensus panel (mononucleotide repeats BAT-25 and BAT-26 and dinucleotide repeats D5S346, D2S123, and D17S250) generated by the National Cancer Institute workshop on microsatellite instability.5Boland CR Thibodeau SN Hamilton SR Sidransky D Eshleman JR Burt RW Meltzer SJ Rodriguez-Bigas MA Fodde R Ranzani N Srivastava S A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.Cancer Res. 1998; 58: 5248-5257PubMed Google Scholar The tumors were also evaluated with five coding mononucleotide repeats [(A)10 in TGFBRII, (A)8 in hMSH3, (G)8 in BAX, (G)8 in IGFIIR, and (C)8 in hMSH6]. The primer sequences and polymerase chain reaction (PCR) conditions for the tetranucleotide repeats, coding mononucleotide repeats, and BAT-26 were as described previously.2Samowitz WS Slattery ML Kerber RA Microsatellite instability in human colonic cancer is not a useful clinical indicator of familial colorectal cancer.Gastroenterology. 1995; 109: 1765-1771Abstract Full Text PDF PubMed Scopus (90) Google Scholar, 6Samowitz WS Slattery ML Regional reproducibility of microsatellite instability in sporadic colorectal cancer.Genes Chromosom Cancer. 1999; 26: 106-114Crossref PubMed Scopus (39) Google Scholar, 10Samowitz WS Slattery ML Potter JD Leppert MF BAT-26 and BAT-40 instability in colorectal adenomas and carcinomas and germline polymorphisms.Am J Pathol. 1999; 154: 1637-1641Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar The primer sequences for the remaining four primer sets of the consensus panel were as described previously.11Dietmaier W Wallinger S Bocker T Kullmann F Fishel R Rüschoff J Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression.Cancer Res. 1997; 57: 4749-4756PubMed Google Scholar PCR of these primers consisted of 38 cycles of 20 seconds at 95°C, 20 seconds annealing, and 40 seconds at 72°C, followed by a 10-minute extension at 72°C. The initial annealing temperature was 60°C for BAT-25 and D2S123 and 64°C for D17S250 and D52346. This annealing temperature was decreased 1 degree for each of the next seven cycles and was 52°C for the final 30 cycles. Both tumoral DNA and normal DNA were PCR amplified with the above primer sets. Microsatellite instability for a given primer set was defined as the appearance of one or more new PCR products either smaller or larger than those produced from normal DNA. Results from the tetranucleotide repeat panel were considered to indicate significant microsatellite instability if three or more of the 10 repeats were unstable. Results were considered to indicate stability if <30% of the repeats were unstable and at least six of the 10 repeats were typed. Results from the consensus panel were considered to indicate significant microsatellite instability if two or more of the five repeats were unstable. Results from the consensus panel were considered to indicate stability if no repeats were unstable and at least four were typed or if one of five repeats were unstable. Using these criteria, 92.1% of tumors were successfully classified as unstable or stable by the tetranucleotide repeats and 90.3% were classified by the consensus panel. Microsatellite instability was also assessed using one of the consensus panel repeats, BAT-26, by itself. Instability in this mononucleotide repeat has been reported to be highly correlated with generalized dinucleotide repeat instability.12Hoang J-M Cottu PH Thuille B Salmon RJ Thomas G Hamelin R BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines.Cancer Res. 1997; 57: 300-303PubMed Google Scholar Instability in the coding mononucleotide repeats was considered in two ways: instability in any of the five coding repeats, and instability in TGFβRII, the coding repeat most frequently mutated in unstable tumors.6Samowitz WS Slattery ML Regional reproducibility of microsatellite instability in sporadic colorectal cancer.Genes Chromosom Cancer. 1999; 26: 106-114Crossref PubMed Scopus (39) Google Scholar, 13Yamamoto H Sawai H Perucho M Frameshift somatic mutations in gastrointestinal cancer of the microsatellite mutator phenotype.Cancer Res. 1997; 57: 4420-4426PubMed Google Scholar Codons 12 and 13 of the K-ras gene were evaluated for mutations. Exon 1 of K-ras was amplified as described previously14Sidransky D Tokino T Hamilton SR Kinzler KW Levin B Frost P Vogelstein B Identification of ras oncogene mutations in the stool of patients with curable colorectal tumors.Science. 1992; 256: 102-105Crossref PubMed Scopus (687) Google Scholar except that primers were tailed with universal primer (UP) and reverse primer (RP) for sequencing. PCR products were sequenced using prism Big Dye terminators and cycle sequencing with Taq FS DNA polymerase. DNA sequence was collected and analyzed on an ABI prism 377 automated DNA sequencer (Applied Biosystems, Foster City, CA). Automated immunohistochemical staining for p53 was performed using the D07 mouse monoclonal antibody and the percentage of p53-positive tumor cell nuclei was determined as described previously.15Lynch BJ Komaromy-Hiller G Bronstein IB Holden JA Expression of DNA topoisomerase I, DNA topoisomerase II-alpha, and p53 in metastatic malignant melanoma.Hum Pathol. 1998; 29: 1240-1245Abstract Full Text PDF PubMed Scopus (29) Google Scholar This antibody and experimental technique have been shown to be highly specific and predictive for p53 mutations in colon cancer.16Baas IO Mulder JR Offerhaus GJ Vogelstein B Hamilton SR An evaluation of six antibodies for immunohistochemistry of mutant p53 gene product in archival colorectal neoplasms.J Pathol. 1994; 172: 5-12Crossref PubMed Scopus (530) Google Scholar Immunostained slides were evaluated by one of the authors (JAH) without knowledge of the respective clinical parameters or the results of the other analyses in this study. We defined overexpression of p53 as tumors with 50% or more tumor cell nuclei staining positively with the antibody.17Rashid A Zahurak M Goodman SN Hamilton SR Genetic epidemiology of mutated K-ras proto-oncogene, altered suppressor genes, and microsatellite instability in colorectal adenomas.Gut. 1999; 44: 826-833Crossref PubMed Scopus (79) Google Scholar Paraffin blocks for this aspect of the study were available on 274 individuals. Unconditional logistic regression models were fit to estimate the association between microsatellite instability and Ki-ras mutation or p53 overexpression after adjusting for age, sex, and tumor site. In these models, different indicators of microsatellite instability were used to predict a dichotomous dependent variable of wild-type Ki-ras versus mutated Ki-ras or p53-negative (<50% p53 nuclear staining) versus p53 overexpression. These data are reported as the odds ratio and 95% confidence interval for having microsatellite instability but lacking either K-ras mutation or p53 overexpression. Instability results for the panel of 10 tetranucleotide repeats, the consensus panel, Bat 26 by itself, TGFβRII, and instability with any coding mononucleotide repeat are shown in Table 1. Overall instability rates were fairly similar among the various measures, ranging from 10.1 to 13.8%. All measures showed more instability in proximal tumors (19.5 to 23.9%) than distal tumors (1.4 to 4%); these differences were all statistically significant (P < 0.001, chi-square test). A representative example of instability in a tetranucleotide repeat, dinucleotide repeat, noncoding mononucleotide repeat (BAT-26), and a coding mononucleotide repeat (TGFβRII) from the same tumor is shown in Figure 1.Table 1Microsatellite Instability (MI) as Determined by Various Measures of InstabilityInstability measureOverall MIMI in proximal tumorsMI in distal tumorsP value*All P values based on chi-square test comparing the percentage of proximal tumors with microsatellite instability versus the percentage of distal tumors with microsatellite instability.10 tetranucleotides13.8% (63/457)23.9% (54/226)4.0% (8/201)< 0.001Consensus panel12.5% (56/448)22.6% (49/217)2.5% (5/202)< 0.001BAT-2611.4% (53/466)21.2% (47/222)2.3% (5/213)< 0.001TGFβRII10.1% (47/466)19.5% (44/226)1.4% (3/210)< 0.001Any coding mononucleotide11.9% (57/481)21.4% (49/229)3.2% (7/220)< 0.001* All P values based on chi-square test comparing the percentage of proximal tumors with microsatellite instability versus the percentage of distal tumors with microsatellite instability. Open table in a new tab Codon 12 or 13 K-ras gene mutations were identified in 155 of 467 (33.2%) tumors. The type and frequency of ras gene mutations are detailed in Table 2. Ras gene mutations were seen in a higher percentage of proximal (42.5%, 94 of 221) than distal (22.1%, 46 of 208) tumors; this difference was statistically significant (P< 0.001, chi-square test). The relationship between ras gene mutations and microsatellite instability (as determined by the various measures of instability) is summarized in Table 3. All measures of instability showed a higher percentage of ras gene mutations in stable tumors (36 to 38.1%) than in unstable tumors (4.7 to 11.8%); these differences were all statistically significant (P < 0.001, chi-square test). A logistic regression analysis revealed that the inverse association of microsatellite instability with ras gene mutations was independent of tumor site, age, and gender. The strength of the inverse association comparing wild-type K-ras to mutant K-ras for the various indicators of instability was similar with odds ratios ranging from 8.3 to 20.0 (Table 4), and all were statistically significant (P < 0.01).Table 2Type and Frequency of ras Gene MutationsBase pair change*1G and 2G are first two bases of codon 12, 5G is second base of codon 13.Amino acid change†Changed codon (12 or 13) indicated by superscript.Percentage of ras mutations2G to AGly12 to Asp34.85G to AGly13 to Asp23.22G to TGly12 to Val19.41G to TGly12 to Cys10.31G to AGly12 to Ser4.52G to A (H)‡H indicates homozygous mutation.Gly12 to Asp1.32G to C (H)Gly12 to Ala1.32G to T (H)Gly12 to Val1.31G to CGly12 to Arg0.62G to CGly12 to Ala0.61G to A (H)Gly12 to Ser0.61G to T (H)Gly12 to Cys0.65G to A (H)Gly13 to Asp0.61 and 5G to AGly12 to Ser0.6Gly13 to Asp* 1G and 2G are first two bases of codon 12, 5G is second base of codon 13.† Changed codon (12 or 13) indicated by superscript.‡ H indicates homozygous mutation. Open table in a new tab Table 3Comparison of K-ras Gene Mutations with Microsatellite InstabilityInstability measureras Mutations in stable tumorsras Mutations in unstable tumorsP value*All P values based on chi-square test comparing the percentage of stable tumors with ras gene mutations versus the percentage of unstable tumors with ras gene mutations.10 tetranucleotides38.1% (143/375)10.2% (6/59)< 0.001Consensus panel36.4% (136/374)11.8% (6/51)< 0.001BAT-2636.8% (144/391)8.3% (4/48)< 0.001TGFβRII36.0% (143/397)4.7% (2/43)< 0.001Any coding mononucleotide36.2% (145/401)9.8% (5/51)< 0.001* All P values based on chi-square test comparing the percentage of stable tumors with ras gene mutations versus the percentage of unstable tumors with ras gene mutations. Open table in a new tab Table 4Logistic Regression Analyses of Inverse Relationship between Microsatellite Instability and K-ras Mutations and p53 OverexpressionKi-ras OR*OR is odds ratio of the absence of an alteration in K-ras or p53 in tumors with microsatellite instability; CI is confidence interval. (95% CI)p53 OR (95% CI)10 tetranucleotides9.1 (3.4–20.0)2.8 (1.2–6.2)Consensus panel9.1 (3.3–25.0)4.5 (1.8–11.5)Bat-2611.1 (3.7–33.3)8.2 (2.6–25.5)TGFβRII20.0 (4.6–100)9.2 (2.6–33.1)Any coding mononucleotide8.3 (3.1–20)12.9 (3.6–45.5)* OR is odds ratio of the absence of an alteration in K-ras or p53 in tumors with microsatellite instability; CI is confidence interval. Open table in a new tab p53 overexpression was identified in 141 of 274 tumors (51.5%). An example of a tumor with p53 overexpression is shown in Figure 2. p53 overexpression was present in a higher percentage of distal (60.9%, 70 of 115) than proximal (41.0%, 57 of 139) tumors, this difference was statistically significant (P < 0.002, chi-square test). The relationship between p53 overexpression and microsatellite instability (as determined by the various measures of instability) is summarized in Table 5. All measures of instability showed a higher percentage of stable tumors with p53 overexpression (54.3 to 57.2%) than unstable tumors with p53 overexpression (9.1 to 26.3%); these differences were all statistically significant (P < 0.001, chi-square test). A logistic regression analysis revealed that the inverse association of microsatellite instability with p53 overexpression was independent of tumor site, age, and gender. Odds ratios for the inverse association comparing p53 negative (<50% nuclear staining) versus p53 overexpression ranged from 2.8 to 12.9 (Table 4), and all were statistically significant (P < 0.05).Table 5Comparison of p53 Overexpression with Microsatellite InstabilityInstability measurep53 Overexpression in stable tumorsp53 Overexpression in unstable tumorsP value*All P values based on chi-square test comparing the percentage of stable tumors with p53 overexpression versus the percentage of unstable tumors with p53 overexpression.10 tetranucleotides54.3% (120/221)26.3% (10/38)< 0.001Consensus panel55.7% (122/219)20.0% (7/35)< 0.001BAT-2656.5% (130/230)12.1% (4/33)< 0.001TGFβRII55.7% (132/237)11.1% (3/27)< 0.001Any coding mononucleotide57.2% (135/236)9.1% (3/33)< 0.001* All P values based on chi-square test comparing the percentage of stable tumors with p53 overexpression versus the percentage of unstable tumors with p53 overexpression. Open table in a new tab Microsatellite instability in the coding mononucleotide repeats is summarized in Table 6; all observed mutations were frameshifts (addition of one base, deletion of one or two bases). TGFβRII contained the most frequently mutated coding repeat, with length alterations in this poly A repeat in 10.1% (47 of 466) of tumors overall, followed by BAX (6.1%), hMSH3 (5.2%), hMSH6 (2.7%), and IGFIIR (2.3%). As seen in Table 6, all coding mononucleotide repeats were more frequently mutated in unstable (as judged by the Bethesda consensus panel) tumors than stable tumors; these differences were all statistically significant (P < 0.001, chi-square test). At least one coding mononucleotide repeat mutation was seen in 85.7% (48 of 56) of unstable tumors but in only 1.0% (4 of 392) of stable tumors; this difference was also statistically significant (P< 0.001, chi-square test).Table 6Type and Frequency of Coding Mononucleotide Repeat InstabilityCoding mononucleotideChanges in repeat lengthOverall mutation frequencyMutations in unstable tumors*Unstable and stable as defined by the Bethesda consensus panel.Mutations in stable tumors*Unstable and stable as defined by the Bethesda consensus panel.P value†All P values based on chi-square test comparing the percentage of stable tumors with the respective mononucleotide repeat mutation versus the percentage of unstable tumors with that mutation.TGFβRII+1,−1, −210.1% (47/466)74.5% (41/55)0.3% (1/383)< .001BAX+1, −16.1% (23/375)39.6% (19/48)0.3% (1/309)< .001hMSH3+1,−1,−25.2% (21/401)39.6% (19/48)0.0% (0/329)< .001hMSH6+1,−12.7% (13/473)16.4% (9/55)0.5% (2/390)< .001IGFIIR+1, −12.3% (9/396)19.1% (9/47)0.0% (0/327)< .001* Unstable and stable as defined by the Bethesda consensus panel.† All P values based on chi-square test comparing the percentage of stable tumors with the respective mononucleotide repeat mutation versus the percentage of unstable tumors with that mutation. Open table in a new tab Table 7 shows a comparison of the panel of 10 tetranucleotide repeats with the other measures of instability. Microsatellite instability as determined by the 10 tetranucleotide repeats was significantly related to microsatellite instability as determined by the consensus panel, BAT-26, TGFβRII, or instability in any coding mononucleotide repeat (P < 0.001, chi-square test). Table 8 shows a comparison of the consensus panel with BAT-26 by itself. There are very few tumors in which either BAT-26 or the consensus panel alone is unstable, and there is a significant relationship between these two measures of microsatellite instability (P < 0.001, chi-square test).Table 7Comparison of Panel of 10 Tetranucleotide Repeats with other Measure of InstabilityPanel of 10 tetranucleotide repeats*P values are based on chi-square tests comparing microsatellite instability as determined by the panel of 10 tetranucleotide repeats with microsatellite instability determined by the other measures of instability.StableUnstableP valueConsensus panelStable3692Unstable551< 0.001BAT-26Stable3839Unstable449< 0.001TGFβRIIStable38216Unstable344< 0.001Any coding mononucleotideStable38413Unstable849< 0.001* P values are based on chi-square tests comparing microsatellite instability as determined by the panel of 10 tetranucleotide repeats with microsatellite instability determined by the other measures of instability. Open table in a new tab Table 8Comparison of BAT-26 (by Itself) with the Consensus PanelBAT-26Consensus panelStableUnstableP value*P value based on a chi-square test comparing microsatellite instability as determined by BAT-26 by itself versus instability determined by the consensus panel.Stable3851Unstable551<0.001* P value based on a chi-square test comparing microsatellite instability as determined by BAT-26 by itself versus instability determined by the consensus panel. Open table in a new tab This study shows highly statistically significant inverse relationships between microsatellite instability and K-ras gene mutations and p53 overexpression in colon cancers. K-ras mutations were identified in 33.2% of tumors. This is consistent with previous studies that, with rare exceptions,18Kern SE Fearon ER Tersmette KWF Enterline JP Leppert M Nakamura Y White R Vogelstein B Hamilton SR Allelic loss in colorectal carcinoma.JAMA. 1989; 261: 3099-3103Crossref PubMed Scopus (386) Google Scholar have identified K-ras mutations in ∼30 to 40% of colon cancers.19Andreyev HJN Norman AR Cunningham D Oates JR Clarke PA Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study.J Natl Cancer Inst. 1998; 90: 675-684Crossref PubMed Scopus (655) Google Scholar, 20Laurent-Puig P Olschwang S Delattre O Remvikos Y Asselain B Melot T Validire P Muleris M Girodet J Salmon RJ Thomas G Survival and acquired genetic alterations in colorectal cancer.Gastroenterology. 1992; 102: 1136-1141PubMed Google Scholar, 21Finkelstein SD Sayegh R Bakker A Swalsky P Determination of tumor aggressiveness in co" @default.
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• W1965219770 title "Inverse Relationship between Microsatellite Instability and K-ras and p53 Gene Alterations in Colon Cancer" @default.
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