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• W1541009912 abstract "To clarify distinct genetic profiles of colorectal cancers based on tumor location (left- and right-sided), we evaluated the status of loss of heterozygosity (LOH), CpG islands methylation phenotype (CIMP), microsatellite instability (MSI), and mutations of p53, Ki-ras, and APC genes in 119 colorectal cancers. Statuses of LOH (at 5q, 8p, 17p, 18q, and 22q), MSI, and CIMP (MINTI, MINT2, MINT31, MLH-1, MGMT, p14, pl6, and RASSF1A) were determined using microsatellite polymerase chain reaction and methylation-specific polymerase chain reaction coupled with a crypt isolation method, respectively. In addition, mutations of p53, Ki-ras, and APC genes were also examined. LOH, MSI, and CIMP status allowed us to classify samples into two groups: low or negative and high or positive. Whereas the frequency of p53 mutations in the LOH-high status was significantly higher in left-sided cancers than in right-sided cancers, CIMP-high in the LOH-high status and MSI-positive status were more frequently found in right-sided cancers compared with left-sided cancers. Finally, location-specific methylated loci were seen in colorectal cancers: type I (dominant in right-sided cancer) and type II (common in both segments of cancer). Our data confirm that distinct molecular pathways to colorectal cancer dominate in the left and right sides of the bowel. To clarify distinct genetic profiles of colorectal cancers based on tumor location (left- and right-sided), we evaluated the status of loss of heterozygosity (LOH), CpG islands methylation phenotype (CIMP), microsatellite instability (MSI), and mutations of p53, Ki-ras, and APC genes in 119 colorectal cancers. Statuses of LOH (at 5q, 8p, 17p, 18q, and 22q), MSI, and CIMP (MINTI, MINT2, MINT31, MLH-1, MGMT, p14, pl6, and RASSF1A) were determined using microsatellite polymerase chain reaction and methylation-specific polymerase chain reaction coupled with a crypt isolation method, respectively. In addition, mutations of p53, Ki-ras, and APC genes were also examined. LOH, MSI, and CIMP status allowed us to classify samples into two groups: low or negative and high or positive. Whereas the frequency of p53 mutations in the LOH-high status was significantly higher in left-sided cancers than in right-sided cancers, CIMP-high in the LOH-high status and MSI-positive status were more frequently found in right-sided cancers compared with left-sided cancers. Finally, location-specific methylated loci were seen in colorectal cancers: type I (dominant in right-sided cancer) and type II (common in both segments of cancer). Our data confirm that distinct molecular pathways to colorectal cancer dominate in the left and right sides of the bowel. Recent studies have described two forms of genetic instability that are associated with colorectal cancer: chromosomal instability (CIN) and microsatellite instability (MSI).1Lengauer C Kinzler KW Vogelstein B Genetic instabilities in human cancers.Nature. 1998; 396: 643-649Crossref PubMed Scopus (3366) Google Scholar2Lengauer C Kinzler KW Vogelstein B Genetic instability in colorectal cancers.Nature. 1997; 386: 623-627Crossref PubMed Scopus (1632) Google Scholar CIN is represented in most cancers and is characterized by frequent Ki-ras and p53 gene mutations and loss of heterozygosity (LOH) in a number of cancer- related genes (LOH type).1Lengauer C Kinzler KW Vogelstein B Genetic instabilities in human cancers.Nature. 1998; 396: 643-649Crossref PubMed Scopus (3366) Google Scholar, 2Lengauer C Kinzler KW Vogelstein B Genetic instability in colorectal cancers.Nature. 1997; 386: 623-627Crossref PubMed Scopus (1632) Google Scholar, 3Sugai T Habano W Nakamura S Sato H Uesugi N Takahashi H Jiao Y-F Yoshida T Itoh C Genetic alterations in DNA diploid, aneuploid and multiploid colorectal carcinomas identified by the crypt isolation technique.Int J Cancer. 2000; 88: 614-619Crossref PubMed Scopus (33) Google Scholar, 4Sugai T Habano W Uesugi N Jiao Y-F Nakamura S Yoshida T Higuchi T Frequent allelic imbalance at the ATM locus in DNA multiploid colorectal carcinomas.Oncogene. 2001; 20: 6095-6101Crossref PubMed Scopus (22) Google Scholar CIN represents chromosomal level, but not genetic level, instability. Therefore, CIN is not identical to LOH type. MSI has a distinct genetic profile that differs from CIN in that mutations of the Ki-ras and p53 genes, as well as LOH, occur only infrequently.1Lengauer C Kinzler KW Vogelstein B Genetic instabilities in human cancers.Nature. 1998; 396: 643-649Crossref PubMed Scopus (3366) Google Scholar, 2Lengauer C Kinzler KW Vogelstein B Genetic instability in colorectal cancers.Nature. 1997; 386: 623-627Crossref PubMed Scopus (1632) Google Scholar, 3Sugai T Habano W Nakamura S Sato H Uesugi N Takahashi H Jiao Y-F Yoshida T Itoh C Genetic alterations in DNA diploid, aneuploid and multiploid colorectal carcinomas identified by the crypt isolation technique.Int J Cancer. 2000; 88: 614-619Crossref PubMed Scopus (33) Google Scholar, 4Sugai T Habano W Uesugi N Jiao Y-F Nakamura S Yoshida T Higuchi T Frequent allelic imbalance at the ATM locus in DNA multiploid colorectal carcinomas.Oncogene. 2001; 20: 6095-6101Crossref PubMed Scopus (22) Google Scholar In a previous study, MSI was found in 10% of sporadic colorectal cancers.5Jass JR Whitehall VL Young J Leggett BA Emerging concepts in colorectal neoplasia.Gastroenterology. 2002; 123: 862-876Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar These findings suggest that the two genetic types are independent of each other and that most colorectal cancers can be classified as either MSI or CIN.6Iacopetta B Are there two sides to colorectal cancer?.Int J Cancer. 2002; 101: 403-408Crossref PubMed Scopus (626) Google Scholar On the other hand, microsatellite stable (MSS) is used to classify colorectal tumors that do not show MSI.7Hawkins N Norrie M Cheong K Mokany E Ku SL Meagher A O'Connor T Ward R CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability.Gastroenterology. 2002; 122: 1376-1387Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar MSI and MSS are also independent classifications that can be used to separate colorectal cancers into two largely nonoverlapping groups.7Hawkins N Norrie M Cheong K Mokany E Ku SL Meagher A O'Connor T Ward R CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability.Gastroenterology. 2002; 122: 1376-1387Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar However, MSS is not the same as CIN. MSS includes two types of genetic alterations: one with a low frequency of LOH (LOH-low) and one with a high frequency of LOH (LOH high). CIN indicates a high frequency of LOH (LOH-high type).8Sugai T Takahashi H Habano W Nakamura S Sato K Orii S Suzuki K Analysis of genetic alterations, classified according to their DNA ploidy pattern, in the progression of colorectal adenomas and early colorectal carcinomas.J Pathol. 2003; 200: 168-176Crossref PubMed Scopus (36) Google Scholar Therefore, MSS should be further broken down to indicate the two genetic types of status, LOH-high and LOH-low, when genetic profiles are analyzed in human tumors.Another recently established molecular alteration that is commonly present in colorectal cancers is the CpG island methylator phenotype (CIMP).9Toyota M Ahuja N Ohe-Toyota M Herman JG Baylin SB Issa JP CpG island methylator phenotype in colorectal cancer.Proc Natl Acad Sci USA. 1999; 96: 8681-8686Crossref PubMed Scopus (2108) Google Scholar This phenotype has been identified at certain sites in the genome that are preferentially methylated in tumors.9Toyota M Ahuja N Ohe-Toyota M Herman JG Baylin SB Issa JP CpG island methylator phenotype in colorectal cancer.Proc Natl Acad Sci USA. 1999; 96: 8681-8686Crossref PubMed Scopus (2108) Google Scholar CIMP is recognized as an important mechanism for gene inactivation, as an alternative to gene mutation or allelic deletion, in tumorigenesis.9Toyota M Ahuja N Ohe-Toyota M Herman JG Baylin SB Issa JP CpG island methylator phenotype in colorectal cancer.Proc Natl Acad Sci USA. 1999; 96: 8681-8686Crossref PubMed Scopus (2108) Google Scholar Previous studies have clearly shown that CIMP is frequently found in MSI cancers, although it is not restricted to this group.7Hawkins N Norrie M Cheong K Mokany E Ku SL Meagher A O'Connor T Ward R CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability.Gastroenterology. 2002; 122: 1376-1387Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar9Toyota M Ahuja N Ohe-Toyota M Herman JG Baylin SB Issa JP CpG island methylator phenotype in colorectal cancer.Proc Natl Acad Sci USA. 1999; 96: 8681-8686Crossref PubMed Scopus (2108) Google Scholar However, the relationship of CIMP to high-LOH-type and low-LOH-type tumors is still not fully understood.It has been suggested that left- and right-sided colorectal cancers differ in their associated genetic alterations in neoplastic transformation based on studies in Western countries, especially Australia and Europe.6Iacopetta B Are there two sides to colorectal cancer?.Int J Cancer. 2002; 101: 403-408Crossref PubMed Scopus (626) Google Scholar10Lindblom A Different mechanisms in the tumorigenesis of proximal and distal colon cancers.Curr Opin Oncol. 2001; 13: 63-69Crossref PubMed Scopus (186) Google Scholar For example, MSI-positive cancers are preferentially found in right-sided colon cancer and in older women.5Jass JR Whitehall VL Young J Leggett BA Emerging concepts in colorectal neoplasia.Gastroenterology. 2002; 123: 862-876Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar6Iacopetta B Are there two sides to colorectal cancer?.Int J Cancer. 2002; 101: 403-408Crossref PubMed Scopus (626) Google Scholar Hawkins et al7Hawkins N Norrie M Cheong K Mokany E Ku SL Meagher A O'Connor T Ward R CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability.Gastroenterology. 2002; 122: 1376-1387Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar indicated a higher incidence of CIMP-positive tumors in right-sided colon cancer compared with left-sided colon cancers. On the other hand, CIN is said to characterize left-sided colorectal cancers.10Lindblom A Different mechanisms in the tumorigenesis of proximal and distal colon cancers.Curr Opin Oncol. 2001; 13: 63-69Crossref PubMed Scopus (186) Google Scholar These findings have provided further evidence for the existence of at least two mechanisms of colorectal cancer.6Iacopetta B Are there two sides to colorectal cancer?.Int J Cancer. 2002; 101: 403-408Crossref PubMed Scopus (626) Google Scholar One group (CIMP+/MSI+) occurs predominantly in the right-sided colon and the other (CIN) in the left-sided colon.6Iacopetta B Are there two sides to colorectal cancer?.Int J Cancer. 2002; 101: 403-408Crossref PubMed Scopus (626) Google Scholar10Lindblom A Different mechanisms in the tumorigenesis of proximal and distal colon cancers.Curr Opin Oncol. 2001; 13: 63-69Crossref PubMed Scopus (186) Google Scholar However, the underlying molecular features are likely to show considerable overlap between the two cancers.6Iacopetta B Are there two sides to colorectal cancer?.Int J Cancer. 2002; 101: 403-408Crossref PubMed Scopus (626) Google Scholar Therefore, it is important to study genetic colorectal carcinogenesis while taking into account whether the tumor is located in the left- or right-sided colon.In this study, we examined sporadic colorectal cancers in an attempt to determine their genetic profiles in terms of LOH status, MSI, CIMP, and tumor location. Mutations of p53, Ki-ras, and APC genes that are associated with LOH-high status (which occurs with almost the same frequency as CIN) were evaluated to clarify their relationships to the genetic profiles at the two sites.Materials and MethodsA total of 119 primary colorectal cancers and corresponding normal tissue specimens were obtained from patients at the Iwate Medical University School of Medicine. Pathological diagnosis and staging were performed according to a combination of a Japanese classification and the modified Dukes' classification.11Turnbull RB Kyle K Watson FR Spratt J Cancer of the colon; the influence of the no-touch isolation technique on survival rates.Ann Surg. 1967; 166: 420-427Crossref PubMed Scopus (761) Google Scholar12Japanese Society for Cancer of the Colon and Rectum Japanese Classification of Colorectal Carcinoma, First English Edition. Kanehara Co., Tokyo1997: 30-63Google Scholar Tumor locations were noted as left- or right-sided.DNA ExtractionCrypt isolation from the tumor and normal mucosa was performed in accordance with a previously reported method to obtain pure glands.13Arai T Kino I Morphometrical and cell kinetic studies of normal human colorectal mucosa: comparison between the proximal and the distal large intestine.Acta Pathol Jpn. 1989; 39: 725-730PubMed Google Scholar14Nakamura S Goto J Kitayama M Kino I Application of the cryptisolation technique to flow-cytometric analysis of DNA content in colorectal neoplasms.Gastroenterology. 1994; 106: 100-107PubMed Google Scholar The isolated gland was processed routinely to confirm its nature using paraffin-embedded histological sections. Contamination by other materials such as interstitial cells was not evident in the samples that were examined, as described in previous reports.15Sugai T Habano W Nakamura S Uesugi N Sasou S Itoh C A unique method for mutation analysis of tumor suppressor genes in colorectal carcinomas using a crypt isolation technique.Arch Pathol Lab Med. 2000; 124: 382-386PubMed Google Scholar16Sugai T Habano W Nakamura S Yoshida T Uesugi N Sasou S Itoh C Katoh R Use of crypt isolation to determine loss of heterozygosity of multiple tumor suppressor genes in colorectal carcinoma.Pathol Res Pract. 2000; 196: 145-150Crossref PubMed Scopus (15) Google Scholar DNA from the tumor and from corresponding normal crypts was extracted by standard sodium dodecyl sulfate proteinase K treatment.Microsatellite AnalysisLOH studies were performed by polymerase chain reaction (PCR) amplification of 13 highly polymorphic microsatellite markers (D5S107, D5S346, D5S299, D5S82, D8S201, D8S513, D8S532, TP53, D18S487, D18S34, D22S274, D22S1140, and D22S1168) located at five chromosomal loci (5q, 17p, 18q, 8p, and 22q).17Sugai T Habano W Uesugi N Jiao YF Nakamura S Sato K Chiba T Ishii M Molecular validation of the modified Vienna classification of colorectal tumors.J Mol Diagn. 2002; 4: 191-200Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Microsatellite sequences were obtained from specific primers reported in the GDB Human Genome Database (http://gdbwww.gdb.org/gdb/). PCR amplification was performed in a 25-μl reaction volume, containing approximately 10 ng of genomic DNA, 1 μmol/L of each primer, 0.2 mmol/L deoxynucleotide triphosphate, 1× reaction buffer containing 1.5 mmol/L MgCl2, and 1.5 U of Taq polymerase (Boehringer Mannheim Co., Mannheim, Germany). Samples were processed for 25 to 30 cycles, with each cycle consisting of 30 seconds at 94°C, 1 minute at 55 to 58°C, and 2 minutes at 72°C, followed by a final 10-minute extension at 72°C. PCR products were loaded onto 6% polyacrylamide gels and run on an ABI PRISM 377 DNA Sequencer (Applied Biosystems, Foster City, CA). The data were collected automatically and analyzed by GeneScan 3.1 software (Applied Biosystems). LOH was determined by calculating the ratio of the peak areas of the constitutional alleles, as described previously.16Sugai T Habano W Nakamura S Yoshida T Uesugi N Sasou S Itoh C Katoh R Use of crypt isolation to determine loss of heterozygosity of multiple tumor suppressor genes in colorectal carcinoma.Pathol Res Pract. 2000; 196: 145-150Crossref PubMed Scopus (15) Google Scholar In this study, we defined LOH as more than a 50% difference in this ratio.Scoring of LOH StatusLOH status was scored according to following criteria. A tumor sample was considered to be LOH-high if two or more of the markers showed LOH. When one or none of the markers showed LOH, the tumor was designated as LOH-low.Analysis of MSIThe primers proposed by the National Cancer Institute Workshop on Microsatellite Instability (BAT25, BAT26, D5S346, D2S123, and D17S250) were used in this study.18Boland CR Thibodeau SN Hamilton SR Sidransky D Eshleman JR Burt RW Meltzer SJ Rodriguez-Bigas MA Fodde R Ranzani GN 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 Products were run on an ABI PRISM 377 fluorescent DNA sequencer. PCR conditions are described elsewhere.16Sugai T Habano W Nakamura S Yoshida T Uesugi N Sasou S Itoh C Katoh R Use of crypt isolation to determine loss of heterozygosity of multiple tumor suppressor genes in colorectal carcinoma.Pathol Res Pract. 2000; 196: 145-150Crossref PubMed Scopus (15) Google Scholar MSI was defined as the presence of an additional peak. A tumor sample was considered to be MSI-high (MSI-H) when two or more of the markers demonstrated instability and MSI-low when only one marker was unstable. However, tumors showing one alteration using the above criteria and categorized as MSI-low were considered MSI-negative or MSS in this analysis.Mutation Analysis of the p53, APC, and Ki-ras GenesSequencing of PCR-amplified products was used to detect mutations of exons 5 to 8 of the p53 gene, exon 1 of the Ki-ras gene, and the mutation cluster region of the APC gene in patients' normal mucosa and tumor DNA samples. PCR conditions and sequencing of mutations were performed as described previously.15Sugai T Habano W Nakamura S Uesugi N Sasou S Itoh C A unique method for mutation analysis of tumor suppressor genes in colorectal carcinomas using a crypt isolation technique.Arch Pathol Lab Med. 2000; 124: 382-386PubMed Google Scholar17Sugai T Habano W Uesugi N Jiao YF Nakamura S Sato K Chiba T Ishii M Molecular validation of the modified Vienna classification of colorectal tumors.J Mol Diagn. 2002; 4: 191-200Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Direct sequencing was performed using fluorescently labeled dideoxynucleotide triphosphates by automated DNA sequence analysis (373A sequencer; Applied Biosystems).CIMP of CarcinomasCIMP status was determined for carcinomas, which were evaluated at eight loci (MINT-1, MINT-2, MINT-31, p14, p16, MGMT, MLH-1, and RASSF-1A) after bisufite treatment. These loci are frequently methylated in colorectal carcinomas.7Hawkins N Norrie M Cheong K Mokany E Ku SL Meagher A O'Connor T Ward R CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability.Gastroenterology. 2002; 122: 1376-1387Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar9Toyota M Ahuja N Ohe-Toyota M Herman JG Baylin SB Issa JP CpG island methylator phenotype in colorectal cancer.Proc Natl Acad Sci USA. 1999; 96: 8681-8686Crossref PubMed Scopus (2108) Google Scholar Methylation-specific PCR was performed using specific primers for either the methylated or the unmethylated examined primers. Primers and conditions have been described previously.19Chan AO Broaddus RR Houlihan PS Issa JP Hamilton SR Rashid A CpG island methylation in aberrant crypt foci of the colorectum.Am J Pathol. 2002; 160: 1823-1830Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar20Rashid A Shen L Morris JS Issa JP Hamilton SR CpG island methylation in colorectal adenomas.Am J Pathol. 2001; 159: 1129-1135Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar In vitro methylated DNA was used as a positive control for methylation, and water was used as a negative control. The results of methylation-specific PCR were scored when there was a clearly visible band on the gel after PCR with methylated and unmethylated primers. Electrophoresis results were interpreted by two independent investigators. When a discrepancy between the two was found, a third opinion was sought. Carcinomas were classified as CIMP-negative/low if less than three loci were methylated and CIMP-high if more than two loci were methylated. Alternatively, CIMP-negative/low and -high were classified into CIMP-low and -high, respectively.Statistical AnalysisThe data were analyzed using the χ2Lengauer C Kinzler KW Vogelstein B Genetic instability in colorectal cancers.Nature. 1997; 386: 623-627Crossref PubMed Scopus (1632) Google Scholar test with the aid of StatView-IV software (Abacus Concepts, Berkeley, CA). Samples were determined to be significantly different at P ≥ 0.05.ResultsIn the present study, differences in clinicopathological findings and genetic alterations in left-sided and right-sided colorectal carcinomas were analyzed. Molecular profiles were categorized into four types: LOH-high, low-LOH, MSI, and CIMP. Clinicopathological findings for left- and right-sided colorectal cancers are listed in Table 1.Table 1Clinicopathological Findings between Left- and Right-Sided Colorectal CancersLeft-sided (%)Right-sided (%)Total84 (70.6)35 (29.4)Sex (male/female)56/2820/15Age (mean)46–93 (64.6)22–94 (62.8)Histological type WDA18 (21.4)6 (17.1) MDA65 (77.4)22 (62.9) PDA1 (1.2)2 (5.7) MC05 (14.3)Stage A14 (16.7)4 (11.4) B33 (39.3)16 (45.7) C22 (26.2)10 (28.6) D15 (17.9)5 (14.3)WDA, well-differentiated adenocarcinoma; MDA, moderately differentiated adenocarcinoma; PDA, poorly differentiated adenocarcinoma; MC, mucinous carcinoma. Open table in a new tab Molecular Alterations in Left- and Right-Sided CancersAlthough the frequency of LOH-high in left-sided colorectal cancer (72 of 84 cases, 85.7%) was higher than that of right-sided cancer (24 of 35 cases, 68.6%), this difference was not statistically significant. There was a significant difference in the frequencies of p53 mutations found in left-sided (49 of 84, 57.6%) and right-sided (9 of 35, 25.7%) cancers (P < 0.05). However, no differences were found in the frequencies of Ki-ras and APC mutations. The CIMP-high status was found in 38 of 119 colorectal cancers that were examined (31.9%). The CIMP-high status was more common in right-sided cancers (22 of 35, 62.9%) compared with left-sided cancers (21 of 84, 25%) (P < 0.01).Mutations ofp53, Ki-ras, andAPC Genes and CpG Islands Methylation Phenotype in LOH High StatusThe frequency of p53 mutations in LOH-high status cancers was significantly higher for left-side cancers than for right-side cancers (Figure 1a, P < 0.01). In contrast, no significant differences in the frequencies of Ki-ras and APC mutations in LOH-high status cancers were observed for left- versus right-sided cancers (Table 2). On the other hand, the CIMP-high status in LOH-high cancers was statistically higher in right- sided (12 of 24, 50%) than in left-sided colon cancers (14 of 72, 19.4%) (Figure 1a, P < 0.01). In addition, there were no differences in the frequency of LOH at each chromosomal locus between left-sided and right-sided cancers, as shown in Table 2.Table 2Frequencies of Allelic Imbalances at Cancer-Related Chromosomal Loci in Left- and Right-Sided Colorectal CancersTotal (left/right)Left-sided (%)Right-sided (%)17p84/3554/77 (70.1)15/25 (60)5q84/3551/83 (61.4)16/30 (53.3)18q84/3569/79 (87.3)24/28 (85.7)8p84/3551/81 (60.7)16/30 (53.3)22q84/3542/81 (51.9)15/29 (51.7) Open table in a new tab Mutations of p53, Ki-ras, and APC Genes and CpG Islands Methylation Phenotype in LOH-Low StatusThe frequency of LOH-low status was 18 of 119 (15.1%) in our study. Although no p53 mutations were detected in right-sided colorectal cancers with LOH-low status (0 of 7), no significant difference was found compared with the frequency of p53 mutations in the left-sided cancers (3 of 11, 27.3%). Ki-ras and APC gene mutations in the LOH-low status were found more frequently in right-sided colorectal cancers (5 of 7, 71.4%; and 3 of 7, 42.9%, respectively) compared with left-sided cancers (4 of 11, 36.4%; and 1 of 11, 9.1%, respectively), but again these differences did not reach statistical significance. The frequency of CIMP status in the LOH-low cancers was high for left-sided cancers (6 of 11, 54.5%) as well as for right-sided cancers (6 of 7, 85.7%). These findings are shown in Figure 1b.Mutations of p53, Ki-ras, and APC Genes and LOH-High Status in CpG Islands Methylation Phenotype Excluding MSI TumorsThe frequencies of CIMP-high status were significantly higher in right-sided cancers (20 of 84, 24.7%) than in left-sided cancers (18 of 35, 51.4%) (P < 0.01). Although p53 gene mutations in the CIMP-high status cancers were found more frequently in left-sided (10 of 20, 50%)compared with right-sided colorectal cancers (3 of 18, 16.7%), the difference did not reach a statistically significant level, as shown in Figure 1c (P = 0.068). On the other hand, although the frequency of Ki-ras mutations was relatively higher in right-sided cancers (12 of 18, 66.7%) than in left-sided cancers (8 of 20, 40%), no significant difference between the two sites was found. There was also no significant difference in the frequency of APC gene mutations in the CIMP-high status cancers between the two locations (left-sided, 8 of 20, 40%; right-sided, 7 of 18, 38.9%).The overall frequencies of promoter hypermethylation in right-side cancers were higher, with the exception of MINT1, MGMT, and RASSF-1A. In particular, the frequencies of MINT-2, MLH-1, p14, and p16 hypermethylations in right-sided cancers were significantly higher than for left-sided cancers (P < 0.01, P < 0.05, P < 0.01, and P < 0.01, respectively). The differences for MINT31 did not reach a significant level (P = 0.052). The data are shown in Figure 2. In the present study, among the eight CpG islands occurring within known promoter regions in colorectal cancers, the hypermethylation patterns fell into two types. One type was found to be frequently methylated in right-sided colon cancers (type I). The other type was methylated in both types of colorectal cancers (type II). Whereas MINT-2, MLH-1, p14, and p16 methylations were classified as type I, MINT-1, MGMT, and RASSF-1A methylations were grouped into type II.Figure 2Frequencies of methylation of MINTI, MINT2, MINT31, MLH-1, MGMT, p14, p16, and RASSF1A promoters for left- and right-sided cancers.View Large Image Figure ViewerDownload Hi-res image Download (PPT)p53, Ki-ras, and APC Gene Mutations, CIMP, and LOH Status in MSI-Positive StatusA significant difference in the frequency of MSI between left- and right-sided colorectal cancers was found (1 of 84 cases vs. 4 of 35 cases, P < 0.05). In the present study, all MSI-positive cases that were observed had a CIMP-high status. Mutations of Ki-ras and APC genes were found in one left-sided cancer. In addition, a p53 mutation was detected in one right-sided cancer. The other three MSI-positive tumors showed no mutations. LOH-status could not be confirmed because of the presence of MSI-positive at individual chromosomal loci. Finally, representative examples of molecular analysis of left- and right-sided cancers are shown in Figures 3 and 4.Figure 3A representative example of molecular alterations in left-sided cancer. b, d, f, h, and i: Multiple LOHs were seen (arrowhead). Although methylation at MINT 1 was found, MINT2, MINT31, p16, p14 (not shown), and RASSF1A promoters were not methylated. Furthermore, mutations of p53, Ki-ras, and APC genes were found (arrowhead). k: A GGC to GAC transition in Ki-ras codon 12 was found, resulting in a Gly to Asp substitution (sequence by reverse primer). l: A CTG to CAG transversion in exon 5 of p53 gene was observed. m: Finally, a CGA to TGA transition in codon 805 of APC gene was found, resulting in a stop codon. The three detectable mutated nucleotides in tumor DNA are indicated by arrows in the photograph (k, l, and m).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 4A representative example of molecular alterations in right-sided cancer. b, d, and f: Multiple LOHs were seen (arrowhead). Arrowheads indicate LOH. k, l, m, o, p, q, and r: In addition, multiple promoter regions were methylated (arrowhead). However, the p53 gene was not mutated (not shown).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Tumor Mutation Spectra of p53, Ki-ras, and APC Mutations in Left- and Right-Sided CancersAlthough the proposed sequence of genetic alterations leading to the development of colorectal cancer involves mutations in all three genes (p53, Ki-ras, and APC), a significant percentage of the tumors contained mutations in only one of these genes: p53 (22 of 119, 18.5%), Ki-ras (18 of 119, 15.1%), and APC (11 of 119, 9.3%). In our study, we characterized tumor mutation spectra in left- and right-sided cancers. The detailed results are shown in Table 3. Only 8 (9.5%) and 2 (5.7%) tumors of left- and right-sided cancers, respectively, contained mutations in all 3 genes, whereas 12 tumors (14.3%) of left-sided and 6 (8.6%) of right-sided cancers conta" @default.
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• W1541009912 date "2006-05-01" @default.
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• W1541009912 title "Analysis of Molecular Alterations in Left- and Right-Sided Colorectal Carcinomas Reveals Distinct Pathways of Carcinogenesis" @default.
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