Analysis of genetic alterations, classified according to their DNA ploidy pattern, in the progression of colorectal adenomas and early colorectal carcinomas

Sugai, Tamostu; Takahashi, Hiroshi; Habano, Wataru; Nakamura, Shinichi; Sato, Kimihiko; Orii, Seishi; Suzuki, Kazuyuki

doi:10.1002/path.1340

Cited by 38 publications

(39 citation statements)

References 32 publications

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“…We found that the frequencies of aneuploidization within serrated adenomas are similar to the results from conventional classical adenomas, 28 as detected with a highly sensitive crypt isolation technique and cytometric analysis. However, the serrated adenomas exclusively showed near-diploid DNA indices rather than the high aneuploid indices reported in traditional tubular or villous adenomas.…”

Section: Discussionsupporting

confidence: 72%

Progressive methylation during the serrated neoplasia pathway of the colorectum

et al. 2005

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Serrated adenoma is a recently described entity characterized by having combined architectural features of hyperplastic polyps and classical adenoma. To understand the role of gene regulation in the progression of the serrated neoplasia pathway, we examined the methylation profiles of the promoter regions of 19 genes, DNA ploidy, and mutator phenotype status. In all, 40 sporadic, classical serrated adenomas were pathologically reviewed and divided into four pathologic groups according to their histologic grades. Methylation-specific PCR was performed using primers for p16, hMLH1, RASSF1A, APC, HIC-1, DAPK, MGMT, SLC5A8, RB1, HCadherin, E-Cadherin, TIMP3, PTEN, THBS1, LKB1, p14, p15, FHIT, and VHL. Dual flow-cytometric analyses using cytokeratin and DAPI and MSI studies using BAT26 were also performed. Methylation was observed in 2.5-82.5% (mean 33.9%) of the CpG islands in the promoter regions of 16 genes. The tumors with higher histologic grades, including carcinomas, showed more extensive methylation compared to those with lower grades, and serrated adenomas in the right colon showed more frequent methylation than those in the left (Po0.05). Tumor-specific promoter methylation of SLC5A8 was observed in 33 (82.5%) of the serrated adenomas. Aneuploidization with near-diploid DNA indices was detected in four out of 28 cases examined (14.3%); two were low-grade serrated adenomas and two were carcinomas in the left colon. The high mutator phenotype was not observed in any of the cases examined. Our results indicate that: (1) aberrant, widespread methylation of CpG islands increases with the histological progression of serrated adenomas; (2) methylation of SLC5A8 is an early event; and (3) additional methylation of the p16, p14, MGMT, TIMP3, and FHIT genes are important tumorigenic steps in the serrated neoplasia pathway.

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Section: Discussionsupporting

confidence: 72%

Progressive methylation during the serrated neoplasia pathway of the colorectum

et al. 2005

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“…If at least one genotype in the single tumor gland sample was seen in these corresponding pooled gland samples, the case was interpreted as consistent between the pooled gland and single tumor gland samples. However, in the other 4 cases, the genotypes of pooled gland samples were not consistent with those of the single gland samples (cases 5,20,26,29), as shown in Figures 4 -6. In addition, in another 11 cases (cases 2, 8, 11, 13, 14, 16, 17, 18, 19, 23 and 24), the predominant microsatellite alteration patterns (predominant genotype) in single tumor gland samples were different from those of the corresponding pooled gland samples.…”

Section: Resultsmentioning

confidence: 84%

“…BAT-25 and -26 are very sensitive markers of colon tumor MSI. 25,26 PCR analysis was performed using a DNA autosequencer (Applied Biosystems 373A sequencer; Applied Biosystems, Foster City, CA) as described elsewhere. 25 Normal alleles were typically represented by a major peak accompanied by a few minor peaks.…”

Section: Analysis Of Msimentioning

confidence: 99%

Analysis of allelic imbalances at multiple cancer‐related chromosomal loci and microsatellite instability within the same tumor using a single tumor gland from colorectal carcinomas

Sugai

Habano

Jiao

et al. 2004

Intl Journal of Cancer

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Genetic changes related to colorectal carcinomas are accumulated in individual tumor glands during disease progression. Microsatellite allelic analysis of individual tumor glands from 30 colorectal carcinomas using a polymerase chain reaction (PCR) assay coupled with crypt isolation was used to detect intratumoral genetic heterogeneity, the sequence of allelic imbalances (AIs) and the microsatellite instability status of single tumor glands during neoplastic progression. In addition, the CpG islands methylated phenotype (CIMP) status was examined using a methylation-specific PCR method. The specimens were divided into 2 groups: a pooled gland sample, which was composed of more than 50 tumor glands, and a single tumor gland sample. The latter consisted of 10 single tumor glands, which were obtained from the same tumor separately. Most colorectal carcinomas (27 of 30 tumors) examined were heterogeneous for at least one genetic alteration, with from 2 to 7 genotypically different subclones detected per tumor. In 12 of the 27 heterogeneous tumors, it was possible to define the order of genetic alterations during the tumor progression. By analyzing multiple single tumor glands within the same tumor, we found that various subclonal expansions were seen within the same tumors.

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“…The overall MSI frequency in adenomas has been reported to be much lower than in carcinomas. About 1-2% of sporadic and up to 67% of the HNPCC associated colorectal adenomas develop the MSI phenotype (Grady et al, 1998;Loukola et al, 1999;Iino et al, 2000;Sugai et al, 2003). The occurrence of MSI was described to be present at early stages and to persist during colorectal tumor progression by some authors (Shibata et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Microsatellite instability of selective target genes in HNPCC-associated colon adenomas

et al. 2005

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Microsatellite instability (MSI) occurs in most hereditary nonpolyposis colorectal cancers (HNPCC) and less frequently in sporadic tumors as the result of DNA mismatch repair (MMR) deficiency. Instability at coding microsatellites (cMS) in specific target genes causes frameshift mutations and functional inactivation of affected proteins, thereby providing a selective growth advantage to MMR deficient cells. At present, little is known about Selective Target Gene frameshift mutations in preneoplastic lesions. In this study, we examined 30 HNPCC-associated MSI-H colorectal adenomas of different grades of dysplasia for frameshift mutations in 26 cMS-bearing genes, which, according to our previous model, represent Selective Target genes of MSI. About 30% (8/26) of these genes showed a high mutation frequency (X50%) in colorectal adenomas, similar to the frequencies reported for colorectal carcinomas. Mutations in one gene (PTHL3) occurred significantly less frequently in MSI adenomas compared to published mutation rates in MSI carcinomas (36.0 vs 85.7%, P ¼ 0.023). Biallelic inactivation was observed in nine genes, thus emphasizing the functional impact of cMS instability on MSI tumorigenesis. Some genes showed a high frequency of frameshift mutations already at early stages of MSI colorectal tumorigenesis that increased with grade of dysplasia and transition to carcinoma. These include known Target Genes like BAX and TGFBR2, as well as three novel candidates, MACS, NDUFC2, and TAF1B. Overall, we have identified genes of potential relevance for the initiation and progression of MSI tumorigenesis, thus representing promising candidates for novel diagnostic and therapeutic approaches directed towards MMRdeficient tumors.

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Analysis of genetic alterations, classified according to their DNA ploidy pattern, in the progression of colorectal adenomas and early colorectal carcinomas

Cited by 38 publications

References 32 publications

Progressive methylation during the serrated neoplasia pathway of the colorectum

Progressive methylation during the serrated neoplasia pathway of the colorectum

Analysis of allelic imbalances at multiple cancer‐related chromosomal loci and microsatellite instability within the same tumor using a single tumor gland from colorectal carcinomas

Microsatellite instability of selective target genes in HNPCC-associated colon adenomas

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