Microsatellite instability in colorectal adenomas

Samowitz, WS; Ml, Slattery

doi:10.1016/s0016-5085(97)70032-5

Cited by 55 publications

(21 citation statements)

References 3 publications

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“…The inverse relationship between p16 methylation and p53 mutations was preserved in adenomas. Finally, methylation of hMLH1 was detected in 0 of 64 colorectal adenomas (data not shown), which is consistent with previous results showing a low frequency of MSI in this preneoplastic lesion (28,29).…”

Section: Epigenetic and Genetic Interactions In Colorectal Adenomassupporting

confidence: 92%

Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype

Toyota

Ohe-Toyota

Ahuja

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

418

311

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Colorectal cancers (CRCs) are characterized by multiple genetic (mutations) and epigenetic (CpG island methylation) alterations, but it is not known whether these evolve independently through stochastic processes. We have recently described a novel pathway termed CpG island methylator phenotype (CIMP) in CRC, which is characterized by the simultaneous methylation of multiple CpG islands, including several known genes, such as p16, hMLH1, and THBS1. We have now studied mutations in K-RAS, p53, DPC4, and TGF␤RII in a panel of colorectal tumors with or without CIMP. We find that CIMP defines two groups of tumors with significantly different genetic lesions: frequent K-RAS mutations were found in CIMP ؉ CRCs (28͞41, 68%) compared with CIMP ؊ cases (14͞47, 30%, P ‫؍‬ 0.0005). By contrast, p53 mutations were found in 24% (10͞41) of CIMP ؉ CRCs vs. 60% (30͞46) of CIMP ؊ cases (P ‫؍‬ 0.002). Both of these differences were independent of microsatellite instability. These interactions between CIMP, K-RAS mutations, and p53 mutations were preserved in colorectal adenomas, suggesting that they occur early in carcinogenesis. The distinct combinations of epigenetic and genetic alterations in each group suggest that activation of oncogenes and inactivation of tumor suppressor genes is related to the underlying mechanism of generating molecular diversity in cancer, rather than simply accumulate stochastically during cancer development.

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Section: Epigenetic and Genetic Interactions In Colorectal Adenomassupporting

confidence: 92%

Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype

Toyota

Ohe-Toyota

Ahuja

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

418

311

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“…On the other hand, hypermethylation of MGMT and p16 are present at relatively high frequency even in small adenomas (17,26,28) and in aberrant crypt foci that are the earliest precursor lesion (29), whereas hypermethylation of hMLH1 is not frequent in these early lesions (48,70). One recent hypothesis linking epigenetics and genetic alterations is that colon cancer cells with APC gene inactivation are protected from methylationinduced cytotoxicity (71) so that lack of APC function due to epigenetic silencing may prevent cell death after exposure to DNA-methylating agents.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic-Genetic Interactions in theAPC/WNT, RAS/RAF, andP53Pathways in Colorectal Carcinoma

Suehiro

Wong

Chirieac³

et al. 2008

Clinical Cancer Research

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Purpose: Early events in colorectal tumorigenesis include mutation of the adenomatous polyposis coli (APC) gene and epigenetic hypermethylation with transcriptional silencing of the O 6 -methylguanine DNA methyltransferase (MGMT), human mut L homologue 1 (hMLH1), and P16/CDKN2A genes. Epigenetic alterations affect genetic events: Loss of MGMT via hypermethylation reportedly predisposes to guanine-to-adenine or cytosine-to-thymine (G:C!A:T) transition mutations in KRAS and P53, and silencing of hMLH1 leads to high levels of microsatellite instability (MSI-H)/mutator phenotype, suggesting that epigenetic-genetic subtypes exist. Experimental Design: We evaluated the relationships of aberrant methylation of APC, MGMT, hMLH1, P16, N33, and five MINTs to mutations in APC, KRAS, BRAF, and P53 in 208 colorectal carcinomas. Results: We found that APC hypermethylation was age related (P = 0.04), in contrast to the other genes, and did not cluster with CpG island methylator phenotype (CIMP) markers. Hypermethylation of APC concurrently with either MGMT or hMLH1 was strongly associated with occurrence of G-to-A transitions in APC [odds ratio (OR), 26.8; P < 0.0002 from multivariable logic regression model], but C-to-T transitions had no associations. There was no relationship of hypermethylation of any gene, including MGMT, with G-to-A or C-to-T transitions in KRAS or P53, although APC hypermethylation was associated with P53 mutation (P < 0.0002). CIMP with MSI-H due to hMLH1 hypermethylation, or CIMP with loss of MGMT expression in nonM SI-H tumors, was associated with BRAF mutation (OR, 4.5; P < 0.0002). CIMP was also associated with BRAF V600E T-to-A transversion (OR, 48.5; P < 0.0002).Conclusions: Our findings suggest that the heterogeneous epigenetic dysregulation of promoter methylation in various genes is interrelated with the occurrence of mutations, as manifested in epigenetic-genetic subgroups of tumors.The development of most colorectal carcinomas (CRC) is thought to be initiated by inactivation of the APC/b-catenin/ Wnt signaling pathway, usually by mutation of one copy of the APC gene followed by a second event that inactivates the other allele (1-4). The second inactivating event is usually described as allelic deletion or mutation but can be epigenetic methylation of cytosines in CpG islands of the promoter region of APC that results in transcriptional silencing (5, 6). Altered APC has wideranging downstream effects on cell-cell adhesion, transcriptional regulation, chromosomal instability, cell migration, proliferation and cell cycle control, differentiation, and apoptosis (1-4).Somatic APC mutation is associated with the development of intraepithelial neoplasia (dysplasia) in aberrant crypt foci and early adenomas (7). The initiating alterations in APC in these early lesions persist whereas additional genetic and epigenetic events accumulate and drive tumor progression. Somatic mutation in the APC gene is present in as many as 80% of sporadic colorectal adenomas and carcinomas (7 -9), and a mutati...

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“…8,11,12 BAT-26 and BAT-40 were polymerase chain reaction (PCR) amplified from normal (blood or normal colonic mucosa) and tumoral DNA for each adenoma or adenocarcinoma. PCR was performed as described previously, 1 except that primers were labeled with fluorescent dye, and the sizes of PCR products were evaluated on an ABI machine (Applied Biosystems Inc., Foster City, CA).…”

Section: Methodsmentioning

confidence: 99%

BAT-26 and BAT-40 Instability in Colorectal Adenomas and Carcinomas and Germline Polymorphisms

Samowitz¹,

Slattery²,

Potter³

et al. 1999

The American Journal of Pathology

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Analysis of the mononucleotide repeats BAT-26 and BAT-40 has reportedly revealed significant microsatellite instability in sporadic colorectal adenomas, whereas studies with dinucleotide and tetranucleotide repeats have not. In addition , BAT-26 has been reported to be "quasimonomorphic" in the germline. We evaluated BAT-26 and BAT-40 in a series of colorectal tumors previously analyzed with a panel of tetranucleotide repeats. Instability in BAT-26 or BAT-40 was significantly associated with tetranucleotide repeat instability in sporadic adenomas and carcinomas (P < 0.0001) and was similarly much less common in adenomas than in carcinomas. Germline polymorphisms in both BAT-40 and BAT-26 were identified , and the frequency of BAT-26 polymorphisms was significantly higher in African Americans than in Caucasians (7.7% versus 0.08% , P < 0.001). BAT-26 and BAT-40 may be very useful in evaluating instability in small tumors , as sufficient DNA to be amplified by large panels of microsatellites is not always available from such lesions. Polymorphisms in these microsatellites , however , limit their utility in determinations of microsatellite instability without corresponding normal DNA. (Am J Pathol 1999, 154:1637-1641)BAT-26 and BAT-40 are poly(A) mononucleotide repeats located in introns of the hMSH2 and 3-␤-hydroxysteroid dehydrogenase genes, respectively.

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Microsatellite instability in colorectal adenomas

Cited by 55 publications

References 3 publications

Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype

Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype

Epigenetic-Genetic Interactions in theAPC/WNT, RAS/RAF, andP53Pathways in Colorectal Carcinoma

BAT-26 and BAT-40 Instability in Colorectal Adenomas and Carcinomas and Germline Polymorphisms

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