Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways

Jass, Jeremy R.; Biden, Kelli G.; Cummings, Margaret C.; Simms, Lisa A.; Walsh, Michael D.; Schoch, Estelle; Meltzer, Stephen J.; Wright, Caroline; Searle, Jeffrey; Young, Joanne; Leggett, Barbara A.

doi:10.1136/jcp.52.6.455

Cited by 212 publications

(183 citation statements)

References 37 publications

(47 reference statements)

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“…Most high-MSI tumors are admixed hyperplastic and adenomatous polyps rather than serrated polyps. 3,4,8,11,14,15 In our study, the right colon showed a higher percentage of methylation and more frequent methylation of the p16, p14, TIMP3, and FHIT genes than the left colon. These results are comparable with the results reported by Burri et al 25 using colonic carcinoma samples.…”

Section: Discussionsupporting

confidence: 50%

“…6 The polyps of this pathway differ morphologically and genetically from those of the traditional adenoma-carcinoma sequence. 7 Genetically, serrated adenomas are differentiated from sporadic tubular adenomas by a high frequency of the low mutator phenotype, 3,8 p53 mutations, 9 KRAS mutations, 9,10 BRAF mutations, 11 and a low frequency of APC gene mutations. 12 However, the prevalence of the high mutator phenotype and its significance during tumorigenesis are controversial and the chromosomal status of serrated adenoma has not been studied.…”

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confidence: 99%

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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: 50%

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confidence: 99%

Progressive methylation during the serrated neoplasia pathway of the colorectum

et al. 2005

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“…This finding leads to the hypothesis that pERK is involved in the mechanism of tumor progression of MMR-proficient CRC and Lynch syndrome by interacting with the wnt signaling pathway and RHAMM: (1) KRAS mutation is found in approximately 35% of unselected CRCs, whereas it is mutated at a particularly low frequency in sporadic MSI-H cancers. [38][39][40][41][42] (2) The molecule ERK, a member of the MAPK pathway, is activated by a cascade of phophorylation events downstream from the ras proto-oncogene. 8 (3) Intracellular and cell surface RHAMM isoforms are important for the activation of ERK by PDGF (platelet-derived growth factor) and mutant (activated) RAS, respectively, while intracellular RHAMMv4 overexpression activates ERK.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the receptor for hyaluronic acid mediated motility is an independent adverse prognostic factor in colorectal cancer

et al. 2006

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RHAMM, a member of the microtubule-associated protein family that interacts with the mitogen-activated protein kinase pathway, is associated with tumor progression, aggressive disease and shortened survival in several tumor types. This study aimed to determine the prognostic value of RHAMM in colorectal cancer (CRC). A series of 1420 unselected, nonconsecutive CRC resections were subdivided into three groups: (1) DNA mismatch repair (MMR)-proficient, (2) MLH1 negative and (3) presumed Lynch syndrome. Immunohistochemical analysis of RHAMM expression (0 vs 40%), increasing expression (increasing percentage positivity) and complete expression (100 vs o100%) was performed using tissue microarray technique and the results were correlated with clinicopathological parameters. Fifty-seven tissue samples of normal colonic mucosa were included as a control group. In a univariate analysis increasing and complete expression of RHAMM were associated with higher N stage (P ¼ 0.023 and 0.021) and worse survival (Po0.0001) in MMR-proficient CRC. Complete expression of RHAMM was associated with worse survival in presumed Lynch syndrome (P ¼ 0.016). In MLH1-negative CRC there was no association between RHAMM expression and the clinicopathological features. In a multivariate analysis, increasing RHAMM expression was an independent adverse prognostic factor in MMR-proficient CRC (Po0.0001) and complete expression in MMR-proficient CRC and presumed Lynch syndrome (Po0.0001 and P ¼ 0.031, respectively). Nuclear pERK expression was associated with increasing RHAMM expression in MMR-proficient CRC (P ¼ 0.012) and with complete RHAMM expression in presumed HNPCC (P ¼ 0.03). Increasing and complete RHAMM expressions are independent adverse prognostic factors in MMR-proficient CRC and presumed Lynch syndrome.

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“…It has been reported that MSS/MSI-L tumors, in contrast to MSI-H tumors, occur most commonly in the left colon and rectum and harbor k-ras, APC, and p53 mutations more frequently, and exhibit silencing of the DNA repair gene O-6-methylguanine DNA methyltransferase (O 6 -MGMT) through promoter methylation. 10,11 MSI-H tumors are predominantly located in the proximal colon and are often characterized histologically by poor differentiation, lymphocytic infiltration and extracellular mucin production. Both MSI-H and MSS/MSI-L tumors appear to arise from hyperplastic polyps evolving to serrated adenomas.…”

Section: B I O S C I E N C E N O T F O R D I S T R I B U T I O Nmentioning

confidence: 99%

Evaluation of Microsatellite Instability, hMLH1 Expression and hMLH1 Promoter Hypermethylation in Defining the MSI Phenotype of Colorectal Cancer

Arnold¹,

Goel²,

Compton³

et al. 2004

Cancer Biology & Therapy

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B i o s c i e n c e . N o t f o r d i s t r i b u t i o n . KEY WORDShMLH1, microsatellite instability, promoter methylation, colorectal cancer, immunohistochemistry ACKNOWLEDGEMENTSThe research for CALGB study 9865 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, Chairman). This work was also sponsored by a grant from the NIH (RO1-CA 72851) to C.R.B and in part by an American Cancer Society-IRG award to A.G. C.N.A. was funded by a grant of the Dr. MildredScheel-Stiftung, Germany. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. For further information regarding who participated in this study, please see table on p. 78. ABSTRACTIntroduction: About 15% of all colorectal cancers (CRCs) demonstrate high levels of microsatellite instability (MSI-H) and are currently best identified by molecular analysis of microsatellite markers. Most sporadic CRCs with MSI-H are known to be associated with the methylation of the hMLH1 promoter. Promoter methylation coincided with lack of hMLH1 expression. We aimed to investigate the association between MSI status, hMLH1 protein expression and methylation status of the hMLH1 promoter, and to determine the usefulness of each method in defining the MSI phenotype in sporadic CRCs. Materials and Methods: CRCs from 173 patients from the Cancer and Leukemia Group B (CALGB) were assessed for their MSI status. An additional cohort of 18 MSI-H tumors from the University of California San Diego (UCSD) was included in the analysis of the MSI-H subgroup. MSI testing was performed by PCR using five standard MSI markers. hMLH1 promoter analysis was investigated by methylation specific PCR (MSP), and expression of the MMR genes hMLH1 and hMSH2 was examined by immunohistochemistry (IHC). Results: Of the 173 CALGB tumors, 111 (64%) were MSS, 35 (20%) were MSI-L and 27 (16%) MSI-H, respectively. Data on hMLH1 protein expression, hMSH2 protein expression and hMLH1 methylation are available on 128, 173 and 81 of these tumors, respectively. Presence of hMLH1 and hMSH2 protein expression was significantly associated with MSI status. Four of 45 (8.9%) MSI-H tumors and 0 of 146 (0%) MSS/MSI-L tumors did not express hMSH2 (p = 0.0028). hMLH1 protein expression was present in 107 of 108 (99%) MSS and MSI-L tumors versus 11 of 20 (55%) MSI-H tumors (p < 0.0001). Of 61 MSS and MSI-L cancers studied for methylation, 11 (18%) were methylated at the hMLH1 promoter whereas 14 of 20 (70%) MSI-H cancers were methylated (p = 0.0001). In 27 MSI-H tumors studied for hMLH1 protein expression and methylation, 93% of tumors with loss of expression (93%) were also methylated while 42% (5/12) with positive immunostaining for hMLH1 were methylated at the hMLH1 promoter (p = 0.009). Conclusions: Promoter methylation and hMLH1 expression are significantly associated with the MSI-H phenotype in CRC. Promoter methylation analysis p...

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Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways

Cited by 212 publications

References 37 publications

Progressive methylation during the serrated neoplasia pathway of the colorectum

Progressive methylation during the serrated neoplasia pathway of the colorectum

Overexpression of the receptor for hyaluronic acid mediated motility is an independent adverse prognostic factor in colorectal cancer

Evaluation of Microsatellite Instability, hMLH1 Expression and hMLH1 Promoter Hypermethylation in Defining the MSI Phenotype of Colorectal Cancer

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