Promoter Hypermethylation Frequency and BRAF Mutations Distinguish Hereditary Non-Polyposis Colon Cancer from Sporadic MSI-H Colon Cancer

McGivern, A; Wynter, Coral; Whitehall, Vicki; Kambara, Takeshi; Spring, Kevin; Walsh, Michael D.; Barker, Melissa; Arnold, Sven; Simms, Lisa A.; Leggett, Barbara A.; Young, Joanne; Jass, Jeremy R.

doi:10.1023/b:fame.0000039861.30651.c8

Cited by 182 publications

(153 citation statements)

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“…37 This case shares a BRAF mutation and promoter hypermethylation, the expected scenario for a non-LS tumor. 10,11,14,15 Walsh et al 22 reported the presence of a BRAF mutation in a member of a LS family that, also showed predisposition to develop colorectal serrated polyps. Interestingly, some evidence suggests that non-LS MSI-H cases may originate from sessile serrated adenoma.…”

Section: Discussionmentioning

confidence: 99%

“…This mutation is strongly associated with MLH1 inactivation secondary to promoter hypermethylation. [10][11][12][13][14][15] It has been used to distinguish LS-associated from sporadic MSI-positive tumors. 10,11,[16][17][18][19][20][21] The lack of BRAF mutations identifies with high sensitivity (96-100%) and lower specificity (22-100%) CRC cases associated with LS.…”

Section: Introductionmentioning

confidence: 99%

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MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

et al. 2012

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The analytical algorithm of Lynch syndrome (LS) is increasingly complex. BRAF V600E mutation and MLH1 promoter hypermethylation have been proposed as a screening tool for the identification of LS. The aim of this study was to assess the clinical usefulness and cost-effectiveness of both somatic alterations to improve the yield of the diagnostic algorithm of LS. A total of 122 colorectal tumors from individuals with family history of colorectal cancer that showed microsatellite instability and/or loss of mismatch repair (MMR) protein expression were studied. MMR germline mutations were detected in 57 cases (40 MLH1, 15 MSH2 and 2 MSH6). BRAF V600E mutation was assessed by single-nucleotide primer extension. MLH1 promoter hypermethylation was assessed by methylation-specific multiplex ligation-dependent probe amplification in a subset of 71 cases with loss of MLH1 protein. A decision model was developed to estimate the incremental costs of alternative case-finding methods for detecting MLH1 mutation carriers. One-way sensitivity analysis was performed to assess robustness of estimations. Sensitivity of the absence of BRAF mutations for depiction of LS patients was 96% (23/24) and specificity was 28% (13/47). Specificity of MLH1 promoter hypermethylation for depiction of sporadic tumors was 66% (31/47) and sensitivity of 96% (23/24). The cost per additional mutation detected when using hypermethylation analysis was lower when compared with BRAF study and germinal MLH1 mutation study. Somatic hypermethylation of MLH1 is an accurate and cost-effective pre-screening method in the selection of patients that are candidates for MLH1 germline analysis when LS is suspected and MLH1 protein expression is absent.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

et al. 2012

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“…There is growing evidence to suggest that concurrent hypermethylation of multiple additional genes may represent an important component in the development and progression of colorectal cancers. [2][3][4][5][6][7][8] This propensity for methylation in such tumors has served as an interesting feature to exploit in the search for novel methylation targets.We have recently applied a global expression profiling-based technique to identify potential novel methylation targets in MSI-H colorectal cancers. One of the genes discovered to have significant differential methylation in microsatellite-unstable cancers was RAB32, a mitochondrial ras family member that encodes an A-kinase anchoring protein.…”

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confidence: 99%

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confidence: 99%

RAB32 hypermethylation and microsatellite instability in gastric and endometrial adenocarcinomas

Shibata

Mori

Cai

et al. 2006

Intl Journal of Cancer

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The recently described gene, RAB32, is a ras proto-oncogene family member that encodes an A-kinase-anchoring protein. RAB32 has been found to be frequently hypermethylated in microsatellite instability-high (MSI-H) colon cancers. We sought to determine the prevalence of RAB32 hypermethylation in gastric and endometrial adenocarcinomas, the 2 other major tumor types in which MSI-H is common. Moreover, we delineated the association of RAB32 hypermethylation with microsatellite instability (MSI) and hMLH1 hypermethylation. MSI status and hypermethylation of the RAB32 and hMLH1 genes were studied in paired primary normal and tumor tissues from 48 patients with gastric cancer. An additional 80 endometrial cancer patients were studied for RAB32 methylation and MSI status. Thirteen (27%) of 48 gastric cancers demonstrated evidence of RAB32 hypermethylation. MSI status was determined in 46 of the tumors, with 7 (100%) of 7 MSI-H tumors, 1 (33%) of 3 MSI-low (MSI-L) tumors and 4 (11%) of 36 microsatellite-stable (MSS) tumors found to harbor RAB32 hypermethylation. RAB32 methylation was significantly associated with intestinal type histology and concomitant hMLH1 hypermethylation in gastric cancer. In contrast, RAB32 methylation occurred in only 1 of 80 endometrial cancers, including 20 MSI-H, 8 MSI-L and 52 MSS tumors. Hypermethylation of hMLH1 was noted in 16 (20%) of 80 endometrial tumors. We conclude that although RAB32 methylation is rare in endometrial cancers, it is strongly associated with hMLH1 hypermethylation and MSI in gastric adenocarcinomas. Given its similar involvement in colon cancer, RAB32 inactivation may represent a component of the oncogenic pathway of microsatellite-unstable gastrointestinal adenocarcinomas. ' 2006 Wiley-Liss, Inc.Key words: RAB32; methylation; microsatellite instability; gastric cancer; endometrial cancer Hypermethylation of promoter region CpG islands is well recognized as an important mechanism of transcriptional repression and loss of gene function. 1 As a key example, hypermethylation of hMLH1 is strongly associated with sporadic cases of microsatellite instability-high (MSI-H) cancers. There is growing evidence to suggest that concurrent hypermethylation of multiple additional genes may represent an important component in the development and progression of colorectal cancers. [2][3][4][5][6][7][8] This propensity for methylation in such tumors has served as an interesting feature to exploit in the search for novel methylation targets.We have recently applied a global expression profiling-based technique to identify potential novel methylation targets in MSI-H colorectal cancers. One of the genes discovered to have significant differential methylation in microsatellite-unstable cancers was RAB32, a mitochondrial ras family member that encodes an A-kinase anchoring protein. RAB32 was found to be methylated exclusively in MSI-H colon cancers, with no evidence of methylation in either non-MSI-H tumors or normal adjacent mucosal tissue. 9 RAB32 has the ability to anchor the cyclic ...

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“…Considering three features of the CIMP-L/0 MLH1m þ subtype-the earlier age of onset, reduced number of methylated CIMP-panel markers (n ¼ 1.125, except for MLH1 methylation), and rare BRAF mutation rate-it is unlikely that this subtype arises from pre-existing serrated adenomas. Several studies have documented frequencies of MLH1 methylation ranging from 0 to 55% in Lynch syndrome tumors, [24][25][26][27][28][29] suggesting that an epigenetic mechanism might act as the second hit required to inactivate the wild-type allele in Lynch syndrome tumors. In Lynch syndrome tumors exhibiting MLH1 methylation, the number of methylated CIMP-panel markers has been demonstrated to be significantly lower than that of sporadic microsatellite-unstable tumors, 11,25 indicating that the MLH1 methylation observed in the sporadic setting is a reflection of a widespread process of CIMP, whereas the MLH1 methylation in Lynch syndrome tumors is a more directed event.…”

Section: Discussionmentioning

confidence: 99%

Subsets of microsatellite-unstable colorectal cancers exhibit discordance between the CpG island methylator phenotype and MLH1 methylation status

et al. 2013

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Although the presence of MLH1 methylation in microsatellite-unstable colorectal cancer generally indicates involvement of the CpG island methylator phenotype (CIMP) in the development of the tumor, these two conditions do not always correlate. A minority of microsatellite-unstable colorectal cancers exhibit discordance between CIMP and MLH1 methylation statuses. However, the clinicopathological features of such microsatellite-unstable colorectal cancers with discrepant MLH1 methylation and CIMP statuses remain poorly studied. Microsatellite-unstable colorectal cancers (n ¼ 220) were analyzed for CIMP and MLH1 methylation statuses using the MethyLight assay. Based on the combinatorial CIMP and MLH1 methylation statuses, the microsatellite-unstable colorectal cancers were grouped into four subtypes (CIMP-high (CIMP-H) MLH1 methylation-positive (MLH1m þ ), CIMP-H MLH1 methylation-negative, CIMP-low/0 (CIMP-L/0) MLH1m þ , and CIMP-L/0 MLH1 methylation-negative), which were compared in terms of their associations with clinicopathological and molecular features. The CIMP-L/0 MLH1 methylation-negative and CIMP-H MLH1m þ subtypes were predominant, comprising 63.6 and 24.1% of total microsatellite-unstable colorectal cancers, respectively. The discordant subtypes, CIMP-H MLH1 methylation-negative and CIMP-L/0 MLH1m þ , were found in 5 and 7% of microsatellite-unstable colorectal cancers, respectively. The CIMP-H MLH1 methylation-negative subtype exhibited elevated incidence rates in male patients and was associated with larger tumor size, more frequent loss of MSH2 expression, increased frequency of KRAS mutation, and advanced cancer stage. The CIMP-L/0 MLH1m þ subtype was associated with onset at an earlier age, a predominance of MLH1 loss, and earlier cancer stage. None of the CIMP-L/0 MLH1m þ subtype patients succumbed to death during the follow-up. Our findings suggest that the discordant subtypes of colorectal cancers exhibit distinct clinicopathological and molecular features, although the proportion of discordant subtypes is low. The microsatellite-unstable colorectal cancers of the same CIMP status tended to exhibit different clinicopathological features depending on MLH1 methylation status.

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Promoter Hypermethylation Frequency and BRAF Mutations Distinguish Hereditary Non-Polyposis Colon Cancer from Sporadic MSI-H Colon Cancer

Abstract: The total number of genes and MINTs methylated in HNPCC was lower than in MSI-H colorectal tumours. No HNPCC tumour showed evidence of widespread promoter hypermethylation or BRAF mutation suggesting this feature could be used as a discriminator between familial and sporadic cases.

Cited by 182 publications

References 35 publications

MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

RAB32 hypermethylation and microsatellite instability in gastric and endometrial adenocarcinomas

Subsets of microsatellite-unstable colorectal cancers exhibit discordance between the CpG island methylator phenotype and MLH1 methylation status

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