A Gene Expression Signature of Genetic Instability in Colon Cancer

Giacomini, Craig P.; Leung, Suet Yi; Chen, Xin; Yuen, Siu Tsan; Kim, Young H.; Bair, Eric; Pollack, Jonathan R.

doi:10.1158/0008-5472.can-04-4163

Cited by 67 publications

(62 citation statements)

References 42 publications

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“…Several studies have examined expression profiles of MSI cancers using DNA microarray. However, these studies either examined MSI cancer cell lines, or the number of MSI cancer samples was comparatively small (8)(9)(10)(11)(12)(13). Furthermore, no studies have highlighted the difference between proximal and distal MSI cancers with regard to gene expression profiles.…”

Section: Introductionmentioning

confidence: 99%

Distal Colorectal Cancers with Microsatellite Instability (MSI) Display Distinct Gene Expression Profiles that Are Different from Proximal MSI Cancers

Watanabe

Kobunai²,

Toda

et al. 2006

Cancer Research

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Promoter methylation of the mismatch repair gene plays a key role in sporadic microsatellite instability (MSI) colorectal cancers. However, promoter methylation often occurs in proximal colon cancers, and molecular phenotypes underlying MSI cancers in distal colon have not been fully clarified. Our goal was to clarify the difference between MSI and microsatellite stability (MSS) cancers and, furthermore, to determine distinct characteristics of proximal and distal MSI cancers. By DNA microarray analysis of 84 cancers (33 MSI and 51 MSS), we identified discriminating genes (177 probe sets), which predicted MSI status with a high accuracy rate (97.6%). These genes were related to phenotypic characteristics of MSI cancers. Next, we identified 24 probe sets that were differentially expressed in proximal and distal MSI cancers. These genes included promoter methylation-mediated genes, whose expression was significantly down-regulated in proximal MSI cancers. Among discriminating genes between MSI and MSS, nine methylation-mediated genes showed down-regulation in MSI cancers. Of these, 7 (77.8%) showed down-regulation in proximal MSI cancers. Furthermore, methylation-specific PCR confirmed that frequency of hMLH1 promoter methylation was significantly higher in proximal MSI cancers (P = 0.0317). These results suggested that there is a difference between proximal and distal MSI cancers in methylation-mediated influence on gene silencing. In conclusion, using DNA microarray, we could distinguish MSI and MSS cancers. We also showed distinct characteristics of proximal and distal MSI cancers. The inactivation form of hMLH, per se, differed between proximal and distal MSI cancers. These results suggested that distal MSI cancers constitute a distinct subgroup of sporadic MSI cancers.

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Section: Introductionmentioning

confidence: 99%

Distal Colorectal Cancers with Microsatellite Instability (MSI) Display Distinct Gene Expression Profiles that Are Different from Proximal MSI Cancers

Watanabe

Kobunai²,

Toda

et al. 2006

Cancer Research

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“…The mechanism responsible for MSI is known to be a failure of the DNA mismatch repair system. Recently, whole-genome transcriptional profiling studies have shown that there are profound transcriptional differences between MSS and MSI cancers (Giacomini et al, 2005;Kruhoffer et al, 2005). However, the causal mechanisms for these differences remain unclear.…”

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confidence: 99%

Dysregulation of the transcription factors SOX4, CBFB and SMARCC1 correlates with outcome of colorectal cancer

et al. 2009

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The aim of this study was to identify deregulated transcription factors (TFs) in colorectal cancer (CRC) and to evaluate their relation with the recurrence of stage II CRC and overall survival. Microarray-based transcript profiles of 20 normal mucosas and 424 CRC samples were used to identify 51 TFs displaying differential transcript levels between normal mucosa and CRC. For a subset of these we provide in vitro evidence that deregulation of the Wnt signalling pathway can lead to the alterations observed in tissues. Furthermore, in two independent cohorts of microsatellite-stable stage II cancers we found that high SOX4 transcript levels correlated with recurrence (HR 2.7; 95% CI, 1.2 -6.0; P ¼ 0.01). Analyses of B1000 stage I -III adenocarcinomas, by immunohistochemistry, revealed that patients with tumours displaying high levels of CBFB and SMARCC1 proteins had a significantly better overall survival rate (P ¼ 0.0001 and P ¼ 0.0275, respectively) than patients with low levels. Multivariate analyses revealed that a high CBFB protein level was an independent predictor of survival. In conclusion, several of the identified TFs seem to be involved in the progression of CRC.

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“…There have been several previous publications describing RERassociated global gene expression changes in CRC using oligonucleotide and cDNA arrays (2,(21)(22)(23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

“…More recently, Jorissen et al (22) published a list of 829 probesets consistently differentially expressed across three independent datasets using primary tissue samples total of 82 RER− cases and 93 RER+ cases, which included the samples analyzed by Watanabe et al (21)(22)(23). Jorissen et al also gave a list of 192 probesets consistently differentially expressed across four independent datasets that included data from 10 RER+ and 10 RER− cell lines (2). All three of the above lists of probesets were downloaded and the corresponding 3′UTR sequences interrogated for the frequencies of mononucleotide repeat lengths, as described in Materials and Methods.…”

Section: Rer-associated Expression Changes Between Crc Cell Lines Arementioning

confidence: 99%

Replication error deficient and proficient colorectal cancer gene expression differences caused by 3′UTR polyT sequence deletions

Wilding

McGowan

Liu

et al. 2010

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

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Replication error deficient (RER+) colorectal cancers are a distinct subset of colorectal cancers, characterized by inactivation of the DNA mismatch repair system. These cancers are typically pseudodiploid, accumulate mutations in repetitive sequences as a result of their mismatch repair deficiency, and have distinct pathologies. Regulatory sequences controlling all aspects of mRNA processing, especially including message stability, are found in the 3′UTR sequence of most genes. The relevant sequences are typically A/U-rich elements or U repeats. Microarray analysis of 14 RER+ (deficient) and 16 RER− (proficient) colorectal cancer cell lines confirms a striking difference in expression profiles. Analysis of the incidence of mononucleotide repeat sequences in the 3′UTRs, 5′UTRs, and coding sequences of those genes most differentially expressed in RER+ versus RER− cell lines has shown that much of this differential expression can be explained by the occurrence of a massive enrichment of genes with 3′UTR T repeats longer than 11 base pairs in the most differentially expressed genes. This enrichment was confirmed by analysis of two published consensus sets of RER differentially expressed probesets for a large number of primary colorectal cancers. Sequence analysis of the 3′UTRs of a selection of the most differentially expressed genes shows that they all contain deletions in these repeats in all RER+ cell lines studied. These data strongly imply that deregulation of mRNA stability through accumulation of mutations in repetitive regulatory 3′UTR sequences underlies the striking difference in expression profiles between RER+ and RER− colorectal cancers.A pproximately 15% of sporadic colorectal cancers (CRCs) are microsatellite unstable (MSI+) as a result of inactivation of one of the components of the DNA mismatch repair system (1). This is mostly because of a combination of epigenetic silencing or mutation, coupled with loss of heterozygosity, of MLH1 and less frequently MSH2 or MSH6 (2, 3). As a result, such tumors are replication error deficient (RER+), which leads to the accumulation of insertion/deletion mutations in mono-, di-, tri-, and tetranucleotide repeats throughout the genome, probably because of DNA polymerase slippage during replication (4, 5).RER+ tumors have distinct clinico-pathologic and genetic profiles in comparison with microsatellite stable/replication proficient tumors (MSI−/RER−). These tumors tend to be right sided (proximal), poorly differentiated with mucinous histology, and have a more favorable prognosis (6-8). In addition, they mostly have a near diploid or pseudodiploid karyotype; RER− tumors are mostly chromosomally unstable and have aneuploid karyotypes (9, 10). The underlying genetic instability in RER+ tumors results in a genetic profile that is distinct from RER− tumors and is characterized by mutation of "susceptible" genes containing repeat sequences within their protein coding regions. For example, although the TGF signaling pathway is commonly disrupted in CRC, RER+ tumors tend...

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A Gene Expression Signature of Genetic Instability in Colon Cancer

Cited by 67 publications

References 42 publications

Distal Colorectal Cancers with Microsatellite Instability (MSI) Display Distinct Gene Expression Profiles that Are Different from Proximal MSI Cancers

Distal Colorectal Cancers with Microsatellite Instability (MSI) Display Distinct Gene Expression Profiles that Are Different from Proximal MSI Cancers

Dysregulation of the transcription factors SOX4, CBFB and SMARCC1 correlates with outcome of colorectal cancer

Replication error deficient and proficient colorectal cancer gene expression differences caused by 3′UTR polyT sequence deletions

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