Colorectal carcinomas with high microsatellite instability: Defining a distinct immunologic and molecular entity with respect to prognostic markers

Edmonston, Tina Bocker; Cuesta, Kimberly H.; Burkholder, Susan; Barusevicius, Alan; Rose, Deborah G.; Kovatich, Albert J.; Boman, Bruce M.; Fry, Robert D.; Fishel, Richard; Palazzo, Juan

doi:10.1053/hupa.2000.20383

Cited by 76 publications

(46 citation statements)

References 28 publications

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“…22 However, no study to date has examined relationship between p27 expression and CIMP. In addition, previous studies have not shown any correlation for p27 expression with MSI status 23 or mutations in the TGFBR2 gene (encoding TGF-b receptor type II) within MSI-H tumors. 24 In this study, using quantitative real-time PCR (MethyLight) assays, 19,[25][26][27] and population-based samples of colorectal cancer from two large prospective cohort studies, we have shown correlations of loss of nuclear p27 expression with CIMP and MSI.…”

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confidence: 74%

Loss of nuclear p27 (CDKN1B/KIP1) in colorectal cancer is correlated with microsatellite instability and CIMP

et al. 2007

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Downregulation of p27 (cyclin-dependent kinase inhibitor-1B, CDKN1B or KIP1) is caused by increased ubiquitin-mediated proteasomal degradation in colorectal cancer, and has been associated with poor prognosis. CpG island methylator phenotype (CIMP) is a phenotype of colorectal cancer with extensive promoter methylation, and associated with high degree of microsatellite instability (MSI-H) and BRAF mutations. We have recently shown that both CIMP and MSI-H are inversely associated with downregulation of p21 (CDKN1A or CIP1), another cyclin-dependent kinase inhibitor. However, no study to date has examined relationship between p27 and CIMP status in colorectal cancer. Using MethyLight assays, we measured DNA methylation in five CIMP-specific gene promoters {CACNA1G, CDKN2A (p16), CRABP1, MLH1 and NEUROG1} in 706 colorectal cancer samples obtained from two large prospective cohorts. Among the 706 tumors, 112 (16%) were CIMP-high tumors with Z4/5 methylated promoters. We assessed p27 and p53 expressions by immunohistochemistry. Loss of nuclear p27 expression {observed in 231 tumors (33%)} was significantly associated with CIMP-high, MSI-H and BRAF mutations, and these associations were much more pronounced among p53-negative tumors than p53-positive tumors. When CIMP-high and non-CIMP-high tumors were stratified by MSI status (or KRAS and BRAF status), CIMP-high and MSI-H (but not BRAF mutations) were still significantly associated with nuclear p27 loss. Nuclear p27 loss did not appear to be directly related to CDKN2A (p16) methylation. We conclude that downregulation of nuclear p27 is associated with CIMP-high and MSI-H in colorectal cancer. These associations are stronger among p53 wild-type tumors, implying important interplay of p27 and p53 functions (or dysfunctions) in the development of various molecular subtypes of colorectal cancer. Modern Pathology (2007) 20, 15-22.

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confidence: 74%

Loss of nuclear p27 (CDKN1B/KIP1) in colorectal cancer is correlated with microsatellite instability and CIMP

et al. 2007

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“…[57][58][59] The cause of the increased proliferation has not been determined up to this time, and our results suggest that the mutational inactivation of TGFBR2 is at least one factor that affects proliferation in these tumors. Other alterations observed in MSI colon cancers that likely affect proliferation include activating mutations in BRAF, which have recently been found in a high proportion of sporadic MSI colon cancers.…”

Section: Discussionmentioning

confidence: 99%

Proliferation and Cdk4 expression in microsatellite unstable colon cancers with TGFBR2 mutations

Grady

Willis

Trobridge

et al. 2005

Intl Journal of Cancer

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Approximately 15% of human colon cancers have microsatellite instability (MSI) and carry frameshift mutations in a polyadenine tract (BAT-RII) in the type II transforming growth factor b (TGFb) receptor (TGFBR2), a required component of the TGF-b receptor. The BAT-RII mutations in MSI colon cancers make the tumors resistant to the effects of TGF-b. In cultured epithelial cells, TGF-b can inhibit cell proliferation and induce apoptosis, and in vitro it can regulate the expression of a variety of cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors. These effects are context-and tissue type-dependent, raising questions about which of these in vitro effects of TGF-b signaling inactivation contribute to the formation of primary colon cancer. Thus, this study sought to determine the pathogenetically relevant effects of TGFBR2 inactivation in primary MSI colon cancers with mutant BAT-RII. Colon cancers with mutant BAT-RII were found to have increased proliferation compared to cancers with wild-type BAT-RII. Assessment of cdk4, cyclin D1 and p27 kip1 expression revealed that only cdk4 expression was increased in the cancers with mutant BAT-RII. In order to determine if TGFBR2 inactivation was the cause of these changes, TGFBR2 was reconstituted in an MSI colon cancer cell line, resulting in decreased proliferation and decreased cdk4 expression and kinase activity. These results suggest that TGFBR2 mutations in primary colon cancers may be responsible for the increased proliferation and cdk4 expression in these tumors and provide evidence that deregulation of cdk4 is a pathogenic in vivo consequence of TGFBR2 inactivation in primary colon cancer. ' 2005 Wiley-Liss, Inc.Key words: colon cancer; TGF-b; cdk4; proliferation TGF-b is a potent negative regulator of epithelial cell growth and in cell culture can cause complete growth inhibition and induce apoptosis of nontransformed colon epithelial cells. 1,2 TGFb mediates its effects through a heteromeric cell surface receptor that consists of 2 serine-threonine kinases, the type I and type II TGF-b receptors. During the malignant transformation of colon epithelial cells, the acquisition of resistance to TGF-b-mediated growth inhibition occurs commonly, suggesting it has a significant pathogenic role in the formation of colon cancer. 2-4 Indeed, previous studies have shown that the malignant progression of colon adenoma cell lines directly correlates with the acquisition of TGFb resistance in the cultured cells. 2,4 Mechanisms of the TGF-b resistance described in colon cancers include mutations in the type II TGF-b receptor (TGFBR2) 5-7 as well as mutations in the TGFb signal transduction molecules MADH2/SMAD2 and MADH4/ SMAD4. [8][9][10] The first of these mutations to be described were TGFBR2 frameshift mutations clustered within a microsatellitelike 10 base pair polyadenine repeat within the TGFBR2 coding region (the BAT-RII tract). Such BAT-RII frameshift mutations are characteristic of colon cancers that arise in the setting of microsatellite instability (MSI), a...

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“…Abnormal p21 protein levels have been documented in colon cancer patients, but mostly in small and heterogeneous patient populations with contradictory conclusions. [19][20][21][22][23] In the a b [23][24][25] Cyclin D1 plays a key role in cell cycle control, as it complexes with CDKs in the G1-phase resulting in S-phase entry. 26 Cyclin D1 activation by APC mutation/WNT signaling seems to contribute to colon neoplasia initiation.…”

Section: Discussionmentioning

confidence: 99%

Cell Cycle Proteins Predict Recurrence in Stage II and III Colon Cancer

et al. 2012

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Purpose. To investigate the prognostic value of multiple cell cycle-associated proteins in a large series of stage II and III colon cancers. Methods. From formalin-fixed, paraffin-embedded tumor samples of 386 patients with stage II and III colon cancer, DNA was isolated and tissue microarrays were constructed. Tissue microarray slides were immunohistochemically stained for p21, p27, p53, epidermal growth factor receptor, Her2/Neu, b-catenin, cyclin D1, Ki-67, thymidylate synthase, and Aurora kinase A (AURKA). Polymerase chain reaction-based microsatellite instability analysis was performed to allow for stratification of protein expression by microsatellite instability status. Results. Overall, low p21, high p53, low cyclin D1, and high AURKA expression were significantly associated with recurrence (P = 0.01, P \ 0.01, P = 0.04, and P \ 0.01, respectively). In stage II patients who did not receive adjuvant chemotherapy (n = 190), significantly more recurrences were observed in case of low-p21 and highp53-expressing tumors (P \ 0.01 and P = 0.03, respectively). In stage III patients who did not receive chemotherapy, high p53 expression was associated with recurrence (P = 0.02), and in patients who received chemotherapy, high AURKA expression was associated with relapse (P \ 0.01). In patients with microsatellite stable tumors, high levels of p53 and AURKA were associated with recurrence (P = 0.01 and P \ 0.01, respectively). Multivariate analysis showed p21 (odds ratio 1.6, 95% confidence interval 0.9-2.8) and AURKA (odds ratio 2.7, 95% confidence interval 1.3-5.6) to be independently associated with disease recurrence. Conclusions. p21, p53, cyclin D1, and AURKA could possibly be used as prognostic markers to identify colon cancer patients with high risk of disease recurrence.

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Colorectal carcinomas with high microsatellite instability: Defining a distinct immunologic and molecular entity with respect to prognostic markers

Cited by 76 publications

References 28 publications

Loss of nuclear p27 (CDKN1B/KIP1) in colorectal cancer is correlated with microsatellite instability and CIMP

Loss of nuclear p27 (CDKN1B/KIP1) in colorectal cancer is correlated with microsatellite instability and CIMP

Proliferation and Cdk4 expression in microsatellite unstable colon cancers with TGFBR2 mutations

Cell Cycle Proteins Predict Recurrence in Stage II and III Colon Cancer

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