Prognostic Biomarker For Colon Cancer Research Articles

Circulating Tumor DNA as a Prognostic Biomarker in Colon Cancer

Adjuvant chemotherapy has been shown to confer a modest incremental survival benefit for patients with stage III colon cancer (N Engl J Med 2004;

SATB2 and CDX2 are prognostic biomarkers in DNA mismatch repair protein deficient colon cancer

DNA mismatch repair protein deficient colon cancer frequently displays reduced CDX2 expression, and recent literature has suggested that negative CDX2 expression is a poor prognostic biomarker in colon cancer. We have recently demonstrated that SATB2 is an immunohistochemical marker that is complementary to CDX2. Using a tissue microarray approach, we evaluated SATB2 and CDX2 immunohistochemical expression in 514 patients with colonic adenocarcinoma including 146 with mismatch repair protein deficient tumors and correlated expression with histopathologic variables, molecular alterations, and survival. Overall, SATB2-negative and/or CDX2-negative expression was identified in 33% of mismatch repair protein deficient tumors compared with only 15% of mismatch repair protein proficient tumors (p < 0.001) and in 36% of BRAF V600E mutated compared with only 13% of BRAF wild-type tumors (p < 0.001). Both SATB2-negative and CDX2-negative colonic adenocarcinomas more often displayed lymphatic invasion, venous invasion, and perineural invasion (all with p < 0.05). SATB2-negative expression was also more frequently identified in tumors with mucinous or signet ring cell differentiation (p < 0.01 for both). In a multivariable analysis of survival in patients with mismatch repair protein deficient tumors (n = 131), only tumor stage (p = 0.01) and SATB2-negative and/or CDX2-negative expression (p = 0.009) independently predicted disease-specific survival. Of the 99 patients with stage II or III mismatch repair protein deficient tumors, death from disease only occurred in patients with either SATB2-negative or CDX2-negative tumors, and no patients with SATB2-positive/CDX2-positive tumors developed recurrence or died of disease. SATB2 and CDX2 expression had no effect on patient survival in mismatch repair protein proficient, BRAF-mutated, or KRAS-mutated tumors. In summary, our results suggest that SATB2 and CDX2 are prognostic biomarkers in patients with mismatch repair protein deficient colon cancer and that inclusion of SATB2 and CDX2 immunohistochemistry may be helpful as part of a comprehensive pathologic risk assessment in mismatch repair protein deficient colon cancer.

Overexpression of FZD7 is associated with poor survival in patients with colon cancer

BackgroundOverexpression of Frizzled-7 (FZD7) has been associated with tumor invasion and distant metastases, but little is known about the relationship between FZD7 expression and prognosis in colon cancer. Patients and methodsA total of 114 patients with colon cancer between June 2010 and December 2010 were enrolled in this study. The expression of FZD7 in cancerous and adjacent non-cancerous tissues was determined by immunohistochemistry, and the association between FZD7 expression and patient’s clinicopathological characteristics was explored. The correlation between FZD7 expression and prognosis of colon cancer patients was analyzed using the Oncomine database and R2. ResultsFZD7 expression levels were significantly higher in colon cancer tissues compared with adjacent non-cancerous tissues (P < 0.001). High expression of FZD7 was significantly associated with metastatic or recurrent disease in colon cancer (P = 0.010). Kaplan-Meier survival analysis demonstrated that colon cancer patients with high expression of FZD7 had a significantly poorer OS (P = 0.013) and DFS (P = 0.010). Cox regression demonstrated that the expression of FZD7 was an independent prognostic factor for DFS (HR = 6.647, P = 0.023). A meta-analysis from the Oncomine database demonstrated that FZD7 mRNA levels were significantly higher in colorectal cancer tissues than in normal colorectal tissues, and FZD7 high expression was associated with a significantly poorer event and relapse-free survival time by analyzing the data from the R2: Genomics Analysis and Visualization Platform. ConclusionsOverexpression of FZD7 was associated with poor survival in patients with colon cancer. Our data suggest that FZD7 expression could be an effective prognostic biomarker for colon cancer.

RBP7 is a clinically prognostic biomarker and linked to tumor invasion and EMT in colon cancer.

RBP7 is a member of the cellular retinol-binding protein (CRBP) family and previous data suggested a link between CRBPs and the malignant transformation of colon cancer cells. Here, we investigated the potential of RBP7 as a predictive biomarker for patients with colon cancer and determined its functional relevance for tumor progression. We analyzed RBP7 protein and mRNA expression in independent tissue collections of colon cancers with recorded follow-up data, including data from TCGA. We used gene set enrichment analyses to characterize its functional role. Effects of RBP7 on migration and invasion were determined in transwell assays. High expression of RBP7 was an independent biomarker of poor cancer specific survival in early and late stage colon cancer, and linked to colon cancer progression. Gene set enrichment analysis revealed a strong association of RBP7, colon cancer invasion and epithelial mesenchymal transition (EMT). Ectopic expression of RBP7 increased migration and invasion of colon cancer cells. Our findings demonstrate that RBP7 is a strong prognostic biomarker in colon cancer that functionally contributes to the malignant phenotype of colon cancer cells. This may aid in risk stratification for the therapeutic management of patients with colorectal cancer.

Independent prognostic genes and mechanism investigation for colon cancer

ProposeWe aimed to explore the potential molecular mechanism and independent prognostic genes for colon cancer (CC).MethodsMicroarray datasets GSE17536 and GSE39582 were downloaded from Gene Expression Omnibus. Meanwhile, the whole CC-related dataset were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed mRNA (DEMs) were identified between cancer tissue samples and para-carcinoma tissue samples in TCGA dataset, followed by the KEGG pathway and GO function analyses. Furthermore, the clinical prognostic analysis including overall survival (OS) and disease-free survival (DFS) were performed in all three datasets.ResultsA total of 633 up- and 321 down-regulated mRNAs were revealed in TCGA dataset. The up-regulated mRNAs were mainly assembled in functions including extracellular matrix and pathways including Wnt signaling. The down-regulated mRNAs were mainly assembled in functions like Digestion and pathways like Drug metabolism. Furthermore, up-regulation of UL16-binding protein 2 (ULBP2) was associated with OS in CC patients. A total of 12 DEMs including Surfactant Associated 2 (SFTA2) were potential DFS prognostic genes in CC patients. Meanwhile, the GRP and Transmembrane Protein 37 (TMEM37) were two outstanding independent DFS prognostic genes in CC.ConclusionsULBP2 might be a potential novel OS prognostic biomarker in CC, while GRP and TMEM37 could be served as the independent DFS prognostic genes in CC. Furthermore, functions including extracellular matrix and digestion, as well as pathways including Wnt signaling and drug metabolism might play important roles in the process of CC.

The epigenetic modifier PBRM1 restricts the basal activity of the innate immune system by repressing retinoic acid-inducible gene-I-like receptor signalling and is a potential prognostic biomarker for colon cancer.

It has long been known that patients suffering from inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). The innate immune system of host cells provides a first-line defence against pathogenic infection, whereas an uncontrolled inflammatory response under homeostatic conditions usually leads to pathological consequences, as exemplified by the chronic inflammation of IBD. The key molecules and pathways keeping innate immunity in check are still poorly defined. Here, we report that the chromatin remodeller polybromo-1 (PBRM1) is a repressor of innate immune signalling mediated by retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs). Knockdown of PBRM1 in colon cancer cells increased the expression of two receptor genes (RIG-I and MDA5) and upregulated interferon (IFN)-related and inflammation-related gene signatures. The innate immune signal stimulated by a double-stranded RNA viral mimic was exaggerated by PBRM1 suppression. PBRM1 cooperated with polycomb protein EZH2 to directly bind the cis-regulatory elements of RIG-I and MDA5, thereby suppressing their transcription. Moreover, upregulation of RIG-I and MDA5 is required for IFN response activation induced by PBRM1 silencing. TRIM25, a protein stimulated by the RLR pathway and IFN production, physically interacted with PBRM1 and induced PBRM1 protein destabilization by promoting its ubiquitination. These findings reveal a PBRM1-RLR regulatory circuit that can keep innate immune activity at a minimal level in resting cells, and also ensure a robust inflammatory response in the case of pathogen invasion. PBRM1 was found to be downregulated in primary tissues from patients with CRC or IBD, and its expression correlated negatively with that of RLR genes and interferon-stimulated genes in CRC samples. Lower PBRM1 expression was associated with advanced pathological grade and poorer survival of CRC patients, indicating that PBRM1 could serve as a potential prognostic biomarker for CRC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Whole exome sequencing identifies novel prognostic biomarker in colon cancer.

e15098 Background: The incidence and mortality of cancer have been increasing in China, of which colorectal cancer (CRC) is ranking the fifth and among the leading cause of cancer-related deaths .Prognostic biomarker for colon cancer treated with standard adjuvant chemotherapy was rare and inconsistent, as gene mutations accumulation contribute to the carcinogenesis, available biomarkers may emerge by genome investigation. Methods: Whole exome sequencing was performed in 13 stage III colon cancers to identify gene alternations in patients with different outcomes, followed by 350 stage II-III colon cancers samples, of which clinicopathological characteristics and survival information were collected simultaneously to evaluate the clinical relevance in this cohort for evaluation of novel gene biomarkers. Results: Eight genes (CD97, ZNF568, WARS2, IL6R, APPL2, C9orf117, ANKRD32, ZNF443) were identified as differently expressed between two groups of good (DFS &gt; 60 months) and poor (DFS &lt; 25 month) separated according to treatment outcomes. ZNF443 was detected in 81.7% (286/350) samples, and ZNF443 (CA) was more common in male compared with female (56.0% vs 40.8%, P = 0.011).ZNF443 (CA) distribution differed related to different N stage, only stage N0 shared a higher frequency over 50% (P = 0.026).ANKRD32 was detected in 212 (93.8%) tumors, and ANKRD32 (CA) appeared more in left sites (included left colon and sigmoid colon, 61.1% vs 41.9%, P = 0.006). Moreover, ANKRD32 (CA) was significantly associated with superior disease-free survival (DFS) in stage III colon cancer patients (P = 0.044, HR 0.49, 95% CI0.24-0.98).Tumor nodal stage appeared as independent prognostic factor for DFS and over-all survival (OS) in stage II-III colon cancer (P &lt; 0.05), and low tumor differentiation indicated a worse OS for colon cancers. While no other significant association was obtained between genes and survival in present study. Conclusions: Whole exome sequencing was efficient in discovering novel gene biomarkers in clinical evaluation. ANKRD32 was independently prognostic for DFS in stage III colon cancer.

The expression of metastasis-associated in colon cancer-1 and KAI1 in gastric adenocarcinoma and their clinical significance

BackgroundThe most common reason for malignant tumor treatment failure is recurrence and metastasis. Metastasis-associated in colon cancer-1 (MACC1) was originally identified as a metastatic and prognostic biomarker for colon cancer and later other solid tumors. Kangai 1 (KAI1), a marker of suppressor of metastasis, is also associated with metastasis and poor prognosis in many tumors. However, the prognostic value of either MACC1 or KAI1 in gastric adenocarcinoma (GAC) is unclear. In this study, we explored the relationship between MACC1 and KAI1 expression, as well as their respective correlation with clinicopathological features, to determine if either could be helpful for improvement of survival prognosis in GAC patients.MethodsThe expression levels of both MACC1 and KAI1 in 325 whole-tissue sections of GAC were examined by immunohistochemistry. Clinical data was also collected.ResultsMACC1 was significantly overexpressed in GAC tissues when compared to levels in normal gastric tissues; KAI1 was significantly down-expressed in GAC tissues when compared to levels in normal gastric tissues. Investigation of association between MACC1 and KAI1 protein levels with clinicopathological parameters of GAC indicated association between the expression of each with tumor grade, lymph node metastasis, invasive depth, and TNM stages. The overall survival time of patients with MACC1- or KAI1-positive GAC tumors was significantly shorter or longer than that of those who were negative. Importantly, multivariate analysis suggested that positive expression of either MACC1 or KAI1, as well as TNM stage, could be independent prognostic factors for overall survival in patients with GAC.ConclusionsMACC1 and KAI1 may represent promising metastatic and prognostic biomarkers, as well as potential therapeutic targets, for GAC.

CDX2 as a Prognostic Biomarker in Colon Cancer.

CDX2 as a Prognostic Biomarker in Colon Cancer.

CDX2 as a Prognostic Biomarker in Colon Cancer.

CDX2 as a Prognostic Biomarker in Colon Cancer.

Clinical relevance of the differential expression of the glycosyltransferase gene GCNT3 in colon cancer

Altered glycosylation is considered a universal cancer hallmark. Mucin-type core 2 1,6-N-acetylglucosaminyltransferase enzyme (C2GnT-M), encoded by the GCNT3 gene, has been reported to be altered in tumours and to possess tumour suppressor properties. In this work, we aimed to determine the possible role of GCNT3 gene expression as prognostic marker in colon cancer. We investigated the differential expression of GCNT3 gene among tumour samples from stage II colon cancer patients by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Univariate and Multivariate Cox regression analyses were used to determine the correlation between GCNT3 expression and disease-free survival. The risk of relapse in GCNT3 low-expressing cancer patients was significantly higher than that in GCNT3 high-expressing patients in both training (Hazard Ratio (HR) 4.26, p=0.002) and validation (HR 3.06, p=0.024) series of patients, and this association was independent of clinical factors. Additionally, qRT-PCR was used to explore the modulation of GCNT3 expression by different antitumour drugs. Three chemotherapeutic agents with different mechanism of action (5-fluorouracil, bortezomib and paclitaxel) significantly induced GCNT3 expression in several cancer cells, being observed the correlation between antitumour action and GCNT3 modulation, whereas this gene was not modulated in cells that do not respond to treatment. Overall, these results indicate that low GCNT3 expression is a promising prognostic biomarker for colon cancer that could be used to identify early-stage colon cancer patients at high risk of relapse. Additionally, our results suggest that this enzyme might also constitute a biomarker to monitor tumour response to chemotherapy in cancer patients.

Utilizing quantitative immunohistochemistry for relationship analysis of tumor microenvironment of head and neck cancer patients

Meeting abstracts Analysis of tumor-infiltrating immune cells using quantitative immunohistochemistry (IHC) has proved to be a powerful prognostic biomarker in colon cancer [[1][1], [2][2]]. Similar observations have been made in patients with oral, head and neck squamous cell carcinoma (OHNSCC),

Kallikrein-related peptidase 6 (KLK6) expression in the progression of colon adenoma to carcinoma.

KLK6 is a secreted trypsin-like serine protease. KLK6 mRNA expression and its association with colon cancer (CC) progression was studied using quantitative real-time PCR. We examined the expression of KLK6 in 232 colon tissues (cancerous, non-cancerous, and adenomatous). We proved that KLK6 expression in CC behaves as a continuous variable, as its expression correlates significantly with increasing tumor stage (p=0.004) and histological grade (p=0.007). Interestingly, the expression of KLK6 in adenomas was significantly higher than that in the cancerous or non-cancerous tissues examined (p<0.001). Cox proportional hazard regression model using univariate analysis revealed that positive KLK6 expression is a significant factor for disease-free survival (DFS) (p=0.017) and overall survival (OS) (p=0.002) of patients. Kaplan-Meier survival curves demonstrated that KLK6-negative expression is significantly associated with longer DFS (p=0.009) and OS (p=0.001). ROC analysis showed that KLK6 expression has significant discriminatory power in distinguishing cancerous from non-cancerous colon tissues (p<0.001), or cancerous from adenoma tissues (p=0.001), or adenoma from non-cancerous colon tissues (p<0.001). Additionally, strong KLK6 immunostaining was seen in the cancer cells of selected CC sections, as well as in glandular cells and inflammatory cells of adenomas. In conclusion, KLK6 may represent a potential unfavorable prognostic biomarker for CC.

Expression of aquaporin-1 is a poor prognostic factor for stage II and III colon cancer

Colorectal cancer is a major cause of cancer-related mortality worldwide, with a high incidence of recurrence following curative resection, particularly among patients with stage II and III disease. There is therefore a need for novel prognostic biomarkers for advanced colon cancer and it was recently reported that aquaporin-1 (AQP1) may be associated with aggressive characteristics of colon cancer cells in experimental data. The association of clinicopathological findings with AQP1 expression was evaluated by tissue microarray (TMA) analysis, to determine whether AQP1 is a prognostic biomarker for colon cancer. A total of 120 consecutive stage II and III colon cancer patients (51 with stage II and 69 with stage III) who underwent curative resection between 1997 and 2008 were analyzed. The TMA was prepared from archival formalin-fixed, paraffin-embedded tissue blocks. Immunostaining was graded semi-quantitatively by considering the staining intensity and the percentage of positive tumor cells. Results showed the AQP1-positive rate to be 35.8%. The expression of AQP1 was associated with lymph node metastasis, lymphovascular and vascular invasion. The 5-year survival rate of the AQP1-positive and -negative groups was 73.7 and 87.9%, respectively. The survival rate of the positive group was significantly lower compared to that of the negative group (P=0.030). Furthermore, the expression of AQP1 was an independent poor prognostic factor according to the multivariate analysis. Therefore, AQP1 may be a promising candidate as a prognostic biomarker for colon cancer.

Abstract 3218: Interrogating the role of NOX4 in colon cancer metastasis.

Abstract Colon cancer is a major cause of cancer-related deaths worldwide. Adjuvant chemotherapy significantly reduces mortality in stage III colon cancer; however, it is only marginally effective in stage II patients. Molecular biomarkers are used to partition tumors into a poor prognosis group that is likely to metastasize and a good prognosis group that has a higher probability to be relapse-free. These biomarkers for relapse risk are of clinical interest, and lead to insight into how a tumor progresses to metastasis. There is increasing evidence that cancer of the ascending (right-side) colon is different from the descending (left-side) colon. There are site-specific differences in histological and molecular characteristics and different signaling pathways have been shown to dominate progression to relapse in right and left-side colon cancer. We have observed that the genes altered in expression between the poor prognosis and good prognosis tumors vary significantly depending on whether the malignancy originates on the right or left side of the colon. We have identified NADPH oxidase 4 (NOX4) to be highly predictive of relapse in stage II and stage III left-side colon cancer where elevated expression of NOX4 is correlated with relapse. Furthermore, NOX4 expression is greatly elevated in the human colon cancer derived metastatic cell line SW620 compared to human cell lines derived from primary adenoma or carcinoma colon tumors. NOX4 silencing using RNA interference results in decreased levels of reactive oxygen species (ROS). The NOX family of genes has been implicated in cancer development in several types of cancer while overproduction of ROS has been implicated in tumor metastasis. We are exploring the newly identified role of NOX4-mediated ROS generation in metastatic colon cancer. To investigate the underlying molecular mechanism we are analyzing the effect of NOX4 silencing via RNA interference and NOX4 inhibition using pharmacological NOX inhibitors on global protein expression patterns in metastatic-derived SW620 cells. Proteomic changes are being assessed by iTRAQ labeling and mass spectrometry. Bioinformatics and cluster analysis will be used to identify the functional role of redox responsive and ROS regulative proteins in colon cancer metastasis. The role of NOX4 as a prognostic biomarker in colon cancer makes it an important target for research in cancer biology and therapeutics. Citation Format: Kerry M. Bauer, Steven Buechler, Amanda B. Hummon. Interrogating the role of NOX4 in colon cancer metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3218. doi:10.1158/1538-7445.AM2013-3218

Expression level and glycan dynamics determine the net effects of TIMP-1 on cancer progression

Tissue inhibitor of metalloproteinases (TIMPs; TIMP-1, -2, -3 and -4) are endogenous inhibitor for matrix metalloproteinases (MMPs) that are responsible for remodeling the extracellular matrix (ECM) and involved in migration, invasion and metastasis of tumor cells. Unlike under normal conditions, the imbalance between MMPs and TIMPs is associated with various diseased states. Among TIMPs, TIMP-1, a 184-residue protein, is the only N-linked glycoprotein with glycosylation sites at N30 and N78. The structural analysis of the catalytic domain of human stromelysin-1 (MMP-3) and human TIMP-1 suggests new possibilities of the role of TIMP-1 glycan moieties as a tuner for the proteolytic activities by MMPs. Because the TIMP-1 glycosylation participate in the interaction, aberrant glycosylation of TIMP-1 presumably affects the interaction, thereby leading to pathogenic dysfunction in cancer cells. TIMP-1 has not only the cell proliferation activities but also anti-oncogenic properties. Cancer cells appear to utilize these bilateral aspects of TIMP-1 for cancer progression; an elevated TIMP-1 level exerts to cancer development via MMP-independent pathway during the early phase of tumor formation, whereas it is the aberrant glycosylation of TIMP-1 that overcome the high anti-proteolytic burden. The aberrant glycosylation of TIMP-1 can thus be used as staging and/or prognostic biomarker in colon cancer. [BMB Reports 2012; 45(11): 623-628]

Prognostic Significance of miR-215 in Colon Cancer

We have previously shown that miR-215 suppressed the expression of key targets such as thymidylate synthase (TS), dihydrofolate reductase, and denticleless protein homolog (DTL) in colon cancer. miR-215 is a tumor suppressor candidate due to the upregulation of p53 and p21 by targeting DTL. However, high levels of miR-215 conferred chemoresistance due to cell cycle arrest and reduced cell proliferation by suppressing DTL. In this study, the clinical significance of miR-215 was further investigated as a potential prognostic biomarker in colon cancer patients. Total RNAs were extracted from 34 paired normal and colon (stage II and III) tumor specimens using the Trizol-based approach. The levels of miR-215 and a closely related miR-192 were quantified using quantitative real-time polymerase chain reaction (qRT-PCR) expression analysis. The expression of DTL mRNA and protein were quantified by real time qRT-PCR and immunohistochemistry. The expression levels of miR-192 (P = .0008) and miR-215 (P < .0001) were significantly decreased in colon tumors compared with normal tissues. DTL was significantly over-expressed and was inversely correlated with miR-215, further suggesting an in vivo physiologic relevance of miR-215 mediated DTL suppression. Kaplan-Meier survival analysis by Cox regression revealed that high levels of miR-215 expression (hazard ratio, 3.516; 95% confidence interval, 1.007-12.28, P = .025) are closely associated with poor patient's overall survival. Furthermore, an elevated expression of a miR-215 target protein DTL was detected in colon cancer tissues whereas no expression was present in normal tissues. miR-215 has a unique potential as a prognostic biomarker in stage II and III colon cancer.

Expression of the Tumor Suppressor Krüppel-Like Factor 4 as a Prognostic Predictor for Colon Cancer

The zinc finger transcription factor Krüppel-like factor 4 (KLF4) regulates numerous physiologic processes, including proliferation, differentiation, and development. Studies also showed that KLF4 is involved in tumorigenesis and somatic cell reprogramming. Here, we aimed to assess whether KLF4 is a prognostic indicator for colon cancer. Levels of KLF4 were measured by immunohistochemical analysis of a tissue microarray containing 367 independent colon cancer sections. Univariate data analysis was done in addition to construction of multivariate models with several clinicopathologic factors to evaluate KLF4 as an independent predictor of survival and cancer recurrence (disease-free survival). Colon cancer tissues had significantly overall lower KLF4 levels compared with noncancer tissues (P < 0.0001). Using logistic regression, a trend was noted for decreased odds of KLF4 expression in higher stages of tumors. In univariate and multivariate analyses, KLF4 was a significant predictor of survival and recurrence. KLF4 expression is significantly downregulated in colon cancer, and loss of KLF4 is an independent predictor of survival and recurrence. These findings suggest that KLF4 may serve as a prognostic biomarker for colon cancer.

K- RAS Mutation in the Screening, Prognosis and Treatment of Cancer

The potential use of K-RAS mutation as a cancer screening biomarker has been investigated for many years. Numerous associations between K-RAS mutation and various cancers have been established, but these associations have not been translated into effective, cost-efficient cancer screening strategies. This lack of progress may be due to the existence of K-RAS mutation in nontumor tissues and/or using detection, rather than quantitation, of K-RAS mutation as the endpoint for cancer risk categorization. K-RAS mutation appears to be a useful prognostic biomarker for colon cancer. Recent progress toward sensitive and quantitative mutation characterization and the successful use of K-RAS mutation in a personalized medicine approach to targeted biological therapy selection are likely to re-direct and expand the use of K-RAS mutation as a cancer biomarker in the near future.

Association of Inflammation-Related and microRNA Gene Expression with Cancer-Specific Mortality of Colon Adenocarcinoma

Inflammatory genes and microRNAs have roles in colon carcinogenesis; therefore, they may provide useful biomarkers for colon cancer. This study examines the potential clinical utility of an inflammatory gene expression signature as a prognostic biomarker for colon cancer in addition to previously examined miR-21 expression. Quantitative reverse transcriptase-PCR. was used to measure the expression of 23 inflammatory genes in colon adenocarcinomas and adjacent noncancerous tissues from 196 patients. These data were used to develop models for cancer-specific mortality on a training cohort (n = 57), and this model was tested in both a test (n = 56) and a validation (n = 83) cohort. Expression data for miR-21 were available for these patients and were compared and combined with inflammatory gene expression. PRG1, IL-10, CD68, IL-23a, and IL-12a expression in noncancerous tissue, and PRG1, ANXA1, IL-23a, IL-17a, FOXP3, and HLA-DRA expression in tumor tissues were associated with poor prognosis based on Cox regression (/Z-score/ >1.5) and were used to generate the inflammatory risk score (IRS). IRS was associated with cancer-specific mortality in the training, test (P = 0.01), and validation (P = 0.02) cohorts. This association was strong for stage II cases (P = 0.002). Expression of miR-21 was associated with IL-6, IL-8, IL-10, IL-12a, and NOS2a, providing evidence that the function of this microRNA and these inflammatory genes are linked. Both IRS and miR-21 expression were independently associated with cancer-specific mortality, including stage II patients alone. IRS and miR-21 expression are independent predictors of colon cancer prognosis and may provide a clinically useful tool to identify high-risk patients.