The prognostic value of c‐Kit,K‐ras codon 12, and p53 codon 72 mutations in Egyptian patients with stage II colorectal cancer

BACKGROUND:

The prognosis for patients with colorectal cancer (CRC) depends mainly on standard clinicopathologic factors. However, patients with similar disease characteristics exhibit various outcomes, especially in stage II. Therefore, the identification of molecular prognostic markers is needed to predict patient outcomes.

METHODS:

The authors assessed the prognostic value of c‐Kit (also called cluster of differentiation 117 [CD117] or KIT), cyclooxygenase‐2 (COX‐2), tumor protein 53 (p53), and Kirsten rat sarcoma viral oncogene homolog (K‐ras) aberrations in 90 patients with stage II CRC using immunohistochemistry and molecular techniques. The results were correlated with standard clinicopathologic prognostic factors, overall survival (OS), and disease‐free survival (DFS).

RESULTS:

COX2 and c‐Kit overexpression was detected in 54.6% and 59.3% of patients, respectively. Overexpression of p53 was detected in 47 patients, including 29 who had mutations, and a unique mutation pattern was detected with 3 hotspots at codons 72, 245, and 273. Overexpression of ras was detected in 44 patients, including 37 who had mutations. On multivariate analysis, c‐Kit overexpression, p53 codon 72 mutations, perforation, and performance status were independent prognostic factors for DFS (P = .054, P = .015, P < .0001, and P = .043, respectively); whereas codon 12 K‐ras mutation, performance status, and perforation were independent prognostic factors for OS (P = .033, P = .006, and P < .0001, respectively).

CONCLUSIONS:

The current results provide evidence for the prognostic value of c‐Kit overexpression in patients with stage II CRC. The high p53 mutation rate and the unique hotspot in codon 72 have not been reported previously in CRC. This may be related to environmental or racial features that are unique to the studied population. Cancer 2010. © 2010 American Cancer Society.     

Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis

Many colorectal tumors lose or downregulate cell surface expression of MHC class I molecules conferring resistance to T-cell-mediated attack. It has been suggested that this phenomenon is due to in vivo immune-tumor interactions. However, evidence of the impact of MHC class I loss on outcomes from colorectal cancer is scarce. In our study of more than 450 colorectal cancers in tissue microarray format, we have shown that both high levels of MHC class I expression and absent MHC class I expression are associated with similar disease-specific survival times, possibly due to natural killer cell-mediated clearance of MHC class I-negative tumor cells. However, tumors with low level expression of MHC class I were found to confer a significantly poorer prognosis, retaining independent significance on multivariate analysis. The existence of these poor prognosis tumors, which may avoid both NK- and T-cell-mediated immune surveillance, has important implications for the design of immunotherapeutic strategies in colorectal cancer.     

Diagnostic value of preoperative serum carcinoembryonic antigen and carbohydrate antigen 19-9 in colorectal cancer

Background

Since the first introduction of tumour markers, their usefulness for diagnosis has been a challenging question. The aim of the present prospective study was to investigate, in colorectal cancer patients, the relationship between preoperative tumour marker concentrations and various clinical variables.

Methods

The study prospectively enrolled 131 consecutive patients with a confirmed diagnosis of colorectal carcinoma and 131 age- and sex-matched control subjects with no malignancy. The relationships of the tumour markers carcinoembryonic antigen (cea) and carbohydrate antigen (ca) 19-9 with disease stage, tumour differentiation (grade), mucus production, liver function tests, T stage, N stage, M stage were investigated.

Results

Serum concentrations of cea were significantly higher in the patient group than in the control group (p = 0.001); they were also significantly higher in stage iii (p = 0.018) and iv disease (p = 0.001) than in stage i. Serum concentrations of cea were significantly elevated in the presence of spread to lymph nodes (p = 0.005) in the patient group. Levels of both tumour markers were significantly elevated in the presence of distant metastasis in the patient group (p = 0.005 for cea; p = 0.004 for ca 19-9).

Conclusions

Preoperative levels of cea and ca 19-9 might provide an estimate of lymph node invasion and distant metastasis in colorectal cancer patients.     

Inverse correlation of HER2 with MHC class I expression on oesophageal squamous cell carcinoma

Background:

As HER2 is expressed in 30% of oesophageal squamous cell carcinomas (ESCCs), T-cell-based immunotherapy and monoclonal antibodies targeted against HER2 are attractive, novel approaches for ESCCs. However, it was shown that there is an inverse correlation between HER2 and MHC class I expression on tumours. Thus, the correlation between HER2 and MHC class I expressions on ESCC was evaluated.

Methods:

Expressions of MHC class I and HER2 in ESCC tissues (n=80) and cell lines were assessed by immunohistochemistry, fluorescence in situ hybridisation (FISH), and flow cytometry. We investigated whether HER2 downregulation with small interfering RNA (siRNA) in ESCC cell lines could upregulate the expression of MHC class I and the antigen presentation machinery components, and could increase their sensitivity for tumour antigen-specific CTLs.

Results:

There was an inverse correlation between HER2 and MHC class I expressions in both tumour tissues and cell lines. Downregulation of HER2 with siRNA resulted in the upregulation of MHC class I expression, leading to increased CTL recognition by tumour antigen-specific CTLs.

Conclusion:

HER2-overexpressing ESCC tumour cells showed a reduced sensitivity for CTLs through the downregulation of MHC class I.     

Thyroid hormone receptor beta1 in normal colon and colorectal cancer-association with differentiation, polypoid growth type and K-ras mutations

The precursors for colorectal cancer include polypoid (conventional), flat and serrated adenomas. Polypoid growth in polypoid adenomas and serrated adenomas is associated with K-ras mutations. The regulation of polypoid or nonpolypoid growth is not well known, but could be related to trophic stimuli, such as thyroid hormones. Hence, we investigated the expression pattern of thyroid hormone receptor TRbeta1 in colorectal mucosa and in colorectal tumours and its relationship to tumour growth type. One hundred fourteen colorectal carcinoma specimens were evaluated for TRbeta1. Normal mucosa, adjacent adenomatous component (N = 46) and lymph node metastases (N = 28) were analysed when present, and the results were confirmed by Western blot analysis in selected cases. Nuclear TRbeta1 was almost always present in normal epithelium (96%), but less frequent in adenomas (83%) and in cancer (68%; p < 0.001 and p < 0.001, respectively). TRbeta1 was associated with polypoid growth, presence of K-ras mutations and also with a higher WHO histological grade and advanced Dukes' stage. Cytoplasmic expression of TRbeta1 was observed in nonneoplastic and neoplastic epithelium. In Western blot analysis, a 58 kDa band corresponding to TRbeta1 was expressed in normal mucosa and in colorectal cancer specimens with positive immunohistochemistry. Association of TRbeta1 expression with growth pattern and the presence of K-ras mutations suggest that abnormalities in thyroid hormone signalling involving TRbeta1 play a role in the development of some types of colorectal adenocarcinomas.     

Favorable outcome in clinically stage II melanoma patients is associated with the presence of activated tumor infiltrating T-lymphocytes and preserved MHC class I antigen expression

In this study we investigated whether the presence of specific populations of tumor infiltrating lymphocytes (TILs) in diagnostic primary melanoma biopsies are related to outcome in clinically stage II melanoma patients. Moreover, we investigated whether the presence of TILs correlates with expression of MHC class I antigen and MHC class II antigen on tumor cells and/or tumor infiltrating antigen presenting cells. Diagnostic primary melanoma samples of 15 patients with an unfavorable outcome were compared with 20 patients with favorable outcome. Patients were matched for age, gender and Breslow thickness. Biopsies were examined for the presence of granzyme B+, CD8+, CD4+ and CD56+ TILs and for expression of MHC class I antigen and MHC class II antigen on tumor and/or tumor infiltrating cells. A favorable clinical outcome was strongly associated with the presence of GrB+ and CD4+ TILs, with expression of MHC class I antigen on tumor cells and with expression of MHC class II antigen on intratumoral antigen presenting cells. These data strongly support the notion that in melanoma patients the cellular immune response is a major factor in preventing melanoma cell dissemination.     

Expression of the stress-related MHC class I chain-related protein MICA is an indicator of good prognosis in colorectal cancer patients

The realization of targeted cancer therapy has driven the need to improve selection of patients with colorectal cancer for adjuvant therapy, leading to a search for potential new prognostic markers. There is accumulating evidence that immunosurveillance acts as an extrinsic tumor suppressor. As genetic instability is an early event in colorectal cancer, this can lead to altered expression of molecules conferring resistance to immune attack. Hence, molecules up or downregulated in this process may impact on patient survival. In our study, 449 colorectal tumors were screened for expression of the stress-related protein MICA, which functions as a ligand for the NKG2D receptor and whose expression confers susceptibility to both T- and NK-cell attack. Intensity of MICA expression was quantified using automated image analysis and MICA expression showed no correlation with conventional clinicopathological variables. In contrast, survival analysis showed a significant correlation between higher levels of MICA expression and improved disease-specific survival, with independent prognostic significance in multivariate analysis. Thus, patients with low levels of MICA and a poor prognosis may be good candidates for aggressive chemotherapy. In contrast, patients with high expression of MICA may be candidates for the antibody therapies, as they should be susceptible to NK killing by antibody dependent cellular cytotoxicity.     

Detection efficiency of colorectal carcinoma recurrence using technetium pertechnetate-anti-carcinoembryonic antigen monoclonal antibody BW 431/26

Background. A new anti-carcinoembryonic antigen (CEA) antibody, BW 431/26 (Scintimun, Behring-Werke, Marburg, Germany), labeled with technetium pertech-netate (Tc-99m), is an intact immunoglobulin G₁ monoclonal antibody that has been used to image colorectal cancer (CRC). This report is part of a prospective multicenter clinical trial initiated by the International Atomic Energy Agency to evaluate the role of this antibody in radioimmunoimaging of patients with suspected disease recurrence. Methods. A group of 31 consecutive patients underwent radioimmunoimaging with Tc-99m-BW 431/26 after resection of their primary CRC. Patient referral was based on either a persistent rise in serum CEA levels of unknown origin and/or questionable findings by other imaging studies. Whole-body planar scans and single photon emission computed tomography scans of selected body regions (e.g., chest, abdomen) were performed up to 24 hours after the intravenous antibody injection. Pathologic antibody concentration localizations by radioimmunoimaging were correlated with surgical, clinical, and other imaging modality findings to validate the accuracy of radioimmunoimaging in detecting CRC recurrence. Results. A total of 75 detected tumoral lesions was evaluated: 26 of 75 were of known origin (36%), and 49 of 75 were of unknown origin (65%). There were four true-negative lesions, one false-negative lesion, and no false-positive lesions; all others were true-positive lesions. Sensitivity was 96.8%, specificity 100%, and accuracy 98.6%. The study was easy to perform, without untoward side effects on patients after antibody administration. Conclusions. Anti-CEA antibody radioimmunoimaging is a highly reliable diagnostic procedure in detecting CRC recurrence and is useful especially for the diagnosis of patients with rising CEA blood levels of unknown origin, thereby significantly affecting patient management. Radioimmunoimaging should become part of the diagnostic workup of patients suspected of having CRC recurrence. Cancer 1995; 76:215-22.     

The 8.1 ancestral MHC haplotype is strongly associated with colorectal cancer risk

Many recent data indicate that some alleles encoded in the central major histocompatibility complex (MHC) region (Class III) of short arm of chromosome 6 may modify the risk of cancer development. Therefore we determined 4 single nucleotide polymorphisms (SNPs) of this region (TNF-alpha -308 G > A, RAGE -429 T > C, HSP70-2 -1267 A > G, LTA 252 A > G) in genomic DNA samples from 183 Hungarian patients with colorectal cancer and 141 age matched control subjects representing the Hungarian population of the same age and gender. No significant differences were found in either SNP tested. When, however, three- or four-locus haplotypes consisting of known constituents of the so-called 8.1 ancestral haplotype (8.1AH) were considered, marked differences were observed. Frequency of TNF-alpha -308A, RAGE -429C, HSP70-2 -1267G, LTA 252G (8.1AH) haplotype was significantly (p = 0.006) more frequent (19.1%) among patients than in the controls (7.7%). Age- and gender-adjusted ratio of the 8.1AH carriers vs. non-carriers to have colorectal cancer was 2.514 (1.130-5.594). This risk was higher in 相似文献   

Deficient expression of components of the MHC class I antigen processing machinery in human cervical carcinoma.

In cervical carcinomas abnormalities in the MHC class I surface expression are a frequent event, which are often associated with the deficient expression of the peptide transporter subunit TAP1 thereby resulting in impaired T cell response. In order to understand the role of other components of the MHC class I antigen processing machinery (APM) in the immune escape, 16 surgically removed primary cervical carcinoma lesions were analyzed for their mRNA expression of the heterodimeric peptide transporter TAP, the constitutive and interferon (IFN)-gamma inducible proteasome subunits and their activators PA28alpha/beta, various chaperones as well as MHC class I antigens. High expression levels of all APM components were detected in normal cervical tissue, whereas 15/16 of cervical carcinoma lesions exhibited an impaired expression of at least one APM component, including the proteasome subunits, their activators PA28alpha/beta, the peptide transporter subunits TAP1 and TAP2, different chaperones, HLA class I heavy chains and beta2-microglobulin (beta2-m). In particular, calnexin expression was strongly downregulated in 69% of cervical cancer lesions analyzed. Such abnormalities were neither associated with a specific human papilloma virus (HPV) or HLA class I phenotype nor with tumor grading and staging. Analysis of five cervical carcinoma cell lines demonstrated a reduced MHC class I surface expression due to deficient expression and function of TAP, LMP subunits or specific HLA-alleles which could be mostly corrected by IFN-gamma treatment. The high frequency of abnormalities of APM component expression together with their potential negative influence on T cell-mediated immune recognition emphasize the need to evaluate the antigen processing pathway in cervical carcinoma patients, particularly in those selected for T-cell-based immunotherapies.     

Identification and characterization of ANO9 in stage II and III colorectal carcinoma

Background and Objectives: The precise role and potential underlying mechanisms of anoctamin 9 (ANO9) remain largely unknown. This study aims to characterize the role and oncogenic mechanisms of ANO9 in stage II and III colorectal cancer (CRC).Methods: We examined the expression of ANO9 in colorectal cancerous tissues and cells using real-time quantitative PCR and immunohistochemistry, respectively. Multiple cellular and molecular approaches such as gene transfection, CCK-8 assay, flow cytometry, and invasion assay were also performed to explore its oncogenic mechanisms. Furthermore, the clinical significance of ANO9 in clinical CRC specimens was assessed by clinical correlation and survival analyses.Results: Lower expression of ANO9 messenger RNA (mRNA) was frequently detected both in CRC tissues with recurrence and metastasis-derived cell lines. Compared with matched nontumorous tissues, lower expression of ANO9 protein was observed in tumors, which was significantly correlated with tumorigenesis (p < 0.05). In vitro functional studies showed that ANO9 contributed to tumor cell proliferation, apoptosis, and invasion. Moreover, investigation of clinical CRC specimens showed that ANO9 were markedly overexpressed in metastatic tissue compared with primary tissue. Decreased expression of ANO9 was correlated with poor prognostic outcomes.Conclusions: This study highlighted the role of ANO9 in progression and metastasis of stage II and III CRC. These findings suggested that up-regulation of ANO9, as a metastasis-related gene, could be a novel approach for inhibiting CRC progression.     

Lack of HLA class II antigen expression in microsatellite unstable colorectal carcinomas is caused by mutations in HLA class II regulatory genes

Colorectal cancers (CRCs) develop on the basis of a deficient DNA mismatch repair (MMR) system in about 15% of cases. MMR‐deficient CRC lesions show high‐level microsatellite instability (MSI‐H) and accumulate numerous mutations located at coding microsatellite loci that lead to the generation of immunogenic neopeptides. Consequently, the host's antitumoral immune response is of high importance for the course of the disease in MSI‐H CRC patients. Accordingly, immune evasion mediated by impairment of HLA class I antigen presentation is frequently observed in these cancers. In this study, we aimed at a systematic analysis of alterations affecting HLA class II antigen expression in MSI‐H CRC. HLA class II antigens are expressed by only two‐thirds of MSI‐H CRCs. The mechanisms underlying the lack of HLA class II antigens in a subset of MSI‐H CRCs remain unknown. We here screened HLA class II regulatory genes for the presence of coding microsatellites and identified mutations of the essential regulator genes RFX5 in 9 (26.9%) out of 34 and CIITA in 1 (2.9%) out of 34 MSI‐H CRCs. RFX5 mutations were related to lack of or faint HLA class II antigen expression (p = 0.006, Fisher's exact test). Transfection with wild‐type RFX5 was sufficient to restore interferon gamma‐inducible HLA class II antigen expression in the RFX5‐mutant cell line HDC108. We conclude that somatic mutations of the RFX5 gene represent a novel mechanism of loss of HLA class II antigen expression in tumor cells, potentially contributing to immune evasion in MSI‐H CRCs.     

The study of colorectal carcinoma associated antigen lea in clinical pathological diagnosis

The colorectal cancer is a disease which seriously threatens human being[1]. Early diagnosis and early treatment are very important to improve the life quality and the survival rate. CEA is a serum tumor marker for colorectal cancer first discovered by Gold and Freedman in 1965[2]. It is a glycoprotein of about 180 KD and a tumor-associated antigen extracted from colon cancer and fetal intestine. It is an extensively used broad-spectrum tumor marker at present. In 1986 Song Jin-dan, using …     

Prognostic value of the ratio of carcinoembryonic antigen concentration to maximum tumor diameter in patients with stage II colorectal cancer

BackgroundRecently, a study from our center indicated that the ratio of preoperative carcinoembryonic antigen (CEA) concentration to maximum tumor diameter (DMAX) may be a prognostic marker for patients with rectal cancer. Therefore, the study aimed to evaluate whether this ratio (CEA/DMAX) has prognostic value for patients with stage II colorectal cancer (CRC).MethodsA prospectively maintained database was searched for patients with pathologically confirmed stage II CRC who underwent surgery between January 2010 and March 2019. Patients were stratified according to the mean CEA/DMAX value into low and high CEA/DMAX groups. Kaplan-Meier, univariable, and multivariable Cox regression analyses were used to evaluate whether the CEA/DMAX could predict overall survival (OS) and disease-free survival (DFS). Nomograms were constructed in terms of the results of multivariable Cox regression analyses.ResultsThe study included 2,499 patients with stage II CRC. The mean CEA/DMAX value was 2.33 (ng/mL per cm). Kaplan-Meier analyses revealed that, relative to the low CEA/DMAX group, the high CEA/DMAX group had significantly poorer OS (67.31% vs. 85.02%, P<0.001) and DFS (61.41% vs. 77.10%, P<0.001). The multivariable Cox regression analysis revealed that CEA/DMAX independently predicted OS (hazard ratio: 2.58, 95% confidence interval: 1.51–4.38, P<0.001) and DFS (hazard ratio: 1.97, 95% confidence interval: 1.38–2.83, P<0.001). Two simple-to-use nomograms comprising CEA/DMAX, age, T stage, and lymphovascular invasion were developed to predict 1-, 3-, and 5-year rates of OS and DFS among patients with stage II CRC. The nomograms had good performance based on the concordance index, receiver operating characteristic (ROC) curve analysis, and calibration curves. Subgroup analyses further confirmed that a high CEA/DMAX was associated with poor OS and DFS among patients with stage II colon cancer and among patients with stage II rectal cancer (both P<0.05).ConclusionsAmong patients with stage II CRC, a high CEA/DMAX independently predicted poor OS and DFS, and the predictive abilities were also observed in subgroup analyses of patients with stage II colon cancer or rectal cancer. Furthermore, we developed two nomograms that had good accuracy for predicting the prognosis of stage II CRC.     

Immunoselective pressure and human leukocyte antigen class I antigen machinery defects in microsatellite unstable colorectal cancers

In colorectal cancer, the immune response is particularly pronounced against tumors displaying the high microsatellite instability (MSI-H) phenotype. MSI-H tumors accumulate mutations affecting microsatellites located within protein encoding regions (coding microsatellites, cMS), which lead to translational shifts of the respective reading frames. Consequently, novel tumor-specific frameshift-derived neopeptides (FSP) are generated and presented by MSI-H tumor cells, thus eliciting effective cytotoxic immune responses. To analyze whether the immunoselective pressure was reflected by the phenotype of MSI-H colorectal cancer cells, we compared here the expression of antigen processing machinery (APM) components and human leukocyte antigen (HLA) class I antigen subunits in 20 MSI-H and 20 microsatellite-stable (MSS) colorectal cancer using a panel of newly developed APM component-specific monoclonal antibodies. In addition, we did a systematic analysis of mutations at cMS located within APM genes and beta2-microglobulin (beta2m). Total HLA class I antigen loss was observed in 12 (60.0%) of the 20 MSI-H lesions compared with only 6 (30.0%) of the 20 MSS colorectal cancer lesions. Moreover, total loss of membraneous HLA-A staining was significantly more frequent in MSI-H colorectal cancer (P = 0.0024). Mutations at cMS of beta2m and genes encoding APM components (TAP1 and TAP2) were detected in at least 7 (35.0%) of 20 MSI-H colorectal cancers but in none of the MSS colorectal cancers (P = 0.0002). These data show that defects of HLA class I antigen processing and presentation seem to be significantly more frequent in MSI-H than in MSS colorectal cancer, suggesting that in MSI-H colorectal cancer the immunoselective pressure leads to the outgrowth of cells with defects of antigen presentation.     

Predictive value of plasma CEA in patients with colorectal carcinoma

Two years follow-up of 46 patients with colorectal carcinoma resected "for cure" shows that of the nine patients with an elevated (less than 5 ng/ml) CEA plasma titer one to six months after surgery, only one, or 11%, had remained disease free. Of the 38 patients with normal (less than 5 ng/ml) plasma CEA, 27, or 71%, were free of disease two years after surgery. In another 85 patients presenting six months to ten years after resection "for cure" of their colorectal carcinoma, normal CEA levels were found in 73, and only five, or 6.4%, of these presented with disease progression when followed for two years; of the 12 patients that presented with CEA values less than 5 ng/ml, disease progression was evident in eight or 67%; in eight patients with CEA levels of greater than 10 ng/ml, the proportion of patients with disease progression increased to 87.5% (7/8). When a patient with a history of colorectal cancer, but seemingly free of disease, presents with levels not only repeatedly above normal (greater than 5 ng/ml) but above the levels found in some nonmalignant conditions (greater than 10 ng/ml), thorough re-examination of the patient to locate the site of possible disease progression is indicated. In 14 such patients further diagnostic methods showed local recurrences in four, metastasis limited to the liver in six, and other metastasis in four. In conclusion, in patients with colorectal carcinoma postoperative elevated CEA plasma levels are a sign of poor prognosis. Consistently elevated CEA levels (greater than 10 ng/ml) are a strong indication of disease progression.     

Measurement of serum total and free prostate-specific antigen in women with colorectal carcinoma

We investigated the diagnostic value and the relationship with clinicopathological features of total and free prostate-specific antigen by measuring the concentrations of these markers in the sera of 75 women with colorectal carcinoma and in 30 healthy women. Measurements were performed by immunoradiometric assay which utilizes monoclonal and polyclonal anti-prostate-specific antigen antibodies; the lowest detection level for both markers was 0.01 ng ml(-1). Free prostate-specific antigen levels were significantly higher in women with colorectal carcinoma than healthy women (P=0.006). The percentage of free prostate-specific antigen predominant (free prostate-specific antigen/total prostate-specific antigen >50%) subjects was 20% in colorectal carcinoma patients and 3.3% in healthy women (P=0.035). Cut-off values were 0.34 ng ml(-1) for total prostate-specific antigen and 0.01 ng ml(-1) for free prostate-specific antigen. In women with colorectal carcinoma, total prostate-specific antigen positivity was 20% and free prostate-specific antigen positivity was 34.6%. When compared to negatives, total prostate-specific antigen positive patients had a lower percentage of well-differentiated (P=0.056) and early stage (stages I and II) tumours (P=0.070). However, patients with predominant free prostate-specific antigen, had a higher percentage of well-differentiated (P=0.014) and early stage tumours (P=0.090) than patients with predominant bound prostate-specific antigen. In conclusion, although the sensitivity of free prostate-specific antigen predominancy is low (20%), in distinguishing women with colorectal carcinoma than healthy women, its specificity is high (96.7%). Free prostate-specific antigen predominancy tends to be present in less aggressive tumours. These findings may indicate clinical significance of preoperative measurement of serum total and free prostate-specific antigen in women with colorectal carcinoma.     

An evaluation and replication of miRNAs with disease stage and colorectal cancer‐specific mortality

MicroRNAs (miRNAs) have been implicated in colorectal cancer (CRC) development and associated with prognostic indicators such as disease stage and survival. Prognostic associations are often based on few individuals and imprecise. In this study, we utilize population‐based data from 1,141 CRC cases to replicate previously reported associations between 121 miRNAs and disease stage and survival. The Agilent Human miRNA Microarray V19.0 was used to generate miRNA data following a stringent quality control protocol. Assessment of survival was done using Cox Proportional Hazard models adjusting for age, disease stage and tumor molecular phenotype. Five miRNAs were associated with more advanced disease stage; hsa‐miR‐145‐5p and hsa‐miR‐31‐5p showed increased expression with more advanced tumor stage, while hsa‐miR‐200b‐3p, hsa‐miR‐215 and hsa‐miR‐451a had decreased expression with more advanced tumors. Thirteen miRNAs were associated with CRC mortality among individuals diagnosed with colon cancer while 14 were associated with CRC mortality after a diagnosis with rectal cancer. Strongest associations were observed for those miRNAs that were expressed in a small subset of tumors. Most notable associations were for hsa‐miR‐145‐3p [hazard ratio (HR) 2.94, 95% confidence interval (CI) 1.54, 5.61], and hsa‐miR‐9‐3p (HR 10.28, 95% CI 1.31, 80.84) with colon cancer and hsa‐miR‐335‐5p (HR 0.17, 95% CI 0.05, 0.54) for rectal cancer. hsa‐miR‐374a‐5p, hsa‐miR‐570‐3p and hsa‐miR‐18a‐5p significantly reduced the hazard of dying for all cases, regardless of tumor site. Our findings illustrate the need for a large sample to evaluate the association of miRNAs with survival and disease stage in order to determine associations by tumor site.     

大肠癌患血清糖链抗原CA50水平及其临床意义

目的研究大肠癌患者血清糖链抗原CA50表达水平及其临床意义。方法采用免疫放射分析法(IRMA)对73名正常人,33例大肠良性疾病及136例大肠癌患者进行了血清CA50水平测定,同时用ELISA法测定了大肠癌患者血清CEA水平。结果大肠癌患者血清CA50水平(41.6±30.9u/ml)显著高于正常人(8.9±5.5u/ml,P<0.01)及良性疾病组(11.2±7.6u/ml,P<0.01)。以20u/ml为阳性界值,CA50对诊断大肠癌的灵敏度为72.1%,特异性为91.5%,有效率82.8%。血清CA50水平升高与大肠癌临床分期、复发和转移等因素密切相关。大肠癌患者血清CA50与CEA水平呈正相关(r=0.58,P<0.01)。结论CA50可作为大肠癌诊断和临床分期的辅助指标之一,有助于鉴别大肠疾病的良恶性,对病情变化、预后及疗效的判定有一定参考价值。