cyclin-d1 and Rectal-Neoplasms

We report a case of adenocarcinoma of the rectum with foci of metaplastic shadow cells. The patient was a 65 year old man with anemia. Macroscopically the tumor was an ordinary rectal cancer. Microscopically, in addition to the features of moderately differentiated adenocarcinoma invading the subserosa, islands of shadow cells in tumor nests were detected in both primary and one of three pericolic metastatic lymph node lesions. Neoplastic glandular cells showed gradual transition to shadow cells. An antibody specific for high-molecular-weight cytokeratins reacted with the shadow cells and intermediate zone epithelial cells surrounding them, but no CEA, low-molecular-weight cytokeratins or cyclin D1 was detectable in them. Cytokeratin 14 was expressed only in the transitional zone epithelial cells. The intermediate zone epithelial cells were regarded as metaplastic squamous cells, from which the shadow cells were derived. The patient died of multiple liver metastases nine and a half months after surgery. To our knowledge, this is the first report of an immunohistochemical study of rectal adenocarcinoma containing shadow cells not only in the primary lesion but also in a metastatic lymph node.

Topics: Adenocarcinoma; Aged; Carcinoembryonic Antigen; Cyclin D1; Epithelial Cells; Humans; Immunohistochemistry; Keratins; Lymph Nodes; Lymphatic Metastasis; Male; Metaplasia; Rectal Neoplasms; Rectum; Tumor Suppressor Protein p53

The purpose of this study was to investigate the association between single nucleotide polymorphism (SNP) of CCND1 A870G and acute adverse events (AEs) in postoperative rectal cancer patients who received capecitabine-based postoperative chemoradiotherapy (CRT).. Four hundred patients with stage II and III rectal cancer received postoperative CRT of capecitabine with or without oxaliplatin were accumulated and prostectively studied in this study. The patients were randomly divided into two groups. Two hundred and twenty-eight patients were treated with concurrent capecitabine and radiotherapy (Cap-CRT), and 172 patients were treated with capecitabine and oxaliplatin plus radiotherapy (Cap-Oxa-CRT). Adverse events were graded according to the Common Terminology Criteria for Adverse Events, v. 3.0 (CTCAE v3.0). The genotype of CCND1 A870G in the patients was detected by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis. The associations between the SNP and acute AEs were indicated by odds ratios (ORs) and 95% confidence intervals (CIs), which were computed with logistic regression model.. A total of 136 patients presented severe AEs. Among them the frequencies of the three genotypes GG, GA and AA were 16.9%, 50.7% and 32.4%, compared with 24.6%, 48.1% and 27.3%, respectively, among the patients without severe AEs. Diarrhea was the most common AE, and severe diarrhea occurred in 109 patients. The frequencies of the three genotypes GG, GA and AA were 15.6%, 47.7% and 36.7% among these patients, compared with 24.4%, 49.5% and 26.1%, respectively, among patients without severe diarrhea. Multivariate logistic regression analysis showed a 1.66-fold increased risk for severe diarrhea in patients with AA genotype (95%CI 1.03 - 2.67, P = 0.038) compared with the cases with GG or GA genotypes. Stratified analysis showed that in the Cap-Oxa-CRT group, patients with AA genotype showed a 2.34-fold increased risk for severe diarrhea (95%CI 1.16 - 4.76, P = 0.018) compared with those with GG or GA genotypes, but in the Cap-CRT group, the SNP was not associated with the risk of severe diarrhea.. The genetic polymorphism of CCND1 A870G might be a potential biomarker for predicting acute AEs in postoperative stage II and III rectal cancer patients treated with adjuvant concurrent chemoradiotherapy of capecitabine and oxaliplatin.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemoradiotherapy, Adjuvant; Cyclin D1; Deoxycytidine; Diarrhea; Female; Fluorouracil; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Polymorphism, Single Nucleotide; Postoperative Period; Prospective Studies; Rectal Neoplasms; Risk Factors

To identify a biomarker profile associated with tumor response to chemoradiation (CRT) in locally advanced rectal cancer.. Rectal cancer response to neoadjuvant CRT is variable. Whereas some patients have a minimal response, others achieve a pathologic complete response (pCR) and have no viable cancer cells in their surgical specimens. Identifying biomarkers of response will help select patients more likely to benefit from CRT.. This study includes 132 patients with locally advanced rectal cancer treated with neoadjuvant CRT followed by surgery. Tumor DNA from pretreatment tumor biopsies and control DNA from paired normal surgical specimens was screened for mutations and polymorphisms in 23 genes. Genetic biomarkers were correlated with tumor response to CRT (pCR vs non-pCR), and the association of single or combined biomarkers with tumor response was determined.. Thirty-three of 132 (25%) patients achieved a pCR and 99 (75%) patients had non-pCR. Three individual markers were associated with non-pCR; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutation (P = 0.0145), cyclin D1 G870A (AA) polymorphism (P = 0.0138), and methylenetetrahydrofolate reductase (NAD(P)H) C677T (TT) polymorphism (P = 0.0120). Analysis of biomarker combinations revealed that none of the 27 patients with both tumor protein p53 (p53) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations had a pCR. Further, in patients with both p53 and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations or the cyclin D1 G870A (AA) polymorphism or the methylenetetrahydrofolate reductase (NAD(P)H) C677T (TT) polymorphism (n = 52) the association with non-pCR was further strengthened; 51 of 52 (98%) of patients were non-pCR. These biomarker combinations had a validity of more than 70% and a positive predictive value of 97% to 100%, predicting that patients harboring these mutation/polymorphism profiles will not achieve a pCR.. A specific biomarker profile is strongly associated with non-pCR to CRT and could be used to select optimal oncologic therapy in rectal cancer patients. ClinicalTrials.org Identifier: NCT00335816.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemotherapy, Adjuvant; Cyclin D1; Drug Resistance, Neoplasm; Female; Fluorouracil; Genes, p53; Genotype; Humans; Leucovorin; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Mutation; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; Organoplatinum Compounds; Polymorphism, Genetic; Predictive Value of Tests; Prognosis; Prospective Studies; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Radiotherapy Dosage; Radiotherapy, Adjuvant; ras Proteins; Rectal Neoplasms; Reproducibility of Results; Sensitivity and Specificity; Treatment Outcome; United States

The aim of this study is to reveal the potential roles of apoptosis markers (Bcl2 and p53), proliferation markers (Ki-67 and CyclD1), and the neuroendocrine marker Chromogranin A as markers for the radioresistance of rectal cancer. Statistically significant differences were found in the expression of p53, Ki-67, and Chromogranin A in groups of patients with and without a favorable prognosis after radiotherapy. The survival analysis revealed that the marker of neuroendocrine differentiation, Chromogranin A, also demonstrated a high prognostic significance, indicating a poor prognosis. Markers of proliferation and apoptosis had no prognostic value for patients who received preoperative radiotherapy. Higher Chromogranin A values were predictors of poor prognosis. The results obtained from studying the Chromogranin A expression suggest that the secretion of biologically active substances by neuroendocrine cells causes an increase in tumor aggressiveness.

Topics: Adenocarcinoma; Adult; Aged; Biomarkers, Tumor; Chromogranin A; Cyclin D1; Female; Follow-Up Studies; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Middle Aged; Neuroendocrine Cells; Prognosis; Proto-Oncogene Proteins c-bcl-2; Rectal Neoplasms; Survival Rate; Tumor Suppressor Protein p53

On account of the acquired drug resistance, the potency of cisplatin-based chemotherapy is far from satisfactory in rectal cancer. Increasing evidence has highlighted the crucial function of aberrantly expressed lncRNAs on the cisplatin resistance in multiple cancers. This research was the first attempt to decipher the underlying function and mechanism of long intergenic non-protein coding RNA 461 (LINC00461) in rectal cancer and also its relation to cisplatin resistance of rectal cancer. Data from this study revealed that LINC00461 expression was upregulated in rectal cancer cells. LINC00461 depletion restrained rectal cancer progression and sensitized rectal cancer cells to cisplatin. Molecular mechanism assays testified that LINC00461 bound with miR-593-5p. Besides, miR-593-5p upregulation improved the sensitivity of rectal cancer cells to cisplatin. Additionally, cyclin D1 (CCND1) was manifested to be a downstream target of miR-593-5p. Furthermore, CCND1 upregulation could reverse the effect of LINC00461 downregulation on rectal cancer progression and cisplatin resistance of rectal cancer. To sum up, LINC00461 mediates cisplatin resistance of rectal cancer by targeting miR-593-5p/CCND1 axis, shedding new light on the treatment of rectal cancer.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cisplatin; Cyclin D1; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Rectal Neoplasms; RNA, Long Noncoding; Up-Regulation

To assess the expression levels of exchange protein 1 directly activated by cAMP (Epac1) and phosphodiesterase 4 (PDE4) in rectal carcinoma, and their associations with clinicopathological indexes. In addition, the associations of PDE4 and Epac1 with A-kinase anchor protein 95, connexin 43, cyclin D1, and cyclin E1 were evaluated.. The PV-9000 two-step immunohistochemistry method was used to determine protein expression in 44 rectal carcinoma tissue samples and 16 paracarcinoma tissue specimens.. The positive rate of PDE4 protein expression in rectal carcinoma tissues was higher than that of paracarcinoma tissues (59.09% vs. 12.5%,. PDE4 and Epac1 expression levels are increased in rectal carcinoma tissues, suggesting that the two proteins may be involved in the development of this malignancy. Meanwhile, correlations between PDE4 and Epac1, PDE4 and Cx43, PDE4 and cyclin E1, and Epac1 and Cx43 suggested synergistic effects of these proteins in promoting rectal carcinoma.

Topics: A Kinase Anchor Proteins; Adult; Aged; Carcinoma; Connexin 43; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclin D1; Cyclin E; Female; Guanine Nucleotide Exchange Factors; Humans; In Vitro Techniques; Male; Middle Aged; Oncogene Proteins; Rectal Neoplasms; Signal Transduction

Topics: Activating Transcription Factor 1; Adenocarcinoma; Colonic Neoplasms; Computational Biology; Cyclic AMP Response Element-Binding Protein; Cyclin D1; Gene Expression Regulation, Neoplastic; Humans; In Situ Hybridization; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Kruppel-Like Transcription Factors; MicroRNAs; Neoplasms; Rectal Neoplasms; RNA, Long Noncoding; Sp1 Transcription Factor; STAT3 Transcription Factor; Transcription Factors

To explore the expression of A-kinase anchor protein 95 (AKAP95), Cyclin D1, Cyclin E1, and Connexin43 (Cx43) in rectal cancer tissues and assess the associations between each of the proteins and pathological parameters, as well as their inter-relationships.. AKAP95, Cyclin D1, Cyclin E1, and Cx43 protein expression rates were evaluated by immunohistochemistry in 50 rectal cancer specimens and 16 pericarcinoma tissues.. The positive rates of AKAP95, Cyclin E1, and Cyclin D1 proteins were 54.00 vs. 18.75%, 62.00 vs. 6.25%, and 72.00 vs. 31.25% in rectal cancer specimens and pericarcinoma tissues, respectively, representing statistically significant differences (P < 0.05). The positive rate of Cx43 protein expression in rectal cancer tissues was 44.00% and 62.50% in pericarcinoma tissues, and the difference between them was not significant (P > 0.05). No significant associations were found between protein expression of AKAP95, Cyclin E1, Cyclin D1, and Cx43, and the degree of differentiation, histological type, and lymph node metastasis of rectal cancer (P > 0.05). However, significant correlations were obtained between the expression rates of AKAP95 and Cyclin E1, Cyclin E1 and Cyclin D1, Cyclin E1 and Cx43 protein, and Cyclin D1 and Cx43, respectively (P < 0.05).. AKAP95, Cyclin E1, and Cyclin D1 protein expression rates were significantly higher in rectal cancer tissues compared with pericarcinoma samples, suggesting an association between these proteins and the development and progression of rectal cancer. In addition, the significant correlations between the proteins (AKAP95 and Cyclin E1, Cyclin E1 and Cyclin D1, Cyclin E1 and Cx43 protein, and Cyclin D1 and Cx43) indicate the possible synergistic effects of these factors in the development and progression of rectal cancer.

Topics: A Kinase Anchor Proteins; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Connexin 43; Cyclin D1; Cyclin E; Female; Humans; Immunohistochemistry; Male; Middle Aged; Oncogene Proteins; Rectal Neoplasms

Human cyclin D1 generates two major isoforms via alternative splicing: cyclin D1a and cyclin D1b. Cyclin D1b is hardly expressed in normal tissues but is frequently expressed in certain types of cancer tissues. To clarify the oncogenic potential of cyclin D1b variant, we developed cyclin D1b transgenic (Tg) mice and analyzed their phenotypes. We detected rectal tumors in 63% (15/24) of the female Tg mice. All rectal tumors had the histological characteristics similar to human sessile serrated adenoma/polyps (SSA/Ps). Adenocarcinomas were also found in 53% (8/15) of the rectal tumors, suggesting that these adenocarcinomas originated from the SSA/P-like lesions. No rectal tumors were found in the ovariectomized female cyclin D1b Tg mice (0/10), indicating that ovarian hormones played a critical role in rectal carcinogenesis in these Tg mice. Both phosphorylation of Erk, without activating MEK, and expression of estrogen receptor β were elevated in the rectal tumors of female cyclin D1b Tg mice compared with normal rectums of female wild-type mice. In addition, we established a cell line, D1bTgRT, derived from a rectal cancer of female Tg mouse. Small interfering RNA-induced cyclin D1b knockdown in this cell line suppressed Erk phosphorylation, anchorage-independent growth, cell invasiveness and tumorigenicity in nude mice. In humans, expression of cyclin D1b messenger RNA was detected in 17% (1/6) of colorectal cancer cell lines and 9.7% (3/31) of colorectal cancer tissues. Taken together, these results indicate that cyclin D1b expression contributes to the female- specific rectal carcinogenesis in mouse model.

Topics: Animals; Cell Line, Tumor; Cyclin D1; Estrogen Receptor beta; Female; Gene Expression Regulation, Neoplastic; Gonadal Steroid Hormones; Humans; MAP Kinase Signaling System; Mice, Inbred C57BL; Mice, Nude; Mice, Transgenic; Neoplasms, Experimental; Ovariectomy; Rectal Neoplasms

Adenocarcinoma of the colon and rectum is the third most common cause of cancer deaths and the sixth most common cancer in the world. Adenomas are benign neoplastic lesions which can be transformed into carcinomas, but this is usually not the case. There should be some risk factors which lead to the development of carcinomas into adenomas. The aim of this study is to find out the early changes and high risk factors related to carcinogenesis in colonic polyps.. In this study, we reviewed nearly 1000 colonoscopic biopsies and chose 72 biopsies. We developed three groups (tubular adenomas group 1, villous adenomas group 2, normal mucosa group 3); each group had 24 different biopsies. P53, Ki-67, bcl-2, cyclin D1, E-cadherin, c-erb B2 immunohistochemistry and human papillomavirus (HPV) in-situ hybridization were used for analysis.. Five of the seventy-two cases were positive in HPV in-situ analysis. Four of them were villous adenomas and one was a tubular adenoma. Ki-67 expression was limited only to crypts in group 3 but in groups 1 and 2, Ki-67 expression was seen both in crypt epithelium and surface epithelium. Cyclin D1, c-erb B2, bcl-2 expression was significantly increased in neoplastic polyps.. Ki-67 expression, both in the crypt and surface epithelium, and cyclin D1, c-erb B2, bcl-2 over-expression may be a clue of dysplastic epithelium and if the role of HPV is elucidated and shown to be important in colonic carcinogenesis, then vaccination might prevent carcinogenesis caused by HPV.

Topics: Adenoma; Aged; Aged, 80 and over; Cadherins; Cell Transformation, Neoplastic; Colonic Neoplasms; Colonic Polyps; Cyclin D1; Female; Humans; Ki-67 Antigen; Male; Middle Aged; Proto-Oncogene Proteins c-bcl-2; Receptor, ErbB-2; Rectal Neoplasms; Tumor Suppressor Protein p53

Neoadjuvant chemoradiation therapy is one of the standard therapeutic regimens for rectal carcinoma. Nevertheless, chemoradiation therapy is not completely devoid of adverse effects, and it would be interesting to try to predict which patient will respond to neoadjuvancy. This study aimed at analyzing factors influencing pathological response after therapy. We reviewed the clinical and morphological data of 39 patients after neoadjuvant chemoradiation therapy. We performed immunohistochemistry for p53, cyclin D1, MIB-1 (Ki67), and bcl-2 protein in paraffin-embedded tissue. In our series, 12 patients did not respond to neoadjuvant therapy, 12 showed a complete response, and 15 a partial response. There was a statistically significant association between response and cardiomyopathy (p=0.02) and tenesmus (p=0.02) and a trend towards significance for age (p=0.08), preoperative TNM (p=0.08), peritumoral inflammatory response (p=0.07), and preoperative CEA (p=0.08). As for immunohistochemistry, we only found a trend towards significance for cyclin D1 (p=0.08). In our series of patients with rectal carcinoma receiving preoperative chemoradiation therapy, few factors were predictive of a histological response. The histological response seems to improve survival and reduce relapses.

Topics: Age Factors; Antineoplastic Agents; Biomarkers, Tumor; Carcinoembryonic Antigen; Combined Modality Therapy; Cyclin D1; Female; Humans; Immunohistochemistry; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Proto-Oncogene Proteins c-bcl-2; Radiotherapy; Rectal Neoplasms; Risk Factors; Treatment Outcome; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases

To rapidly detect molecular alterations in different malignancies and investigate the possible role of Tp53, C-myc, and CCND1 genes in development of tumors in human organs and their adjacent normal tissues, as well as the possible relation between well- and poorly-differentiated tumors.. A tissue array consisting of seven different tumors was generated. The tissue array included 120 points of esophagus, 120 points of stomach, 80 points of rectum, 60 points of thyroid gland, 100 points of mammary gland, 80 points of liver, and 80 points of colon. Expressions of Tp53, C-myc, and CCND1 were determined by RNA in situ hybridization. 3' terminal digoxin-labeled anti-sense single stranded oligonucleotide and locked nucleic acid modifying probe were used.. The expression level of Tp53 gene was higher in six different carcinoma tissue samples than in paracancerous tissue samples with the exception in colon carcinoma tissue samples (P < 0.05). The expression level of CCND1 gene was significantly different in different carcinoma tissue samples with the exception in esophagus and colon carcinoma tissue samples. The expression level of C-myc gene was different in esophagus carcinoma tissue samples (chi2 = 18.495, P = 0.000), stomach carcinoma tissue samples (chi2 = 23.750, P = 0.000), and thyroid gland tissue samples (chi2 = 10.999, P = 0.004). The intensity of signals was also different in different carcinoma tissue samples and paracancerous tissue samples.. Over-expression of the Tp53, CCND1, and C-myc genes appears to play a role in development of human cancer by regulating the expression of mRNA. Tp53, CCND1 and C-myc genes are significantly correlated with the development of different carcinomas.

Topics: Breast Neoplasms; China; Colonic Neoplasms; Cyclin D1; Esophageal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Proto-Oncogene Proteins c-myc; Rectal Neoplasms; RNA, Messenger; Stomach Neoplasms; Thyroid Neoplasms; Tissue Array Analysis; Tumor Suppressor Protein p53

To investigate whether CCND1 genetic variations associated with a constitutive nuclear protein may influence either the pathologic response to preoperative RT or the prognosis in a series of rectal cancer patients.. Seventy rectal cancer patients treated by neoadjuvant radiotherapy were included in the study. CCND1 exon 5 mutations were screened, and the G870A polymorphism was assessed for correlation with clinical variables, tumor response, and patient outcome.. No exon 5 mutation was found. Concerning the G870A polymorphism, the A/A variant was significantly associated with radiosensitivity (p = 0.022). Moreover, patients harboring the A allele were correlated with a lower risk of local failure (p = 0.017). Also, combination of the G870A polymorphism with the post-therapeutic lymph node status allowed the elaboration of a prognostic index, which accurately distinguished subgroups of patients with predictable recurrence-free (p = 0.003) and overall (p = 0.044) survival.. Although CCND1 exon 5 mutations are rare in rectal cancer, G870A polymorphism is a frequent variation that may predict radiosensitivity and prognosis.

Topics: Adult; Aged; Aged, 80 and over; Cyclin D1; DNA Mutational Analysis; Female; Genes, bcl-1; Genetic Markers; Genotype; Humans; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Polymorphism, Genetic; Prognosis; Rectal Neoplasms

The Ras-association domain family 1A (RASSF1A) tumour suppressor gene is inactivated in a variety of solid tumours, usually by epigenetic silencing of the promoter and/or allelic loss of its locus at 3p21.3. RASSF1A induces cell cycle arrest through inhibition of cyclin D1 accumulation. In this work, 62 endocrine tumours from different sites in the gut were investigated for methylation of the RASSF1A promoter using the polymerase chain reaction, the presence of 3p21.3 deletions by loss of heterozygosity analysis, and cyclin D1 expression by immunohistochemistry. Methylation was found in 20/62 (32%) cases and was restricted to foregut tumours; deletion at 3p21.3 was found in 15/58 (26%) informative cases and restricted to malignant foregut tumours; cyclin D1 hyper-expression was found in 31/58 (53%) cases and correlated with RASSF1A methylation. Our data suggest that RASSF1A is involved in the development of endocrine tumours derived from the foregut only, and that the presence of both RASSF1A methylation and 3p21.3 deletion is associated with malignancy. These results may provide a rationale for foregut-targeted therapy for aggressive endocrine carcinomas entailing the use of demethylating agents.

Topics: Adult; Aged; Aged, 80 and over; Appendiceal Neoplasms; Carcinoma, Neuroendocrine; Cyclin D1; Duodenal Neoplasms; Female; Gastrointestinal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Ileal Neoplasms; Intestinal Neoplasms; Loss of Heterozygosity; Male; Methylation; Middle Aged; Pancreatic Neoplasms; Promoter Regions, Genetic; Rectal Neoplasms; Stomach Neoplasms; Tumor Suppressor Proteins

Colorectal cancer is a common cancer all over the world. Aberrations in the cell cycle checkpoints have been shown to be of prognostic significance in colorectal cancer.. The expression of cyclin D1, cyclin A, histone H3 and Ki-67 was examined in 60 colorectal cancer cases for co-regulation and impact on overall survival using immunohistochemistry, southern blot and in situ hybridization techniques. Immunoreactivity was evaluated semi quantitatively by determining the staining index of the studied proteins.. There was a significant correlation between cyclin D1 gene amplification and protein overexpression (concordance = 63.6%) and between Ki-67 and the other studied proteins. The staining index for Ki-67, cyclin A and D1 was higher in large, poorly differentiated tumors. The staining index of cyclin D1 was significantly higher in cases with deeply invasive tumors and nodal metastasis. Overexpression of cyclin A and D1 and amplification of cyclin D1 were associated with reduced overall survival. Multivariate analysis shows that cyclin D1 and A are two independent prognostic factors in colorectal cancer patients.. Loss of cell cycle checkpoints control is common in colorectal cancer. Cyclin A and D1 are superior independent indicators of poor prognosis in colorectal cancer patients. Therefore, they may help in predicting the clinical outcome of those patients on an individual basis and could be considered important therapeutic targets.

Topics: Biomarkers, Tumor; Colonic Neoplasms; Cyclin A; Cyclin D1; Egypt; Female; Histones; Humans; Ki-67 Antigen; Male; Middle Aged; Prognosis; Rectal Neoplasms; Statistics, Nonparametric; Survival Analysis

Early-stage adenocarcinoma of the rectum treated with curative intent has a favorable overall prognosis; however, 20%-30% of the patients recur, and the majority ultimately die of disease. Recurrence and tumor-related mortality may be attributable to molecular abnormalities in primary tumors accounting for their more aggressive biological behavior. This study evaluates such molecular phenotypes with regard to cell cycle regulation and proliferation and determines their significance for patient outcome.. One hundred patients with primary T(2-3), N(0) adenocarcinoma of the rectum uniformly treated by surgery alone were studied. Core biopsies of pathological specimens were assembled on tissue microarrays, and expression of p53, mdm-2, p21, Bcl-2, p27, cyclin D1, and Ki-67 was analyzed by immunohistochemistry. Molecular profiles were correlated with disease-free (DFS) and disease-specific survival (DSS).. Despite previously described prognostic relevance of some of the investigated molecules in analyses where different stages of colorectal cancer were included, none of the cell cycle-regulatory or proliferation-related markers was associated with recurrence or survival. However, patients with tumors demonstrating down-regulation of p27, a cyclin-dependent kinase inhibitor and tumor suppressor gene associated with development of metastases, showed a trend toward reduced DFS and DSS (P = 0.06 and P = 0.07, respectively).. In this homogeneous group of patients with early-stage, node-negative adenocarcinoma of the rectum uniformly treated by surgery alone, the investigated cell cycle-regulatory and proliferation-associated proteins appear to have no prognostic significance. However, down-regulation of p27 appears to be associated with a trend toward reduced DFS and DSS, which suggests further investigation of other p27-related pathways potentially relevant for metastatic disease.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; Disease-Free Survival; Female; Humans; Immunoenzyme Techniques; Ki-67 Antigen; Male; Middle Aged; Neoplasm Proteins; Nuclear Proteins; Protein Array Analysis; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-mdm2; Rectal Neoplasms; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

This study examined the prognostic value of the cyclin-dependent kinase inhibitors p21(Waf1/Cip1) and p27Kip1, and the cell cycle regulating proteins cyclin D1 and p53 after curative surgery for rectal cancer.. Formalin-fixed, paraffin-embedded tissue samples of 160 rectal carcinomas resected curatively within a 5-year period were used. Immunohistochemical analysis used monoclonal antibodies p21(Waf1/Cip1) (clone SX118), p27Kip1 (clone SX53G8), cyclin D1 (clone DCS-6), and p53 (DO-1). Positive nuclear protein expression was assessed at the 10% level. Results of immunohistochemistry were studied for correlation with clinical and histopathological data of the prospective tumor registry including recurrence and patient survival.. Of the 160 rectal carcinomas 36% were p21(Waf1/Cip1) positive, 44% p27Kip1 positive, 48% cyclin D1 positive, and 39% p53 positive. The p21(Waf1/Cip1) staining pattern was correlated with p27Kip1 and p53 expression and with UICC stage and lymph node status. p53 status was not correlated to any clinical or histopathological variable. p27Kip1 expression was associated with tumor size and cyclin D1 expression. Tumor progression caused by local and distant recurrence occurred in 20%. p21(Waf1/Cip1), p27Kip1, and p53 were strong predictors of recurrence. p21(Waf1/Cip1) and p53 but not p27Kip1 were independently correlated with disease-free survival. UICC stage was independently related to both recurrence and survival. The best prognosis was in p21(Waf1/Cip1) positive and p53 negative rectal carcinomas.. Reflecting tumor biology by immunohistochemical assessment of cell cycle regulators, p21(Waf1/Cip1) and p53 were independently predictive of prognosis in rectal cancer, and p27Kip1 was independently related to recurrence. However, cyclin D1 had no independent relationship to prognosis. Clinically, UICC stage was a strong predictor of prognosis after curative surgery for rectal cancer.

Topics: Aged; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases; Enzyme Inhibitors; Female; Humans; Immunohistochemistry; Male; Prognosis; Proto-Oncogene Proteins p21(ras); Rectal Neoplasms; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

Increased expression of a key cell cycle regulator, cyclin D1, may have relevance to carcinogenesis and clinicopathological characteristics of some cancers. This study represents the first application of in situ hybridization, ISH, to detect cyclin D1 mRNA in tissue sections from colorectal carcinomas. This approach was selected because of its unique potential to clarify whether increased expression of cyclin D1 mRNA correlates with clinical and pathological parameters. The ISH ofa non-radioactive oligonucleotide probe (Biogenex) was immunocytochemically detected in paraffin embedded sections from biopsy or resection specimens. Tumors ranged from well to poorly differentiated, and from stages A, B, C, and D. Ten year survival data were available on the majority of patients. Intensity of tumor and background (smooth muscle) signals were independently scored from 0 to 3. Overexpressed cyclin D1 mRNA was seen in 86% of cases compared to background. This frequency is similar to that reported for pancreatic carcinoma. The average signal intensity score in tumor foci was 1.9 with a background score of 0.05 (p<001). All cases showed specific staining judged by the cytoplasmic localization and a tumor signal:background ratio >1. Expression did not differentiate cancers based on grade, stage or survival (p>1), but did differentiate carcinoma and severe dysplasia from mild dysplasia. We conclude that ISH of cyclin D1 mRNA is an effective and relatively specific means of detecting activity of this gene in colonic neoplasms. The high frequency of overexpression implies that gene activity by itself is not likely to predict a tumor s biological or clinical behavior. On the other hand, these data suggest that increased cyclin D1 gene activity may be an early event in colorectal carcinogenesis. They also are consistent with findings showing cyclin D1 is inducible by a variety of oncogene products.

Topics: Adenocarcinoma; Adenoma, Villous; Adult; Aged; Aged, 80 and over; Colonic Neoplasms; Cyclin D1; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; In Situ Hybridization; Israel; Male; Middle Aged; Reagent Kits, Diagnostic; Rectal Neoplasms; RNA, Messenger; RNA, Neoplasm; Sensitivity and Specificity; Survival Analysis

Topics: Adult; Colonic Neoplasms; Colorectal Neoplasms; Cyclin D1; Female; Humans; Incidence; Japan; Kidney Transplantation; Male; Middle Aged; Neoplasm Staging; Neoplasms; Postoperative Complications; Rectal Neoplasms; Retrospective Studies; Tumor Suppressor Protein p53

Recurrent colorectal cancers respond poorly to anticancer treatment including radiotherapy. To better understand the biological characteristics of the recurrent colorectal tumor, we investigated various biomarkers regulating cell proliferation and cell loss in paired primary and recurrent colorectal tumor specimens within each individual.. From a total of 11 colorectal adenocarcinoma patients, 22 specimens of paired primary and recurrent tumors were obtained for analysis. Apoptosis was evaluated by TUNEL labeling of apoptotic DNA fragmentation. Other biomarkers including proliferating cell nuclear antigen (PCNA), p53, WAF1, p34cdc2, and cyclins B1 and D1 were analyzed by immunohistochemical stains.. PCNA index (PCNAI) showed an increase in 6 and a decrease in 5 recurrent tumors compared to primary tumors. Median PCNAI in primary and recurrent tumors were 33.5 and 48.3, respectively (p = 0.16). In contrast, the apoptotic index (AI) decreased in 9 of 11 recurrent tumors compared to primary tumors. Median AI decreased from 4.3 in primary tumors to 1.4 in recurrent tumors (p = 0.04). The p53 expression increased in more than half of recurrent tumors compared to primary tumors. Mean staining score increased from 0.7 in primary tumors to 1.2 in recurrent tumors (p = 0.059). WAF1 and cyclin B1 did not show significant change. In contrast, both cyclin D1 and p34cdc2 increased significantly in recurrent tumors. These two biomarkers showed increased expression in 8 (cyclin D1) and 7 (p34cdc2) recurrent tumors, respectively, compared to their primary counterparts. Mean staining scores of both biomarkers in recurrent tumors increased by more than twofold compared to those in primary tumors and these differences were statistically significant (cyclin D1, p = 0.007; p34cdc2, p = 0.008).. This study showed significantly decreased apoptosis in recurrent colorectal tumors compared to their primary counterparts. The underlying regulatory mechanisms included increased expression of p53 and altered cell cycle regulators such as increased cyclin D1 and p34cdc2. With further study, it may be used for developing a new therapeutic strategy for the treatment of recurrent colorectal cancer.

Topics: Adult; Aged; Apoptosis; Biomarkers, Tumor; CDC2 Protein Kinase; Cell Division; Colonic Neoplasms; Cyclin B; Cyclin B1; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; DNA Fragmentation; Female; Humans; In Situ Nick-End Labeling; Male; Middle Aged; Neoplasm Recurrence, Local; Proliferating Cell Nuclear Antigen; Rectal Neoplasms; Sigmoid Neoplasms; Tumor Suppressor Protein p53