Combined evaluation of expressions of cyclin E and p53 proteins as prognostic factors for patients with gastric cancer.

BACKGROUND: There is a lack of consistency regarding the prognostic value of cyclin E overexpression in gastric cancer (gastric cancer). Our aim was to report on this overexpression and to analyze its correlations with the clinicopathologic variables. Another aim was to examine if aberrant expression of both cyclin E and p53 might increase the malignant potential of gastric cancer. METHODS: Specimens from 89 patients with gastric cancer treated with "curative" intent were evaluated for cyclin E and p53 expressions using immunohistochemical method. The correlations between cyclin E overexpression alone or in combination with p53 expression and the patient's clinicopathologic variables were analyzed. RESULTS: Cyclin E overexpression and p53 expression were shown in 35 (39.3%) and 46 (51.7%) tumors, respectively. The incidence of cyclin E overexpression was significantly higher in deeply invasive cancers (P < 0.0001), in cancers with lymph node metastasis (P = 0.003), and in cancers with advanced stages (P < 0.0001). There were no significant correlations with other clinicopathologic variables. Patients in whom their tumors showed cyclin E overexpression alone or in combination with p53 survived less than patients with negative cyclin E tumors. Multivariate analysis revealed that combined cyclin E overexpression and p53 expression was significantly associated with poor survival after adjusting for other variables (hazard ratio, 3.12; P = 0.009). CONCLUSIONS: Cyclin E overexpression is a common event in gastric cancer. Gastric cancer with cyclin E overexpression exhibit increased aggressiveness in the presence of aberrant p53. The combination of cyclin E overexpression with the p53 expression in gastric cancer further distinguished a subgroup of patients with poor prognosis.     

Cyclin D1 expression is associated with poor prognostic features in estrogen receptor positive breast cancer

Cyclins D1 and E play an important role in breast carcinogenesis. High cyclin E expression is common in hormone receptor negative and high grade aggressive breast cancer, whereas cyclin D1 in hormone receptor positive and low grade breast cancer. Experimental data has suggested that cyclin D1 and E mediate cell proliferation by different mechanisms in estrogen receptor (ER) positive and negative breast cancer. To test this hypotheses in large breast cancer material and to clarify the histopathological correlations of cyclin E and D1, especially the association with proliferation, we analyzed cyclin E and D1 immunohistochemical expression on breast tumour microarrays consisting of 1348 invasive breast cancers. High cyclin D1 expression was associated with high grade (P < 0.0005), high cyclin A (P < 0.0005) and Ki67 (P < 0.0005) expression among ER positive but with low grade (P = 0.05) and low Ki67 (P = 0.01) expression among ER negative breast cancers. Cyclin E and D1 expression correlated positively in ER positive (P < 0.0005) but had a negative correlation in ER negative tumours (P = 0.004). Cyclin E associated with high grade among all tumours (P < 0.0005). In conclusion, the findings of this study show that cyclin D1 has separate roles, and proliferation is driven by different mechanisms in ER positive and negative breast cancers.     

Astrocyte-elevated gene-1 overexpression is associated with poor prognosis in gastric cancer

Astrocyte-elevated gene-1 (AEG-1) plays an important role in diverse cancers and its up-regulation is associated with poor survival of patients. However, the status of AEG-1 expression and its significance in gastric cancer are still unclear. In this study, the expression of AEG-1 was studied in different gastric cancer cell lines and gastric cancer tissues. Expression of AEG-1 was significantly higher in gastric cancer tissues than that in normal tissues. Overexpression of AEG-1 was found in 62.9% of gastric cancers and significantly associated with TNM stage and Ki-67 proliferation index (P < 0.01). For survival study, overexpression of AEG-1 was significantly associated with poor survival (P < 0.01). Further multivariate analysis suggested that AEG-1 overexpression was an independent prognostic factor for the disease. We demonstrated that inhibition of AEG-1 expression by specific siRNA clearly inhibited SGC-7901 cell growth and enhanced cell apoptosis (P < 0.01). Inhibition of AEG-1 reduced phosphorylation of AKT and glycogen synthase kinase (GSK)-3β (Ser 9) and decreased the level of β-catenin, lymphoid enhancer binding factor 1 (LEF1), and Cyclin D1. This indicated that AEG-1 may play a role in Wnt/β-catenin-mediated cancer progression. Taken together, overexpression of AEG-1 could be a useful prognostic factor in patients with gastric cancer. Targeted inhibition of AEG-1 may provide a novel therapeutic strategy for gastric cancer.     

Phenotypic shift in human differentiated gastric cancers from gastric to intestinal epithelial cell type during disease progression

Background. The phenotypic expression of tumor cells is widely thought to resemble that of the tissue of origin. In the present study, to assess phenotypic changes that occur with disease progression, we investigated human differentiated gastric cancers at different depths of invasion for component cancer cell types. Methods. Using a combined mucin histochemical and immunohistochemical approach, we classified surgical specimens of 301 differentiated gastric cancers into three types: gastric epithelial cell (G) type, intestinal epithelial cell (I) type and mixed gastric and intestinal (GI) type, according to the phenotypic differentiation of the component cancer cells. The relation between the phenotypic type of cancer and their depth of invasion was evaluated. Results. The proportion of G type cancers was 41.4% in early (tumor invasion of mucosa or submucosa) cases, decreasing to 22.2% in advanced (tumor invasion of muscularis propia or deeper) cases, whereas the proportion of I type cancers increased with progressive disease from 23.5% to 31.1% (P < 0.01). Cancers invading the subserosa or deeper included more I type cases and fewer G type than cancers limited to the mucosa (P < 0.01). In most cases of each phenotypic type, intestinal metaplasia was recognized in the surrounding background mucosa, but no clear relation was shown between the phenotype of cancers and the degree of intestinal metaplasia in the background mucosa, suggesting that intestinal metaplasia is not always a preneoplastic lesion. Conclusions. A phenotypic shift from G to I type expression was observed with the progression of human differentiated gastric cancers. Intestinalization may occur independently in cancerous and noncancerous gastric mucosa. Received for publication on May 1, 1998; accepted on Oct. 22, 1998     

Cyclin E deregulation is an early event in the development of breast cancer

Cyclin E has been shown to be overexpressed in some human breast cancers, however, data to support deregulation of cyclin E as an early event in human mammary tumor development is lacking. We analyzed surgical specimens from 183 patients with breast carcinomas and evaluated cyclin E expression in areas of invasive carcinoma, adjacent carcinoma in situ (CIS), and non-neoplastic breast parenchyma. Overexpression of cyclin E was seen in one-third of invasive carcinoma samples, one-third of the CIS component and nearly half of the non-neoplastic breast epithelial cells adjacent to carcinoma (44% vs. 33%, P ≤ 0.05). Nuclear labeling for cyclin E was highly concordant between areas of in invasive carcinoma, CIS and non-neoplastic breast epithelial cells from the same patient (P < 0.0001). Localization of cyclin E to the cytoplasm was seen in a small proportion of tumor samples. Our findings suggest that cyclin E deregulation is an early event in the progression from histologically benign mammary epithelial cells to invasive carcinoma and occurs through both overexpression and altered cellular localization.     

Overexpression of cyclin D1 and cyclin E in N-nitrosomethylbezylamine-induced rat esophageal tumorigenesis

Dysregulation of Gl cyclins has been implicated in several humanmalignancies. To further investigate the role of Gl cyclinsin chemical carcinogenesis, the expression of cyclin Dl andcyclin E was analyzed by RT-PCR and immunohistochemical studiesin N-nitrosomethylbenzylamine (NMBA)-induced rat esophagealtumongenesis. Cyclin Dl mRNA levels were increased 2.8-foldin 25 week (P < 0.05) and 6.8-fold in 45 week (P < 0.01)papillomas induced by NMBA, when compared with normal rat esophagealepithelium. Cyclin E mRNA levels were increased 6.2-fold in25 week (P < 0.01) and 6.9-fold in 45 week (P < 0.01)papillomas. Immunohistochemical staining revealed exclusivenuclear staining of both cyclin Dl and cyclin E. Furthermore,there was a sequential increase in cyclin Dl and cyclin E-positivecells from normal epithelium, to preneoplastic lesions, to papillomas.These findings suggest that overexpression of cyclin Dl andcyclin E occur relatively early in rat esophageal tumongenesisand participate in tumor progression in this model.     

粘膜内和粘膜下胃癌中Cyclin E表达的变化及意义

目的 探讨浸润加深时早期胃癌中Ｃｙｃｌｉｎ Ｅ的表达变化及其意义。 方法 用免疫组化法检测５７例粘膜层和５１例粘膜下层胃癌中Ｃｙｃｌｉｎ Ｅ及ｐ５３的表达。 结果 Ｃｙｃｌｉｎ Ｅ的强阳性率为粘膜内癌０％（０／５７）。粘膜下癌１８％（９／５１）（Ｐ〈０．０５）。在粘膜层胃癌：Ｃｙｃｌｉｎ Ｅ的阴性和低表达组间几乎所有的观察指标均无明显差异。在粘膜下层胃癌：Ｃｙｃｌｉｎ Ｅ高表达率在ｐ５３阳性者为３     

Expression of p16, cyclin D<Subscript>1</Subscript> and RB protein in gastric carcinoma and premalignant lesions

Objective: To investigate the expression of p16, cyclin D₁ and Rb protein in gastric carcinoma and premalignant lesions including dysplastic gastric mucosa and intestinal metaplasia gastric mucosa. Methods: Using SP immunohistochemical methods, the expression of p16, cyclin D1 and Rb proteins was detected in 10 specimens of normal gastric mucosa, 15 specimens of dysplastic gastric mucosa, 15 specimens of intestinal metaplasia gastric mucosa, 30 specimens of gastric carcinoma. The clinical characteristics of the 30 patients with gastric carcinoma were analysed to explore the relationship between the parameter detected and biological action of gastric cancer. Results: Expression of p16 protein was detected in 90% of normal gastric mucosa, 86.67% of dysplastic gastric mucosa, 86.67% of intestinal metaplasia gastric mucosa, 36.67% of gastric carcinoma. The positive rate of p16 protein expression in gastric carcinoma is significantly lower than that in normal gastric mucosa and gastric premalignant lesions mucosa (P<0.01). Expression of cyclin D₁ protein was detected in 10% of normal gastric mucosa, 20% of dysplastic gastric mucosa, 20% of intestinal metaplasia gastric mucosa, 53.33% of gastric carcinoma. The positive rate of cyclin D₁, protein expression in gastric carcinoma is significantly higher than that in normal gastric mucosa and gastric premalignant lesions mucosa (P<0.05). Expression of Rb protein was detected in 90% of normal gastric mucosa, 80% of dysplastic gastric mucosa, 80% of intestinal metaplasia gastric mucosa, 50% of gastric carcinoma. The positive rate of Rb protein expression in gastric carcinoma is significantly lower than that in normal gastric mucosa (P<0.05). The expression of p16, cyclin D₁ gene were associated with the degree of differentiation of gastric carcinoma, lymphnodes metastasis and distant metastasis. Conclusion: p16, Cyclin D₁ and Rb gene play important role in gastric carcinoma genesis. The expression of p16, cyclin D₁ and Rb gene have some value to the diagnosis at earlier stage of gastric cancer. Detection of expression of p16, cyclin D₁ gene would be helpful to judge the prognosis of gastric cancer. Biography: MIAO Lin (1966–), male, master of medicine, associate professor, Second Affiliated Hospital, Nanjing Medical University, majors in gastroenterological cancer.     

A Golgi-specific protein PAQR3 is closely associated with the progression,metastasis and prognosis of human gastric cancers

BackgroundThe aim of this study is to determine whether PAQR3, a protein specifically localized in the Golgi apparatus, is associated with tumor progression, metastasis and survival of human patients with gastric cancer.Patients and methodsPAQR3 expression status was investigated in a large panel of gastric cancer (n = 300) and their corresponding para-cancerous histological normal tissues (PCHNT) at both mRNA and protein levels. The correlation of PAQR3 expression levels with clinical features such as metastasis and prognosis was analyzed. The effect of PAQR3 on the growth and migration of gastric cancer cells was also determined.ResultsPAQR3 was frequently down-regulated in gastric cancer samples compared with PCHNT at both mRNA and protein levels (both P < 0.0001). The expression level of PAQR3 was negatively correlated with Helicobacter pylori infection (P < 0.0001), tumor size (P < 0.0001), tumor stage (P < 0.0001), venous and lymphatic invasion (P < 0.0001), distant and nodal metastasis (P < 0.0001), and patient survival (P < 0.0001). Down-regulation of PAQR3 was highly correlated with increased epithelial–mesenchymal transition (EMT) in gastric cancer samples. In addition, PAQR3 overexpression was able to negatively modulate cell proliferation, migration and EMT of gastric cancer cells.ConclusionPAQR3 is markedly down-regulated in human gastric cancers. PAQR3 expression level is closely associated with the progression and metastasis of gastric cancers. PAQR3 is also a new genetic signature that can predict the prognosis of the patients with gastric cancer.     

Induction of centrosome amplification and chromosome instability in human bladder cancer cells by p53 mutation and cyclin E overexpression

Centrosome amplification frequently occurs in human cancers and is a major cause of chromosome instability (CIN). In mouse cells, centrosome amplification can be readily induced by loss or mutational inactivation of p53. In human cells, however, silencing of endogenous p53 alone does not induce centrosome amplification or CIN, although high degrees of correlation between p53 mutation and CIN/centrosome amplification in human cancer can be detected, suggesting the presence of additional regulatory mechanism(s) in human cells that ensures the numeral integrity of centrosomes and genomic integrity. Cyclin E, a regulatory subunit for CDK2 that plays a key role in centrosome duplication, frequently is overexpressed in human cancers. We found that cyclin E overexpression, together with loss of p53, efficiently induces centrosome amplification and CIN in human bladder cancer cells but not by either cyclin E overexpression or loss of p53 alone. We extended these findings to bladder cancer specimens and found that centrosome amplification is strongly correlated with concomitant occurrence of cyclin E overexpression and p53 inactivation but not with either cyclin E overexpression or p53 inactivation alone. Because cyclin E expression is strictly controlled in human cells compared with mouse cells, our findings suggest that this stringent regulation of cyclin E expression plays an additional role underlying numeral homeostasis of centrosomes in human cells and that deregulation of cyclin E expression, together with inactivation of p53, results in centrosome amplification.     

The Effect of Helicobacter pylori Infection on hMSH2 and P53 Proteins in Gastric Carcinogenesis

OBJECTIVE To investigate the effect of Helicobacter pylori （H pylon） infection on expression of hMSH2 and P53 and its possible carcinogenic mechanism. METHODS H pylori infection was detected using a rapid urease test and haematoxylin and eosin （H＆E） staining. The hMSH2 and P53 proteins in gastric cancer （GC） tissue, its adjacent mucosa, gastritic mucosa and normal gastric mucosa were detected by the immunohistochemical SP method. RESULTS （1） The positive rate of hMSH2 expression in GC tissue （62.7%）was higher than those in non-cancer tissues （P〈0.001）; the positive rate of hMSH2 expression in poorly differentiated adenocarcinoma （76.4%） was higher than that in other carcinomas （P〈0.05）. The positive rate of P53 expression in GC tissue （51.9%） was higher than that in noncancer tissues （P〈0.001）; the positive rate of P53 expression in well-differentiated adenocarcinoma （32.6 %） was lower than that in other carcinomas （P〈0.01）. （2） The positive rate of hMSH2 expression in GC tissue with H pylori infection was lower than that without the infection （52.8% vs. 74.5%; P〈0.05）. The positive rate of P53 expression in GC tissue with H pylori infection was higher than that without the infection （61.4% vs. 40.6%; P〈0.05）.（3） The expression of hMSH2 and P53 in GC tissue correlated positively （r=0.457, P〈0.01）. CONCLUSION High expression of hMSH2 and P53 as well as their interaction may be involved in gastric carcinogenesis; H pylori infection affecting expression of hMSH2 and P53 may be one of its carcinogenic mechanisms.     

CD147 overexpression is a prognostic factor and a potential therapeutic target in bladder cancer

CD147, also named extracellular matrix metalloproteinase inducer (EMMPRIN), has been shown to be involved in the progression of malignancy by regulating expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). The goal of this study was to evaluate the role of CD147 in the biology of bladder cancer and to determine its potential as a therapeutic target. CD147 protein expression was detected by immunohistochemistry in 108 bladder cancers using a tissue microarray annotated with patient follow-up. In immunohistochemistry, CD147 protein expression was associated with poor prognosis (P < 0.001), lymph node status (P < 0.001), tumor stage (P = 0.003), histologic grade (P = 0.011). Multivariate analysis showed that CD147 overexpression was an independent prognostic factor (P = 0.019). Infection of T24 bladder cancer cells with an adenovirus that expressed a small interfering RNA (siRNA) against CD147 efficiently inhibited CD147 protein and mRNA expression. This resulted in decreased proliferation, soft agar colony formation, migration, and invasion of T24 cells in vitro. Moreover, downregulation of CD147 reduced secretion of MMP-2 and MMP-9 and expression of VEGF in these cells. Our findings suggest that CD147 overexpression plays an important role in progression of bladder cancer, and CD147 could be a potential target of bladder cancer therapy.     

KIAA0247 inhibits growth,migration, invasion of non‐small‐cell lung cancer through regulating the Notch pathway

Lung cancer remains the leading cause of cancer‐related death worldwide. Previous studies have shown that the novel KIAA0247 gene potentially targeted by the tumor suppressor p53 may inhibit the development of several cancers. However, the exact function of KIAA0247 in non‐small‐cell lung cancer (NSCLC) is unknown. The purpose of the present study was to clarify the role of KIAA0247 in NSCLC. KIAA0247 expression was evaluated in tumors and adjacent normal tissues of 197 NSCLC patients by immunohistochemistry and real‐time PCR and analyzed for association with clinicopathological parameters. Results indicated that KIAA0247 levels positively correlated with cell differentiation (P < .001) and patient survival (P < .0001) and negatively correlated with lymph node metastasis (P < .001) and advanced p‐TNM stage (P < .001). In cultured NSCLC cell lines, KIAA0247 overexpression inhibited cell migration, invasion, and proliferation and downregulated the expression of Jagged1, Notch1 intracellular domain (NICD), Snail, cyclin D1, RhoA, RhoC, and MMP9, while upregulating that of E‐cadherin and p21. The Notch inhibitor DAPT reduced the biological effects of KIAA0247 knockdown, suggesting that KIAA0247 decreased the carcinogenic activity of NSCLC cells through downregulation of Notch signaling. Our results indicate that KIAA0247 inhibits NSCLC progression by reducing the metastatic potential of cancer cells through downregulation of the Notch pathway, which may underlie the association of KIAA0247 expression with favorable clinicopathological characteristics of NSCLC patients. These findings suggest that KIAA0247 is a candidate prognostic biomarker and potential therapeutic target in NSCLC.     

Expression of EphA2 and E-cadherin in Gastric Cancer: Correlated with Tumor Progression and Lymphogenous Metastasis

In this study, gastric cancer progression was correlated with the over-expression of erythropoietin-producing hepatocellular (Eph)A2 receptor and down-expression of epithelial cadherin (E-cadherin). Immunohistochemistry of EphA2 and E-cadherin were performed on these tumor samples from 165 primary lesions of gastric cancer. The results showed that expression of EphA2 was obviously increased in gastric cancer tissues (P < 0.01), which was positively correlated with the depth of cancer invasion, tumor-node-metastasis (TNM) stage and lymph node metastasis (P < 0.05). Meanwhile, the expression of E-cadherin was significantly reduced (P < 0.01), which was negatively correlated with the depth of cancer invasion, grade of tumor differentiation, TNM stage and lymph node metastasis (P < 0.05). The correlation between EphA2 and E-cadherin expression was negative (r = −0.198, P = 0.011). In conclusion, either the over-expression of EphA2 or the down-expression of E-cadherin is correlated with cancer progression and lymphogenous metastasis in gastric cancer, suggesting that both of them may play an important role in tumor progression and metastasis.     

FBXW7 is involved in the acquisition of the malignant phenotype in epithelial ovarian tumors

FBXW7 is a ubiquitin ligase that mediates ubiquitylation of oncoproteins, such as c‐Myc, cyclin E, Notch and c‐Jun. FBXW7 is a known tumor‐suppressor gene, and mutations in FBXW7 have been reported in various human malignancies. In this study, we examined the sequences of the FBXW7 and p53 genes in 57 ovarian cancer clinical samples. Interestingly, we found no FBXW7 mutations associated with amino acid changes. We also investigated FBXW7 expression levels in 126 epithelial ovarian tumors. FBXW7 expression was negatively correlated with the malignant potential of ovarian tumors. That is to say, FBXW7 expression levels in ovarian cancer samples were significantly lower than those in borderline and benign tumors (P < 0.01). FBXW7 expression levels in serous carcinoma samples were the lowest among four major histological subtypes. In addition, p53‐mutated ovarian cancer samples showed significantly lower levels of FBXW7 expression compared with p53 wild‐type cancer samples (P < 0.001). DNA methylation arrays and bisulfite PCR sequencing experiments revealed that 5′‐upstream regions of FBXW7 gene in p53‐mutated samples were significantly higher methylated compared with those in p53 wild‐type samples (P < 0.01). This data indicates that p53 mutations might suppress FBXW7 expression through DNA hypermethylation of FBXW7 5′‐upstream regions. Thus, FBXW7 expression was downregulated in ovarian cancers, and was associated with p53 mutations and the DNA methylation status of the 5′‐upstream regions of FBXW7.     

Cyclin E和p53的同时表达预测粘膜下层胃癌预后的作用

探讨Ｃｙｃｌｉｎ Ｅ和ｐ５３的同时表达对预测粘膜下层胃癌预后的作用。方法：用免疫组化法检测４８例粘膜下层胃癌中Ｃｙｃｌｉｎ Ｅ和ｐ５３的表达。结果：粘膜下层胃癌中Ｃｙｃｌｉｎ Ｅ阴性、阳性和强阳性组的ｐ５３表达率分别为１９％（５／２７）、４２％（５／１２）、８９％（８／９）（Ｐ〈０．０１）。同时表达的总发生率为２７％（１３／４８）。同时表达的发生率分别为：幽门部癌４６％（１１／２４）,侵入淋巴结者     

Overexpressed targeting protein for Xklp2 (TPX2) serves as a promising prognostic marker and therapeutic target for gastric cancer

The targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a putative oncogene in different human cancers. This study assessed TPX2 expression in gastric cancer tissue samples and then determined the effects of TPX2 knockdown on the regulation of gastric cancer cell malignant behaviors in vitro. Tissue samples from 115 gastric cancer patients were analyzed for TPX2 expression. The effects of TPX2 siRNA on gastric cancer cells were assessed in vitro, including cell viability, cell cycle distribution, apoptosis, migration, and invasion. The data showed that TPX2 was overexpressed in gastric cancer tissues compared to that in the adjacent normal epithelia. Moreover, TPX2 overexpression was associated with a poor overall survival and was an independent prognostic predictor of gastric cancer. In addition, the in vitro study further confirmed the ex vivo data, i.e., knockdown of TPX2 expression reduced gastric cancer cell viability but induced apoptosis and arrested cells at the G2/M phase of the cell cycle. Knockdown of TPX2 expression also inhibited the tumor cell migration and invasion capacity in vitro. At the gene level, knockdown of TPX2 expression upregulated the levels of cyclin B1, cdk4, p53, Bax, caspase-3, and E-cadherin, but downregulated the levels of cyclin D1, cdk2, N-cadherin, slug, matrix metalloprotease (MMP)-2, and MMP-9, suggesting that knockdown of TPX2 expression suppressed tumor cell epithelial–mesenchymal transition (EMT). This study demonstrated that detection of TPX2 overexpression could serve as a prognostic marker and therapeutic target for gastric cancer.     

Molecular analysis of gastric differentiated‐type intramucosal and submucosal cancers

Identification of the molecular characteristics of intramucosal (IMCs) and submucosal cancers (SMCs) is essential to our understanding of early gastric carcinogenesis. However, little is known regarding the differences between the 2 lesions. One hundred and forty‐eight patients with primary early gastric cancer [IMC, 106; SMC, 42] were characterized for expression of cell cycle‐related proteins and loss of heterozygosity (LOH). We also examined microsatellite instability (MSI) and methylation status. For LOH and methylation studies, we used a panel of 17 microsatellite markers (3p, 4p, 5q, 9p. 13q, 17p, 18q and 22q) and promoter regions of 9 genes (MLH‐1, RUNX3, p16, HPP1, RASSF2A, SFRP1, DKK‐1, ZFP64 and SALL4) that are frequently altered or methylated in gastric cancers. Overexpression of p53 and cyclin D1 was observed in SMC. In addition, low expression of p27 was more frequent in SMC than in IMC. Frequencies of 4p, 9p, 13q and 22q were significantly higher in SMC than in IMC. The SALL4 gene was frequently methylated in SMC compared with IMC. However, other gene methylations were common in both IMC and SMC. The frequency of LOH‐high status/methylation‐low status was significantly higher in SMC than in IMC. However, LOH‐low status/methylation‐high status in SMC was more frequently found in IMC. Our data confirm that methylation of cancer‐related genes plays a major role in the development of IMCs. Importantly, the results also show that gastric submucosal progression is characterized by the accumulation of specific genetic alterations. In addition, changes of cell cycle‐related proteins are associated with cancer progression.     

Plenary lectures

Cyclooxygenase-2 (COX-2) is an important factor in gastric carcinogenesis, and COX-2 expression in gastric cancer patients correlates with prognosis. We have now studied the impact of COX-2 in comparison to six other tissue tumor markers, DNA index, and S-phase fraction (SPF) in a large series of gastric cancer specimens. From 342 consecutive patients, 337 archival tissue specimens were available for immunohistochemistry of COX-2, HuR, cyclin A, MMP-2, p53, p21, and Ki-67 and 313 for analysis of DNA index and S-phase fraction by flow cytometry. Associations between factors were assessed by chi-square test and survival analysis by the Kaplan–Meier method and Cox model. A significant association emerged between of COX-2 and p53 (p < 0.0001), Ki-67 (p = 0.013), DNA ploidy (p < 0.0001), and SPF (p < 0.0001). In an extended multivariate analysis, COX-2 and p53 expression were independent prognostic factors for poor survival, in addition to high stage and non-curative surgery. In gastric cancer, COX-2 expression associated with markers for apoptosis and proliferation, and furthermore, it was confirmed that COX-2 and p53 are strong prognostic indicators.     

Overexpression of cyclin D1 and p53 associated with disease recurrence in colorectal adenocarcinoma

Multiple genetic changes occur during the evolution of normal cells into cancer cells. It has been reported that both cyclin D1 and p53 genes play major roles in oncogenesis and/or cell cycle control in various cancers. In this study, we examined the overexpression of cyclin D1 and p53 by the immunohistochemical method and investigated the correlation between expression of these antigen and prognosis in patients with colorectal adenocarcinoma. Disease-free survival was significantly lower in the patients with cyclin D1-strongly positive tumors than in those with cyclin D1-negative tumors. Similarly, disease-free survival of the patients with p53-strongly positive tumors was significantly lower than that of those with p53-negative tumors. Moreover, multivariate analysis indicated that both cyclin D1 and p53 overexpression are independent prognostic factors in patients with colorectal adenocarcinoma. In conclusion, both cyclin D1 and p53 overexpression may be useful predictors of disease recurrence in patients with colorectal adenocarcinoma. Int. J. Cancer 74:310-315, 1997. © 1997 Wiley-Liss, Inc.