Expression of Fhit,Mlh1, and P53 protein in human gallbladder carcinoma

There is limited information on the molecular changes involved in the pathogenesis of gallbladder carcinoma (GBC). The Fragile Histidine Triad (FHIT) gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a candidate tumor suppressor gene in a variety of human malignancies. Recent studies have suggested that Fhit inactivation can be a consequence of defects in mismatch repair proteins. We analyzed Fhit and Mlh1 protein expressions using immunohistochemical methods in 20 GBCs and three gallbladder adenomas (GBAs) to elucidate the role of Fhit protein in gallbladder carcinogenesis. In addition, we examined whether Fhit and Mlh1 protein expressions correlated with P53 expression and clinicopathological findings. Significant loss or reduction in Fhit expression was noted in nine (45%) of the GBCs and one of the GBAs. Loss of Mlh1 protein expression was detected in six (30%) of the GBCs and one of the GBAs. Reduced Fhit expression was significantly associated with the absence of Mlh1 protein expression in the GBCs and the GBAs (p=0.0186). P53 overexpression was present in 11 (55%) of the GBCs, but none of the GBAs. Fhit and Mlh1 protein expressions were not significantly associated with P53 expression and clinicopathological findings. These results suggested that reduced Fhit expression might be involved in the development of GBC and be correlated with Mlh1 expression.     

Fhit expression in human gastric adenomas and intramucosal carcinomas: correlation with Mlh1 expression and gastric phenotype

The fragile histidine triad (FHIT) gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a candidate tumour suppressor gene involved in a variety of tumours, including gastric carcinomas. Recently, it has been reported that the FHIT gene may be a target of damage in some of mismatch-deficient tumours. To clarify further the role of the Fhit protein in gastric carcinogenesis, we investigated whether Fhit expression in early gastric neoplasia is associated with mismatch repair protein expression and cellular phenotype. Fhit, Mlh1 and phenotypic expression were evaluated immunohistochemically in 87 early gastric neoplasias, comprising 32 adenomas and 55 intramucosal carcinomas, resected by endoscopic mucosal resection therapy. Significant loss or reduction of Fhit expression was noted in four (12.5%) of the 32 adenomas and 21 (38.2%) of the 55 intramucosal carcinomas. The rate of abnormal Fhit expression was significantly higher in intramucosal carcinomas than in adenomas (P=0.021). Moreover, reduced Fhit expression was found to be significantly associated with loss of Mlh1 expression in early gastric neoplasia (P=0.0011). Furthermore, we also detected a significant association between reduced Fhit expression and gastric phenotype (P=0.0018). These results suggested that reduced Fhit expression occurs in the early stage of gastric carcinogenesis and could be correlated with a lack of Mlh1 expression and gastric phenotype.     

Msh2, Mlh1, Fhit, p53, Bcl-2, and Bax expression in invasive and in situ squamous cell carcinoma of the uterine cervix.

To analyze relevant factors and their effects on neoplastic progression in cervical carcinoma, a panel of genetic markers was studied. Paraffin-embedded tissue sections were obtained from 37 patients with carcinoma of the uterine cervix, 14 noninvasive squamous cell carcinomas (NISCCs), and 23 invasive squamous cell carcinomas (ISCCs). Immunoreactivity of Msh2, Mlh1, Fhit, p53, Bcl-2, and Bax proteins was examined by immunohistochemical staining with appropriate antibodies. Positive staining of Msh2 was detected in 13 of 14 (92.9%) NISCCs and in 13 of 23 (56.5%) ISCCs (P < 0.02). Mlh1 immunoreactivity was observed in 10 of 14 (71.4%) NISCCs and in 8 of 23 (34.8%) ISCCs (P < 0.04). Overexpression of p53 protein was found in 4 of 14 (28.6%) NISCCs and in 16 of 23 (69.6%) ISCCs (P < 0.02). Bcl-2 overexpression was detected in 2 of 14 (14.3%) NISCCs and in 15 of 23 (65.2%) ISCCs (P < 0.003). No significant difference in the two types of lesion was found for Bax and Fhit expression. The relationship between Mlh1, Msh2, and p53 protein expression was significant (P < 0.001 and P < 0.001, respectively), as was that between Fhit and Bax immunoreactivity (P < 0.02). In conclusion, we consider that altered expression of Msh2, Mlh1, p53, and Bcl-2 may be a critical event during cervical cancer progression, whereas Fhit may be a component of a proapoptotic pathway.     

Multidrug resistance-associated protein (MRP) expression is correlated with expression of aberrant p53 protein in colorectal cancer

Multidrug resistance-associated protein (MRP) is one of the major factors responsible for non-P-glycoprotein (Pgp)-mediated multidrug resistance of human tumour cells. In this study, we examined MRP and aberrant p53 expression in 54 colorectal cancers (CRC), 35 carcinoma in adenomas (CIA) and 40 adenomatous polyps by immunohistochemical procedures. 38 of 54 (70%) CRCs, 16 of 35 (46%) CIAs and 3 of 40 (8%) adenomatous polyps were MRP positive (χ² test, P<0.0001). 36/54 (67%) CRCs, 10/35 (29%) CIAs and 0/40 adenomatous polyps were p53 positive. 30 of the 36 p53-positive CRCs were also MRP positive and 8/10 CIAs were both p53 and MRP positive. MRP overexpression correlated with aberrant p53 accumulation in CRCs and CIAs (χ² test, P≤0.01). Coexpression of MRP and p53 in the same cells was confirmed in the CRCs and CIAs by double staining procedures. These results suggested that MRP overexpression is related to aberrant p53 expression in CRC.     

Expression of Fhit, Mlh1, p16INK4A and E-cadherin in early gastric neoplasia: Correlation with histological grade and gastric phenotype

An increasing number of tumor suppressor genes (TSGs) that are inactivated by hypermethylation of CpG islands in the promoter have been reported in gastric carcinomas. The aim of this study is to evaluate the clinical significance of TSG protein expression, which correlates with the promoter status, methylated or not, during the early stages of gastric carcinogenesis and to examine its relationship with mucin phenotype. The protein expression of 4 TSGs including Fhit, Mlh1, p16INK4A and E-cadherin was examined using immunohistochemical methods in 103 early gastric neoplasias, comprising 41 adenomas and 62 intramucosal carcinomas, obtained by endoscopic mucosal resection. In addition, phenotypic expression patterns (gastric-, intestinal- and mixed-phenotypes) were also examined. The expression of Fhit, Mlh1, p16 and E-cadherin was lost or reduced in 7.3, 12.2, 12.2 and 9.8% of the adenomas and in 35.5, 29.0, 29.0 and 32.3% of the intramucosal carcinomas, respectively. The absent expression of p16 was significantly associated with the degree of dysplasia in the adenomas (p=0.038). The average number of proteins among the 4 TSGs, whose expression was lost or reduced per sample, was significantly higher in the intramucosal carcinomas (1.35) than in the adenomas (0.41) (p=0.00013). Similarly, the average number was significantly higher in the gastric-type tumors (2.05) than in the intestinal-type tumors (0.49) (p=0.0000019). We demonstrated an increase in the number of TSG proteins whose expression is reduced or lost in the early stages of gastric tumorigenesis, and that this increase is associated with histological grade and gastric phenotype.     

Abnormal Fhit protein expression and high frequency of microsatellite instability in sporadic colorectal cancer

The role of Fhit protein in the oncogenesis of colorectal cancer is still in debate. Recent studies have revealed that reduced Fhit protein expression is associated with a deficiency of the mismatch repair protein. One hundred and twenty unselected patients who underwent curative resection for sporadic colorectal cancer in a three-year period were evaluated for microsatellite instability (MSI) using six microsatellite markers, and for the presence of Fhit and mismatch repair (MMR) proteins (Mlh1 and Msh2) by means of immunostaining. The relations between these markers were analysed. Reduced or absent Fhit expression was noted in 18 out of 118 patients. This altered expression was significantly higher in right-sided cancer (P = 0.005), mucinous tumours (P = 0.005) and in poorly differentiated histological types (P = 0.0001). MSI was found in 22 out of 109 patients, more so in right-sided cancer (P = 0.0001), poorly differentiated histology (P = 0.0001), and mucinous tumours (P = 0.0001). No association was found with TNM stage. MSI was present in 66.7% of tumours with altered Fhit expression and in only 10% of tumours with preserved or intermediate Fhit expression (P = 0.0001). Of the tumours with reduced or absent Fhit expression, 72.2% had loss of nuclear Mlh1 or Msh2 expression compared with only 14% of the preserved or intermediate Fhit expression tumours (P = 0.0001). These results support the hypothesis that deficiency in a MMR gene could be a cause of the high frequency of alterations in Fhit expression, and they permit the suggestion that FHIT gene alteration may be part of the genetic pathway involving MSI through which some colorectal cancers arise.     

Loss of p27 expression and microsatellite instability in sporadic colorectal cancer

BACKGROUND: The role of the loss of p27 protein expression in the oncogenesis of colorectal cancer is still in debate. In this study, we prospectively examined the immunohistochemical expression of p27 in 108 consecutive colorectal cancers, and we analysed the relationship with the results, the clinicopathological data, microsatellite instability (MSI) and other genetic alterations of tumours. METHODS: Unselected patients (108) who underwent curative colorectal resection for sporadic colorectal cancer in a three-year period were evaluated for MSI using 6 microsatellite markers, and for the presence of p27, p53, Fhit, Mlh1 and Msh2 proteins by means of immunostaining. The relationships between these markers were analysed. p27 protein expression was examined for association with disease recurrences and survival. RESULTS: Lack of p27 expression was noted in 33 out of 108 (30.5%) colorectal cancer cases (P<0.05). This altered expression was significantly higher in proximal cancers (P<0.05), mucinous tumours (P<0.001), poorly differentiated histology (P<0.01), cancers with MSI (P<0.05), tumours with altered expression of Mlh1 (P<0.01), of Msh2 (P<0.05), and of Fhit (P<0.01). Overall survival was better in the patient group with altered level of phenotypic p27 expression, although the difference does not reach statistical significance (P=0.069). The analysis performed only for patients with tumour at stage II showed significantly better survival when the tumour exhibited altered p27 expression (P<0.02). CONCLUSIONS: The results of the present study support the hypothesis that altered expression of p27 may be part of the genetic pathway involving MSI, which is responsible for the development of some colorectal cancers.     

Clinicopathological significance of fragile histidine triad transcription protein expression in breast carcinoma.

The fragile histidine triad (Fhit) gene, which is frequently lost in many cancers, was identified as a candidate tumor suppressor gene at chromosome 3p locus 14.2. Loss of Fhit expression is an important step in tumor progression from premalignancy, to in situ, to invasive breast carcinoma. To determine whether the absence of Fhit protein correlates with other established pathological-clinical parameters or prognosis, we assessed Fhit expression using immunohistochemistry in 166 invasive breast carcinomas. Lost or significantly decreased Fhit protein expression was identified in 70 cases (42.2%). Fhit expression was inversely correlated with histological grade (P < 0.0001), negative estrogen receptor status (P = 0.0016), p53 overexpression (P = 0.0040), and tumor proliferation activity (P = 0.0006). Survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that reduced expression of Fhit was associated with a poor outcome (P = 0.0086, by log-rank test). Multivariate analysis using the stepwise Cox proportional hazard model showed that lymph node metastasis was related to poor survival rates; in addition, patients with loss of Fhit expression still tended to have poor survival (P = 0.0563). Therefore, loss of Fhit expression is associated with higher malignant phenotypes and appears to be a prognostic factor in breast carcinoma.     

Loss of fragile histidine triad expression in colorectal carcinomas and premalignant lesions

Abnormal expression of the fragile histidine triad (FHIT) candidate tumor suppressor gene has been observed in a variety of human tumors, but little is known about its expression during colorectal tumorigenesis. Sections of 70 aberrant crypt foci (ACF), 55 adenomas, 84 primary colorectal carcinomas, and 13 metastatic lesions were evaluated immunohistochemically for Fhit expression. All normal colonic epithelium showed a strong expression of Fhit; 44% of carcinomas showed a marked loss or absence of Fhit expression. The proportion of carcinomas with reduced expression showed an increasing trend (a) with decreasing differentiation and (b) in tumors with metastases (62%) compared with tumors without metastases (38%). The proportion of metastatic lesions (12 of 13) with reduced expression of Fhit was even greater. Although only a small proportion of ACF and adenomas showed a reduction of Fhit expression, the reduced expression of Fhit was strongly associated with the degree of dysplasia in both ACF (P = 0.0002) and adenomas (P = 0.0085). The findings of reduced expression of Fhit in a small proportion of colonic precancerous lesions and in increased proportions of primary and metastatic colorectal cancers suggest that Fhit plays a role in the development and progression of some colon carcinomas.     

大肠肿瘤p53蛋白过表达对原位Th1／Th2平衡的影响

目的：评价p53蛋白过表面对大肠腺瘤和大肠癌局部辅助T细胞（Th1/Th2)平均的影响,进而探讨大肠癌发生的免疫学机制,方法：研究对象包括大肠腺瘤30例,大肠癌38例,癌旁正常粘膜68例作为对照组。石蜡切片以免疫组化法检测p53蛋白表达,采用酶联免疫吸附试验（ELISA）检测肠组织培养上清液中4种细胞因子（IL－2,IL－4,IL－10,IFN－r)水平。结果：p53蛋白表达阳性组培养上清液的IL－2,IFN－r水平显著低于阴性组和对照组（P＜0．01）,而IL－10则高于阴性组及对照组（P＜0．05）,各组IL－4水平未显示差异（P＞0．05）,结论：p53蛋白表达引起原位Th1/Th2平衡失调,表现为由Th1向Th2漂移,初步推断：p53基因失活在大肠癌发生的免疫学机制中可能具有重要作用。     

Clinicopathological and patient characteristics of early gastric neoplasia endoscopically resected with loss of Mlh1 expression

Hypermethylation of the promoter region of the MLH1 gene leads to loss of Mlh1 protein expression and plays a key role in the development of gastric cancer. Little is known about the association between Mlh1 expression and the clinicopathological and patient characteristics in early gastric neoplasia, particularly in endoscopically resected tumors. Immunohistochemistry was used to examine Mlh1 expression in 140 early gastric neoplasias obtained by endoscopic resection and comprising 31 gastric adenomas (GAs) and 109 early gastric cancers (EGCs), and compared them to corresponding clinicopathological and patient data. P53 expression and phenotypic profiles were also analyzed. The rate of reduced Mlh1 expression and P53 overexpression was 9.6 and 6.5% in GAs, and 27.5 and 27.5% in EGCs, respectively. In elderly patients (≥65 years of age), the aberrant expression of Mlh1 in EGCs was more significant in female than in male patients (59.9 vs. 29.8%; P=0.016). In addition, the frequency of aberrant Mlh1 expression in EGCs increased significantly in patients with oncological family histories and elevated gross type (P=0.033 and P=0.04, respectively). Moreover, a significant correlation was observed among aberrant Mlh1, P53-negative and HGM expression. The present findings suggest that loss of Mlh1 expression is associated with age, gender, oncological family history and tumor growth pattern in EGC. Patient and tumor characteristics are key factors in the screening, surveillance and diagnosis of early gastric neoplasia, particularly in elderly individuals.     

Correlation of Skp2 with carcinogenesis, invasion, metastasis, and prognosis in colorectal tumors

In colorectal tumors, S-phase kinase-associated protein 2 (Skp2) still has numerous important questions unanswered: its expression in adenomas, its correlation with key clinicopathological indices, its association with patient prognosis, its variation in lymph node metastases, and its association with many cell-cycle regulators. To answer these questions in colorectal tumors, Skp2, cyclin A, cyclin B1, cyclin E, CDK2, and Ki67 were immunohistochemically stained in 12 normal mucosa, 36 adenomas, 11 carcinomas in adenomas, 102 primary carcinomas, and 12 paired lymph node metastases; and Skp2 was examined by Western blot in 8 pairs of normal mucosa and carcinomas. Situated in nuclei, Skp2 expression significantly increased from normal mucosa through adenoma to primary carcinoma (p<0.0001), from mild through moderate to severe dysplasia in adenomas (p=0.038), from peripheral adenoma to paired central carcinoma (p=0.0033), and from primary carcinoma to lymph node metastasis (p=0.015), and these increases were confirmed by Western blot. Expression, however, relatively declined significantly in the primary carcinomas showing deep invasion (p=0.0113), lymph nodal metastases (p=0.0268), and poor prognosis for all (p=0.0104) or stage III patients (p=0.0119). High Skp2 was also significantly linked with elevated cyclin A, cyclin B1, cyclin E, CDK2 (in primary carcinomas only), and Ki67 in both adenomas and primary carcinomas. Thus, overexpression of Skp2 is associated with colorectal carcinogenesis and late metastasis to lymph nodes, whereas relative reduction of Skp2 is correlated with local invasion of primary carcinoma.     

c-erbB-2、ras、p53基因产物在大肠癌及癌前病变中的表达

目的：探讨c－erbB－2、ras、p53基因的表达与大肠癌发生发展的关系以及其对大肠癌早期诊断、预后判断的价值。方法：对45例大肠癌及36例癌旁非腺瘤型不典型增生、17例大肠腺瘤，用免疫组化方法检测基因产物的表达。结果：p53在大肠癌的阳性表达率为57．8％，p53蛋白高表达的癌旁非腺瘤型不典型增生及大肠腺瘤均为中度或高度不典型增生。p53蛋白表达与大肠癌的组织分化程度、淋巴结转移有关（P＜0．05）。p21、p185蛋白表达与大肠癌组织学分型、癌组织浸润程度、淋巴结转移无关，而与癌组织分化程度有关（P＜0．05）。结论：p53蛋白表达可能是大肠病变恶性倾向的一个独立标志。p53、p21、p185蛋白对大肠癌的发生、发展起重要作用。     

Reduced Fhit expression occurs in the early stage of esophageal tumorigenesis: no correlation with p53 expression and apoptosis

The FHIT gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a candidate tumor suppressor gene involved in multiple tumors, including esophageal carcinoma. We analyzed Fhit expression using an immunohistochemical method in invasive carcinoma, carcinoma in situ (CIS) and dysplasia, in paraffin sections of 75 esophageal squamous cell carcinomas (ESCs) to further elucidate the role of Fhit protein in esophageal carcinogenesis. In addition, we also examined whether Fhit expression correlated with p53 expression and apoptosis. Compared to adjacent normal mucosa, significant loss or reduction of Fhit expression was noted in 67 of 75 (89.3%) invasive ESCs, in 13 of 19 (68.4%) CIS lesions, and in 10 of 23 (43.5%) dysplastic lesions. There was a progressive loss or reduction of Fhit expression with progressive increases in the severity of histopathological changes (p < 0.001). However, there was no association between Fhit expression and clinicopathological findings, including tumor stage, lymph node metastasis, or overall survival. Moreover, Fhit expression was not significantly associated with p53 expression and apoptosis. These results indicate that abnormal Fhit expression is a common event in the early stage of ESC development and may occur independently of p53 expression and apoptosis mechanisms.     

非小细胞肺癌FHIT基因蛋白表达缺失及与突变型p53表达相关性

[目的]了解非小细胞肺癌组织(NSCLC)中脆性组氨酸三联体(FHIT)基因蛋白(Fhit)表达缺失及其与突变型p53基因蛋白(p53)表达的相关性.[方法]应用免疫组织化学方法了解NSCLC组织中Fhit及p53的表达.[结果]62.2%(56/90)的NSCLC组织显示Fhit表达缺失,同时48.9%(44/90)有突变型p53表达;两者的异常表达在非鳞组中明显相关(P＜0.001),而在鳞癌组中无相关性(P=0.079);另外,两者的异常表达在非吸烟组中明显相关(P=0.006),而在吸烟组中无相关性(P=0.113).[结论]Fhit表达缺失和突变型p53表达是NSCLC中常见事件;而且两者在non-SqCC和非吸烟的肺癌者中有明显的相关性.     

大肠癌中CD44V6、p53、PCNA的表达及意义

目的　探讨 CD44 V6、p5 3、PCNA在大肠癌中的表达与病理及生理学行为之间的关系。方法　采用免疫组化S- P法检测 CD44 V6、p5 3、PCNA在 5 1例大肠癌中的表达。结果　 5 1例大肠癌 CD44 V6阳性表达率 41.18% (2 1/ 5 1)。CD44 V6在低分化大肠癌的检出率为 5 3.85 % (7/ 13)明显高于高分化大肠癌 36 .84% (7/ 19) (P<0 .0 5 ) ,在浆膜外的阳性表达率 5 3.38% (8/ 15 )明显高于肌层 33.33% (2 / 6 ) (P<0 .0 5 ) ,有淋巴结转移者阳性表达率为 6 3.16 % (12 / 19)明显高于无淋巴结转移者 31.2 5 % (10 / 32 ) (P<0 .0 5 )。p5 3在 5 1例大肠癌中阳性检出率为 5 0 .5 9% (2 6 / 5 1) ,其表达与大肠癌的组织类型、分化程度和淋巴结转移未见明显相关。而与浸润深度呈正相关 ,p5 3在浆膜外层的阳性表达率为5 3.33% (8/ 15 )明显高于肌层 33.33% (2 / 6 ) (P<0 .0 5 )。 PC-NA的表达与病理分级、浸润深度和淋巴结转移未见显著相关性 (P>0 .0 5 )。结论　 CD44 V6的表达与大肠癌的临床病理生理学行为密切相关 ,而 p5 3与大肠癌浸润深度关系密切。因此 CD44 V6和 p5 3蛋白可为一个准确预测大肠癌预后的生物学指标。而 PCNA作为大肠癌预后的标记物不够理想     

环氧化酶-2和p53与大肠癌的临床病理研究

 目的 探讨环氧化酶-2（COX-2）和p53在人大肠癌中的表达及与临床病理特征的关系。方法 应用免疫组织化学染色法检测72例经手术切除原发性大肠癌组织和21例正常大肠黏膜组织中COX-2和p53的表达。结果 大肠癌组织中 COX-2和 p53阳性表达率分别为70.8 ％和62.5 ％。与正常大肠黏膜组织中阳性表达率28.6 ％和23.8 ％相比较，差异均有统计学意义（P＜0.05）。COX-2在有淋巴结转移组、肝转移组、C与D期组中表达率均高于相应对照组，而p53在有淋巴结转移组、肝转移组、低分化组中表达率高于相应对照组，且差异均有统计学意义（P＜0.05）。COX-2的表达与p53的表达呈正相关性（r = 0.642，P＜0.01）。结论 COX-2和p53的异常表达可能是大肠癌发生、发展过程中的一个重要环节。COX-2和p53的异常在大肠癌的发生, 发展中起协同作用，p53突变可能是大肠癌中 COX-2过表达的因素之一。     

Fhit蛋白在胰腺癌中的表达及其与临床病理的关系

目的：探讨胰腺癌中脆性三联组氨酸（Fragile histidine triad，FHTT）基因蛋白Fhit表达状况及其与临床病理指标的可能关系。方法：采用兔抗人Fhit蛋白抗体和枸酸-微波-SP免疫组化方法检测50例福尔马林固定、石蜡包埋的胰腺癌蜡块标本中Fhit表达状况并分析其与组织学分类、组织学分级以及淋巴结转移的关系。结果：癌组织Fhit表达阳性率为78％（39/50）；而正常胰腺组织Fhit表达阳性率为94％（47/50），二者比较，差异有显著性（P=0.020）。癌组织Fhit表达强度较正常胰腺组织高者为10例（24.0％）。Fhit蛋白低表达癌组织中Fhit染色阳性细胞数量及强度较其正常胰腺组织明显减少及降低。管状腺癌组Fhit蛋白表达降低阳性率与非管状腺癌组（3/5）比较，差异无显著性（P=1.000）。50例胰腺癌中，I级癌Fhit蛋白表达降低阳性率为12.5％（1/8），Ⅱ级癌为65.0％（13/20），Ⅲ级癌63.6％（14/22），Ⅰ级癌与Ⅱ-Ⅲ级癌组比较，差异有显著性（P=0.015）。伴局部淋巴结转移的胰腺癌Fhit蛋白表达降低阳性率为84.6％（11/13），无淋巴结转移癌为45.9％（17/37），已伴淋巴结转移癌组与未转移部组比较，差异有显著性（P=0.023）。结论：胰腺癌Fhit表达状况可能与组织学分类、分级以及淋巴结转移相关，提示Fhit表达降低可能对胰腺癌的演化和进展具有一定重要作用并可能成为一个新的预后指标。     

Expression of AID, P53, and Mlh1 proteins in endoscopically resected differentiated-type early gastric cancer

AIM: To analyze the expression of the tumor-related proteins in differentiated-type early gastric carcinoma (DEGC) samples. METHODS: Tumor specimens were obtained from 102 patients (75 males and 27 females) who had received an endoscopic tumor resection at Tottori University Hospital between 2007 and 2009. Ninety-one cancer samples corresponded to noninvasive or intramucosal carcinoma according to the Vienna classification system, and 11 samples were submucosal invasive carcinomas. All of the EGCs were histologically differenti- ated carcinomas. All patients were classified as having Helicobacter pylori (H. pylori ) infections by endoscopic atrophic changes or by testing seropositive for H. pylori IgG. All of the samples were histopathologically classified as either tubular or papillary adenocarcinoma according to their structure. The immunohistochemi- cal staining was performed in a blinded manner with respect to the clinical information. Two independent observers evaluated protein expression. All data were statistically analyzed then. RESULTS: The rates of aberrant activation-induced cytidine deaminase (AID) expression and P53 overexpression were both 34.3% in DEGCs. The expression of Mlh1 was lost in 18.6% of DEGCs. Aberrant AID expression was not significantly associated with P53 overexpression in DEGCs. However, AID expression was associated with the severity of mononuclear cell activity in the non-cancerous mucosa adjacent to the tumor (P = 0.064). The rate of P53 expression was significantly greater in flat or depressed tumors than in elevated tumors. The frequency of Mlh1 loss was significantly increased in distal tumors, elevated gross-type tumors, papillary histological-type tumors, and tumors with a severe degree of endoscopic atrophic gastritis (P < 0.05). CONCLUSION: Aberrant AID expression, P53 overexpression, and the loss of Mlh1 were all associated with clinicopathological features and gastric mucosal alterations in DEGCs. The aberrant expression of AID protein may partly contribute to the induction of nuclear P53 expression.     

Associations of Ki-ras proto-oncogene mutation and p53 gene overexpression in sporadic colorectal adenomas with demographic and clinicopathologic characteristics.

In colorectal tumorigenesis, Ki-ras proto-oncogene mutation often occurs early in the adenoma-adenocarcinoma sequence, whereas mutation of the p53 gene is associated with late progression to carcinoma. We evaluated the relationship of demographic and clinicopathologic characteristics to Ki-ras mutation and p53 gene product overexpression in 1,093 baseline sporadic colorectal adenomas from 926 individuals enrolled in a phase III recurrence prevention trial. Ki-ras mutation was found in 14.7% of individuals and p53 overexpression was found in 7.0% of those tested. Multivariate analysis found older age, rectal location, and villous histology to be independently associated with Ki-ras mutation. Individuals with an advanced adenoma (>or=1 cm or high-grade dysplasia or villous histology) had a 4-fold higher likelihood of Ki-ras mutation [odds ratios (OR), 3.96; 95% confidence intervals (CI), 2.54-6.18]. Ki-ras mutations in codon 12 and of the G-to-A transition type were more frequent in older individuals, whereas G-to-T transversion was more frequent in rectal adenomas than in the colon. Multivariate analysis showed that previous history of a polyp (P = 0.03) was inversely associated with p53 overexpression. Large adenoma size (>or=1 cm), high-grade dysplasia, and villous histology were independently associated with p53 overexpression, with the strongest association for advanced adenomas (OR, 7.20; 95% CI, 3.01-17.22). Individuals with a Ki-ras mutated adenoma were more likely to overexpress p53 (OR, 2.46; 95% CI, 1.36-4.46), and 94.8% of adenomas with both alterations were classified as advanced (P 相似文献