p53 overexpression in flat serrated adenomas and flat tubular adenomas of the colorectal mucosa

The expression of the p53 protein was investigated in flat serrated neoplasias as well as in other histological phenotypes of flat or exophytic hyperplasias or neoplasias of the colorectal, mucosa. A total of 104 such lesions were analyzed: 24 were flat serrated neoplasias (22 flat serrated adenomas and 2 flat serrated adenocarcinomas), 26 flat tubular adenomas, 17 flat hyperplastic polyps, 29 exophytic tubular and/or villous neoplasias (23 adenomas and 6 exophytic adenocarcinomas) and the remaining 8, exophytic hyperplastic polyps. Deparaffinized, rehydrated sections were treated immunohistochemically to detect those overexpressing the p53 protein. Lesions having slight (+), moderate (++) or intense (+++) staining were considered immunoreactive. The results showed that 50% of the flat serrated adenomas with low-grade dysplasia (LGD) and 66.7% of those with high-grade dysplasia (HGD) had p53 immunoreactivity. None of the flat tubular or of the exophytic adenomas with LGD expressed p53, but immunoreactivity was present in 61.5% of the flat tubular adenomas with HGD and in 52.3% of the exophytic adenomas with HGD. All adenocarcinomas had an intense p53 reaction. Weak p53 expression was demonstrated by 11.7% of the flat hyperplastic polyps but none of the exophytic polyps reacted. The occurrence of p53 expression in flat serrated adenomas with LGD suggested that, despite its low histological profile, one-half of those lesions could be biologically already committed to independent growth. The occurrence of p53 expression in nearly 12% of the flat hyperplastic polyps was totally unexpected and deserves further investigation. Flat serrated adenoma emerges as a novel, independent histological entity among the various phenotypes of flat neoplasias of the colorectal mucosa.     

hTERT expression in colorectal adenocarcinoma: correlations with p21, p53 expressions and clinicopathological features

Background The clinicopathological roles and relationships of hTERT, p21 and p53 proteins have not been studied in depth in colorectal cancer. The aim of the present study is to investigate the clinicopathological roles of expression of hTERT protein expression and its relationship with the expression of p21 and p53 proteins in a large cohort of patients with colorectal adenocarcinoma. Materials and methods Expressions of hTERT, p21 and p53 proteins were investigated in 188 patients with colorectal adenocarcinomas by immunohistochemistry. The findings were correlated with the clinicopathological features and survival data of colorectal adenocarcinomas. Results hTERT, p53 and p21 proteins were detected in 63%, 100% and 62% of the patients with colorectal carcinoma. High level of hTERT protein expression was noted in patients with metastases (p = 0.038) and in patients with rectal cancer (p = 0.046). Loss or low level of p21 protein was often noted in non-mucinous colorectal adenocarcinoma when compared with mucinous adenocarcinoma (p = 0.001). Furthermore, p53 expression was more frequently noted in non-mucinous adenocarcinoma (p = 0.001). The level of expression of p21 protein was positively correlated with expression of level of hTERT protein (p = 0.00001). The survival of the patients was related to staging (p = 0.001) and p53 protein expression (p = 0.038) of the tumours. Conclusions hTERT protein expression is an indicator of the biological aggressiveness of the cancer. The level of expression of the protein was also related to the distal location and level of p21 expression of the tumours.     

Immunohistochemical evaluation of tissue-specific proteolytic enzymes in adenomas containing foci of early carcinoma: correlations with cathepsin D expression and other malignant features

BACKGROUND: Cathepsin D (CD) is an aspartyl lysosomal protease, and the prognostic value of CD expression has been studied in a variety of tumors, however, its role in early adenocarcinomas remains unclear. AIM OF THE STUDY: We evaluated the expression of CD in a series of colorectal adenomas with severe dysplasia containing foci of early carcinoma and compared the results to several histopathological and immunohistochemical features. METHODS: Adenomas were obtained by endoscopic polypectomy from 33 patients. Twenty-four of the 33 adenomas contained well-differentiated adenocarcinomas and nine adenomas contained moderately differentiated adenocarcinomas. RESULTS: Positive CD expressions were observed in 25% of well-differentiated adenocarcinomas and in 66.7% of moderately differentiated adenocarcinomas (p < 0.05). Of the 12 adenocarcinomas with positive CD expression, four had positive CD expression in their adenomas (p < 0.01), 6 showed positive Ki-67 expression in their adenomas (NS), and 10 had positive p53 expression in their adenomas (p < 0.05). No significant association was seen between the level of CD expression and adenoma size. CONCLUSIONS: The expression of CD in adenocarcinoma correlated significantly with differentiation, and with the levels of CD and p53 expression in the adenomas of the polyp.     

Clinicopathologic evaluation of the trend toward histologically poor differentiation with submucosal invasion in superficial early colorectal adenocarcinomas

We examined differences in the degree of differentiation in intramucosal and submucosal areas of involvement in early colorectal adenocarcinomas of 131 patients and compared these findings with tumor morphology. In addition, K-ras and p53 protein expression was determined in cases where poorly differentiated adenocarcinoma was detected in the submucosa. We identified 6 patients with both intramucosal differentiated (well-to-moderately differentiated) adenocarcinoma and submucosal poorly differentiated adenocarcinoma (MwSp). The morphological tumor type was superficial in all MwSp cases. The observed MwSp adenocarcinomas had a significantly higher frequency of lymphatic invasion than the more common superficial type of adenocarcinoma. Genetic analysis of these MwSp lesions was carried out using the polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) method to detect the presence of K-ras codon 12 point mutations, and an immunologic staining technique was used to identify the presence of p53 protein overexpression. The K-ras mutation rate was 33.3%, and the p53 overexpression rate was 66.7% for the MwSp adenocarcinomas. Our findings suggest that the rapidly reduced histologic differentiation observed in some of these superficial colorectal adenocarcinomas may play a role in their higher degree of invasiveness. Received: November 17, 1999 / Accepted: July 7, 2000     

Reduced p16 expression correlates with lymphatic invasion in colorectal cancers

BACKGROUND/AIMS: P16, the tumor suppressor gene, plays a crucial role in the most important regulatory pathway involved in the G1/S transition, but its role in gastrointestinal neoplasia remains unclear. METHODOLOGY: To evaluate the possible p16 role in the development of colonic neoplasms, the authors studied p16 immunohistochemical expression of 84 lesions of colorectal cancers, 6 lesions of hyperplastic polyps, 59 lesions of adenomas and 8 lesions of carcinoma in adenoma. Immunohistochemical staining was processed by streptavidin biotin technique. The degree of expression pattern was classified into four types: absent, scattered, or nested, diffuse. Also, the correlation between immunohistochemical expression pattern and clinicopathological features was evaluated. RESULTS: Compared with normal colonic mucosa, in which virtually no p16 expression was observed, p16 was overexpressed in hyperplastic polyps (33%:2/6) adenomas (46%:27/59), carcinoma in adenoma (88%:7/8) and in adenocarcinomas (98%:82/84). In colorectal cancers, when divided into positive (diffuse or nested) and negative (absent or scattered) subgroups, the negative group showed a higher ratio of lymphatic infiltration (p = 0.04), a higher ratio of deeper invasion (p < 0.01) and a higher ratio showing histology of mucinous carcinoma or poorly differentiated adenocarcinoma (p < 0.01). CONCLUSIONS: In colorectal cancers, a significant correlation of reduced p16 expression and lymphatic invasion was observed, which suggested and colorectal cancers with reduced p16 expression have more aggressive potential of lymphatic infiltration. Also a significant correlation between the overexpression of p16 and tumor progression was demonstrated.     

p53 Protein Overexpression in Colorectal Tumors from Patients with Familial Adenomatous Polyposis: Is it an Early or Late Event?

Objectives : Tumor development is a multistep process associated with multiple genetic alterations. Familial adenomatous polyposis (FAP) is a classical paradigm to study genetic alterations in the development of colorectal neoplasms. In this study, we investigated the timing of p53 overexpression by immunohistochemistry in colorectal carcinogenesis in FAP patients and in sporadic adenomas and adenocarcinomas. Methods : We examined 40 microadenomas, 114 tubular adenomas, and three adenocarcinomas from five FAP patients and 30 sporadic adenomas and 14 sporadic adenocarcinomas. Results: p53 overexpression was observed in 43 of 114 adenomas with mild and moderate dysplasia and in three of three adenocarcinomas and in none of 40 microadenomas from FAP patients. In sporadic tumors, six of 30 adenomas with moderate to severe dysplasia and 11 of 14 carcinomas showed p53 overexpression. Uninvolved colonic mucosa in FAP patients, control patients, and patients with sporadic tumors did not stain for p53. Conclusions : These results indicate that p53 overexpression occurs early in the development of colorectal adenomas in FAP, whereas it is a late event in the development of sporadic tumors.     

Correlation of Ki-67, p53, and Adnab-9 immunohistochemical staining and ploidy with clinical and histopathologic features of severely dysplastic colorectal adenomas

Variations of Ki-67, p53, and Adnab-9 monoclonal antibody reactions in colonic adenomas may be associated with colonic cancer risk. We studied the predictive value of these markers for adverse behavior in severely dysplastic colorectal adenomas, such as an associated carcinoma, multiplicity of adenomas, and subsequent development of adenomas. For this purpose we compared the clinical, gross, and histologic characteristics of highly dysplastic index polyps in 42 patients with Ki 67, p53, and Adnab-9 immunostaining and other molecular markers. Polyps were removed endoscopically, and severely dysplastic polyps were stained immunohistochemically with Ki-67, Adnab-9, and p53 protein by the avidin biotin conjugate (ABC) technique. Quantitative DNA (QDNA) was analyzed by computer-assisted image analysis. Ki-67 immunohistochemistry showed reversal of normal distribution of nuclear staining from the normal basal position to the upper third of the colonic crypts. This abnormality of immunostaining in dysplastic adenomas was the earliest detected by the panel we used. A statistically significant correlation was seen between invasiveness of carcinoma in the index polyp and polyp size (P = 0.003), sessile morphology (P = 0.037), and villous or tubulovillous histology (P = 0.019). In the index adenoma, p53 positivity was correlated with multiplicity at initial examination (P = 0.053), villous histology (P = 0.053), invasiveness of carcinoma (P < 0.003), and recurrence of colorectal adenomas (P = 0.025). Although p53 positivity and aneuploidy were correlated with invasiveness of carcinoma in the index polyp (P = 0.025), Adnab-9 positivity was not. However, Adnab-9 positivity in the index polyp was associated with multiplicity of adenomas (P = 0.04) as well as recurrence of adenomas (P < 0.024). In conclusion, in addition to the morphologic and histologic markers already known, Ki-67, Adnab-9 antibody, and p53 protein may be prognostic indicators useful in follow-up of patients with severely dysplastic colorectal adenomas. Adnab-9 antibody may identify a field defect in above-average-risk adenoma-bearing patients.     

大肠小扁平腺瘤、息肉样腺瘤p53、p21表达的研究

目的:观察大肠小扁平腺瘤p53、p21基因的表达,探讨小扁平腺瘤与息肉样腺瘤生物学行为的不同及其与大肠癌的关系.方法:利用免疫组化法研究50例小扁平腺瘤(A组)和30例息肉样腺瘤(B组)以及20例正常大肠黏膜(C组)的p53、P21基因表达情况.结果:p53、p21 在A、B、C 三组中阳性率分别为58%、56%;33.3%、36.7%;5%、10%.P53阳性率三组间差异有显著性(P＜0.05).p21阳性率:A、B组分别与C组有差异显著性(P＜0.05);A组高于B组,但卡方检验P＞0.05,无统汁学差异;A组进一步与B组中直径＜1.0cm的腺瘤的p21阳性率(30%)比较,差异有显著性(P＜0.05).结论:大肠小扁平腺瘤p53、p21基因的异常表达提示小扁平腺瘤的生物学行为与息肉样腺瘤有差别,可能更易于恶变.     

Immunoexpression of p53 and cyclin D1 in adenomas of the gallbladder]

INTRODUCTION: Gallbladder adenomas are infrequent neoplasms whose relation to adenocarcinoma is not well understood. It has been suggested that adenomas and adenocarcinomas follow different molecular pathways. MATERIAL AND METHODS: This is a comparative, cross-sectional study in which we compared p53 and D1 cyclin expression in adenomas and adenocarcinomas of the gallbladder. RESULTS: We included 12 cases in each group. Expression of p53 occurred in 83.3% of adenocarcinomas and in 16.6% of adenomas (p = 0.003). D1 cyclin was expressed in a similar number of adenomas and adenocarcinomas. CONCLUSION: Our results support the hypothesis that p53 is an important step in the pathogenesis of adenocarcinomas but not of adenomas of the gallbladder. D1 cyclin is apparently a common pathway involved in the genesis of both tumors.     

HMG-CoA还原酶的表达与结直肠肿瘤的相关性研究

目的初步探讨HMG-CoAR蛋白的表达与结直肠癌患者分期和预后之间的关系。方法采用免疫组织化学法检测HMG-CoAR蛋白在结直肠癌组织、腺瘤组织和正常组织中的表达情况,并检测CK20和p53作为对比,了解HMG-CoAR蛋白与结直肠肿瘤间的关系。结果 HMG-CoAR蛋白在组织中的表达定位于细胞核,各组间HMG-CoAR蛋白的表达差异有统计学意义（P〈0.001）,由正常组织至癌组织依次降低;HMG-CoAR蛋白在结直肠癌组织中的表达与肿瘤的Duke分期相关（P=0.031）,进展期者多为低表达;HMG-CoAR与CK20、p53的表达呈负相关（P〈0.001）。结论 HMG-CoAR随着结直肠肿瘤的进展而表达降低,与肿瘤的发生和分期相关,有望作为结直肠癌诊断的预测因子。     

Colorectal Mucinous Adenocarcinoma: The Clinicopathologic Features and Significance of p16 and p53 Expression

Purpose This study was designed to examine the clinicopathologic features and p53 and p16 expressions in colorectal mucinous adenocarcinoma and colorectal signet-ring cell carcinoma. Methods The clinicopathologic features of 36 patients with colorectal mucinous adenocarcinoma and colorectal signet-ring cell carcinoma were analyzed and compared with 228 patients with colorectal adenocarcinomas. The p53 and p16 expressions in the colorectal mucinous adenocarcinoma and colorectal signet-ring cell carcinoma were studied by immunohistochemistry. Results Colorectal mucinous adenocarcinoma and colorectal signet-ring cell carcinoma accounted for 14 percent of colorectal cancer. The median age at presentation was 67 years. Family history of colorectal cancer in their first-degree relatives was seen in 14 percent of these patients. Fifty-six percent of the carcinomas were located in the proximal colorectum, most commonly in the transverse colon. Two patients had ulcerative colitis. Compared with the usual colorectal adenocarcinoma, colorectal mucinous adenocarcinoma and colorectal signet-ring cell carcinoma was found more often in proximal colorectum (P = 0.002), larger (P = 0.05), and in advanced stages (P = 0.018). Forty-four percent (n = 16) of the colorectal mucinous adenocarcinoma and colorectal signet-ring cell carcinoma showed p53 expression. All the patients with colorectal mucinous adenocarcinoma and colorectal signet-ring cell carcinoma with a positive family history of colorectal adenocarcinoma had tumors that showed p53 expression (P = 0.012). Seventy-eight percent (n = 28) of the tumors showed p16 expression. The median survival of the patients with these tumors was 23 months. The survival of these patients with colorectal mucinous adenocarcinoma and colorectal signet-ring cell carcinoma was poorer if the lesions were of advanced stages (P = 0.023) or with family history of colorectal cancer (P = 0.0015). Also, patients with colorectal mucinous adenocarcinoma and colorectal signet-ring cell carcinoma that did not express p16 and p53 had better survival than other patients (P = 0.04). Conclusions Colorectal mucinous adenocarcinoma and colorectal signet-ring cell carcinoma had distinctive clinicopathologic features. Tumor staging, family history of colorectal cancer, and status of p53 and p16 expressions might predict prognosis in these patients. Supported by a grant from the Queensland Cancer Fund. Presented at the Health and Medical Research Conference of Queensland, Brisbane, Queensland, Australia, November 3 to 4, 2005     

Immunohistochemical expression of bcl-2, bcl-xL, bax, p53 proteins in gastric adenoma and adenocarcinoma]

BACKGROUND/AIMS: The aim of this study was to investigate the immunohistochemical expression of bcl-2, bcl-xL, bax, and p53 proteins according to the pathological parameters such as grade of dysplasia, histological type, depth of invasion, lymph node metastasis, and TNM stage in the gastric adenoma and gastric adenocarcinoma. METHODS: Immunohistochemical staining using monoclonal bcl-2, bcl-xL, bax, p53 antibodies were performed on paraffin embedded specimens from forty-one gastric adenomas and 100 gastric adenocarcinomas. RESULTS: The expression rate of bcl-2 was higher in adenomas (34.2%), especially in high grade dysplasia (52.4%), than adenocarcinomas (2.0%). The expression rate of bcl-xL was higher in adenocarcinomas (55.0%) than adenomas (22%). The expression rate of the bax was higher in adenocarcinomas (58.0%) than adenomas (14.6%). In the adenocarcinoma, the bax expression was significantly related with the depth of invasion, lymph node metastasis, and TNM stage. The expression rate of p53 was higher in adenocarcinomas (64.0%) than adenomas (14.6%). CONCLUSIONS: Bcl-2 protein would be related with the development of gastric adenoma, especially with high grade dysplasia. Bcl-xL and p53 proteins would be involved in the development of relatively early stage of gastric adenocarcinoma but not in tumor progression. Bax protein would be involved in the development of gastric adenocarcinoma and related with depth of invasion, lymph node metastasis, and TNM stage.     

Expression of maspin in colon cancers: its relationship with p53 expression and microvessel density

We studied the expression of maspin in colonic adenocarcinoma compared with adenoma and metastatic adenocarcinoma as well as the relationship with its possible regulator, p53. The colonic specimens consisted of 24 adenomas, 49 adenocarcinomas, and 17 metastatic adenocarcinomas. Immunohistochemical staining of paraffin sections was done with microwave-based antigen retrieval methods. The Ki-67 index and the microvessel density were counted using an image analysis system. Maspin expression was positive in 75.5% of adenocarcinomas and 91.7% of adenomas. Only 47.1% of the nodal metastasis showed positive maspin expression. In colonic adenocarcinomas, p53 expression was positive in 44.7% of the maspin-positive groups compared with 100% of the maspin-negative groups (P < 0.005). Colonic adenocarcinomas with the positive maspin expression groups showed less intense microvessel density (181.1 ± 54.2) than those of the negative maspin expression groups (256.1 ± 75.4, P < 0.001). In conclusion, we demonstrated maspin expression in colon cancer with a sequential decreased expression rate from adenoma to metastatic carcinomas, which signifies the tumor suppressive function of maspin, and an inverse correlation with p53 and microvesel density, which indicates the regulatory effect of p53 on maspin and anti-angiogenesis effect of maspin.     

Mad2 and p53 expression profiles in colorectal cancer and its clinical significance

AIM: To investigate the expression of tumor suppressor gene p53 and spindle checkpoint gene Mad2, and to demonstrate their expression difference in colorectal cancer and normal mucosa and to evaluate its clinical significance.METHODS: Westemn blot and immunohistochemistry methods were used to analyze the expression of Mad2 in colorectal cancer and its corresponding normal mucosa. The expression of p53 was detected by immunohistochemistry method in colorectal cancer and its corresponding normal mucosa.RESULTS: Mad2 was significantly overexpressed in colorectal cancer compared with corresponding normal mucosa (P＜0.001), and it was not related to the differentiation of adenocarcinoma and other dinical factors (P＞0.05).The ratio of Mad2 protein in cancer tissue (C) to that in its normal mucosa tissue (N) was higher than 2, which was more frequently observed in patients with lymph gland metastasis (P＜0.05). p53 protein expression was not observed in normal mucosa. The rate of p53 positive expression in adenocarcinomas was 52.6%. There was a significant difference between adenocarcinomas and normal mucosa(P＜0.001), which was not related to the differentiation degree of adenocarcinoma and other clinical factors (P＞0.05).CONCLUSION: Defect of spindle checkpoint gene Mad2and mutation of p53 gene are involved mainly in colorectal carcinogenesis and C/N＞2 is associated with prognosis of colorectal cancer.     

c-erbB-2 、bcl-2和p53在结直肠肿瘤中的表达及其临床意义

背景：c-erbB-2、bcl-2和突变型p53在结直肠腺瘤癌变过程中相互调节并发挥重要作用。目的：探讨结直肠肿瘤中c-erbB-2、bcl-2和D53蛋白的表达及其临床意义。方法：取42例结直肠腺癌、10例腺瘤和10例正常结直肠黏膜组织，以免疫组化方法检测其中c-erbB-2、bcl-2和p53蛋白的表达，分析其表达与腺癌临床病理特征的关系。结果：c-erbB-2、bcl-2和p53蛋白在腺癌、腺瘤和正常黏膜组织中的表达差异均有统计学意义（P〈0．05），bcl-2蛋白在腺癌组织中的表达低于腺瘤组织，c-erbB-2和p53蛋白在腺癌组织中的表达高于腺瘤和正常黏膜组织。c-erbB-2蛋白的表达随腺癌分化程度的降低而增高，bcl-2蛋白的表达随腺癌分化程度的降低而降低：c-erbB-2和p53蛋白的表达与淋巴结转移和Dukes分期呈正相关。腺癌组织中bcl-2与p53蛋白的表达呈负相关（rs=-0．301，P〈0．05）。结论：c-erbB-2与结直肠癌的进展、分化和转移相关。腺癌组织中p53高表达和bcl-2相对低表达提示两者可能参与了结直肠癌的发生、发展过程，bcl-2过表达可能在结直肠癌发生的早期起作用。     

粪便中p53与APC突变检测在大肠癌诊断中的意义

目的探讨在大肠癌患者粪便中检测p53、APC基因突变的可行性及其应用前景和意义。方法从36例大肠癌患者、10例大肠腺瘤患者以及30例正常对照者的粪便中分别提取DNA,应用PCR-SSCP法检测粪便中p53、APC基因突变情况。结果36例大肠癌患者粪便中p53及/或APC基因突变检出率为77.78%(19/36),二者突变率分别为52.78%(19/36)和36.11%(13/36);10例大肠腺瘤中p53基因突变检出率为0%,APC为20%;30例正常对照粪便中p53、APC基因突变检出率均为0%。p53的突变随大肠癌分化程度的降低而增高(P<0.05);APC基因突变与大肠癌组织学类型无关(P>0.05)。结论联合检测粪便中p53与APC突变在大肠癌诊断和筛查中有潜在的应用价值。     

大肠平坦型腺瘤、隆起型腺瘤和腺癌的p53、c-myc和ki-67表达比较

目的 检测大肠平坦型腺瘤、隆起型腺瘤和浸润性大肠癌p53、c-myc和ki-67的表达水平,探讨其基因调控机制.方法 选取2002至2006年间行结肠镜检查并经病理证实的平坦型、隆起型腺瘤和腺癌的病变标本,用免疫组织化学二步法检测p53、c-myc和ki-67的表达水平,分析三者表达水平在各组病变的差异和意义.结果 p53、c-myc和ki-67在平坦型腺瘤、隆起型腺瘤和腺癌中阳性表达率分别为3.33%(1/30)、8.06%(5/62)和69.44%(25/35);33.33%(10/30)、58.06%(36/62)和80.56%(29/36);23.33%(7/30)、19.35%(12/62)和50.00%(18/36);在正常组织中均无明显表达.结论 平坦型腺瘤、隆起型腺瘤和大肠癌三者具有不同的p53、c-myc和ki-67表达,提示三者的发生、发展可能存在不同基因调控机制,平坦型腺瘤的癌发生途径可能与隆起型腺瘤不同.     

Mutation of p53 tumor suppressor gene in flat neoplastic lesions of the colorectal mucosa

PURPOSE: In a recent comparative histologic survey of flat colorectal neoplasias, we found more lesions with highgrade dysplasia (HGD) and carcinoma in Japanese than in Swedish patients. The purpose of this work was to assess the p53 protein overexpression in flat colorectal neoplasias in Swedish patients and to compare results with those reported in Japan. METHOD: A total of 57 neoplastic lesions of the colorectal mucosa were investigated: 29 had been regarded both at endoscopy and at histology as flat and the remaining 28 as exophytic. Deparaffinized, rehydrated sections were treated immunohistochemically to detect the p53 protein. Lesions having a moderate (++) or high (+ + +) staining were considered as overexpressing the p53 protein. RESULTS: Results indicated that 16.7 percent (1/6) of the exophytic adenomas with low-grade dysplasia (LGD) had distinct p53 overexpression as well as 57.1 percent (8/14) of those with HGD and 87.5 percent(7/8) with invasive growth. In flat neoplastic lesions, 7.7 percent (1/13) of the tubular adenomas with LGD, 25 percent (3/12) of tubular adenomas with HGD, and 75 percent (3/4) of adenocarcinomas arising in flat adenomas had p53 overexpression. CONCLUSIONS: In Swedish patients, the proportion of flat and exophytic colorectal neoplasias showing p53 immunoreactivity increased with increasing degree of dysplasia, the highest percent being recorded in lesions with invasive growth. Because a similar stepwise increase was reported for exophytic and flat colorectal neoplasias in Japan, it seems that the comparison of results in both countries is justifiable. One possible conclusion from this comparison is that the higher proportion of flat neoplastic colorectal lesions with HGD and carcinoma in the Japanese (compared with the Swedish) takes place for reasons extraneous to the overexpression of the p53 protein.Supported by grants from the the Cancer Society, Stockholm, and the Karolinska Institute.     

Relationship between somatostatin receptor subtype expression and clinicopathology, Ki-67, Bcl-2 and p53 in colorectal cancer

AIM: To study the SSTR1, 2, 3, 4, 5 expression and their relationships with clinico-pathological factors, cell proliferation, Bcl-2 and p53 expression in colorectal cancer cells. METHODS: Immunohistochemical staining of five SSTR subtypes, Ki-67, Bcl-2 and p53 was performed by the standard streptavidin-peroxidase (SP) technique for the paraffin sections of 127 colorectal cancers, and expression of five SSTR subtypes in 40 specimens of normal colorectal mucosae was detected with the same method. RESULTS: Positive staining for five SSTR subtypes was observed in colorectal cancer cells and normal colorectal mucosae. SSTR1 was the most predominant subtype in both colorectal cancer and normal colorectal mucosa, and the second was SSTR5 or SSTR2. As compared with normal colorectal mucosa, SSTR4 was more frequently expressed in colorectal cancer cells (2.5% vs 18.9%, P< 0.05); the expression of SSTR2, 4, 5 in moderately to well differentiated colorectal adenocarcinoma was significantly higher than that in poorly differentiated ones (P< 0.05), the SSTR1 expression in colorectal cancer with positive lymph node metastasis was significantly higher than that with negative lymph node metastasis (72.2% and 54.5%, P< 0.05). In addition, in the ulcerative type of colorectal cancer, SSTR2 expression was obviously decreased (P < 0.05); the correlation did not reach a statistical significance between the five SSTR subtypes expression and Dukes'stages (P> 0.05), but the frequency of SSTR1 expression increased with Dukes' stage, while SSTR3 and SSTR5 expression decreased with Dukes' stage. Moreover, there was no correlation between expression of the five SSTR subtypes and other clinicopathological factors such as age, sex, tumor site, tumor depth, distant metastasis. The proliferative indexes in colorectal cancer cells with negative expression of SSTR2 and SSTR3 were significantly higher than that with positive expression (P<0.05). The Bcl-2 expression in colorectal cancer cells with positive expression of SSTRl, 2, 3, 5 was significantly lower than that with negative expression (P<0.05). There was no correlation between five SSTR subtypes and p53 expression. CONCLUSION: The most predominant SSTR subtype is SSTR1, and the second is SSTR2 or SSTR5. Five SSTR subtypes play different roles in the development of colorectal cancer. SSTR2 and SSTR3 can inhibit the proliferation and promote apoptosis of tumor cells.     

Genetic epidemiology of mutated K-ras proto-oncogene, altered suppressor genes, and microsatellite instability in colorectal adenomas

BACKGROUND: The genetic epidemiology of colorectal adenomas has not been studied prospectively in colonoscopy patients without cancer. AIMS: To study genetic alterations in colorectal adenomas and correlate these with patient demographics and adenoma characteristics. METHODS: Mutations and allelic deletions in 201 adenomas from 60 patients were compared with demographic features, adenoma characteristics, and family history. RESULTS: The most common alteration was K-ras proto-oncogene mutation, present in 35% of adenomas and 65% of patients. Patients 65 years of age and older had a decreased probability of K-ras mutations (26% versus 45%). Overexpression of p53 gene product was present in only 6% of adenomas but was more frequent in villous or tubulovillous adenomas (19% versus 3%). Allelic loss of chromosome 18q was present in only 2% of adenomas and was significantly less frequent than p53 overexpression. DNA replication errors (RER) were present in 7% of adenomas and 15% of patients, including multiple adenomas in four patients (two with hereditary non-polyposis colorectal cancer syndrome). Only 36% of RER positive adenomas had alteration of BAT-26 alleles, none had alteration of BAT-25, and only one (8%) had mutation in the transforming growth factor beta type II receptor gene. RER positive adenomas were more likely to have a K-ras mutation. In patients with multiple adenomas, there was concordance of p53 overexpression and RER but not of K-ras mutations. CONCLUSIONS: Genetic progression in colorectal adenomas is heterogeneous, involving factors related to patient age and the presence of RER for the occurrence of ras mutations, but different intraindividual characteristics for the occurrence of p53 alterations and RER.