胃癌细胞中DPC4基因失活与启动子区 的突变

 目的研究胃癌细胞系中DPC4基因表达和启动子区域的突变情况,并分析了两者之间的关系。方法采用RT-PCR法检测9种胃癌细胞系中DPC4基因的表达情况;克隆和测序DPC4启动子区域的突变情况;应用TFSEARCH ver.1.3软件分析DPC4启动子区域的转录因子结合位点。结果DPC4在SNU5、SNU16、SNU484、SNU638和KATOⅢ细胞中表达较高,而在SNU216、MKN28、MKN74 和 AGS细胞中表达较低或缺失。测序结果表明,MKN74细胞DPC4启动子区域出现了两处碱基置换突变,而在其它8种细胞系中没有发现突变。两处突变可能会影响转录因子MZF-1和IK-2与DPC4启动子的结合。结论DPC4基因在胃癌中频繁发生失活,而其启动子区域的突变可能是导致其失活的原因之一。     

非小细胞肺癌中DPC4基因的表达与微血管形成的关系

目的：探讨DPC4（deleted in pancreatic carcinoma locus4，DPC4）基因在非小细胞肺癌（NSCLC）中的表达及其与微血管形成的关系。方法：利用免疫组织化学S-P法检测52例NSCLC组织、19例相应的癌旁正常肺组织中DPC4、VEGF的表达，用CD34标记血管内皮细胞并计算微血管密度MVD值。结果：DPC4在肺癌原发灶中的阳性表达率为63．5％（33／52），与癌旁正常肺组织中的阳性表达率89．5％（17／19）相比，DPC4阳性表达水平显著降低（P〈0．05）；DPC4与组织学类型、肿瘤细胞分化程度无关（P〉0．05），但与淋巴结转移显著相关（P〈0．05）。52例NSCLC中，DPC4的表达与VEGF、MVD值均呈负相关（r=-0．303，P=0．020）。结论：DPC4的低表达可能是肺癌发生过程的早期事件，可促进肺癌的淋巴结转移，并可通过直接或间接的作用促进肺癌血管生成。     

DPC4基因在胰腺癌中的改变

目的 研究DPC4（deleted in pancreatic cancer locus4)基因在胰腺癌中的改变。方法 用多聚酶链反应－单链构象多态性分析（PCR－SSCP）银染技术及PCR产物直接测序法检测胰腺癌细胞系P1、P2、P3、P4、P7、11例新鲜冷冻胰腺癌组织中DPC4基因第1、2、3、4、8、11外显子的缺失和突变。结果 5株人胰腺癌细胞系中,3株（P1、P2、P3）存在DPC4基因突变,DPC4基因改变率为3／5。11例新鲜冷冻胰腺癌细胞中,3例有DPC4基因的纯合性缺失,2例有基因突变,DPC4基因改变率为5／11（45．5％）。结论DPC4作为一种抑癌基因,其改变在胰腺癌的形成中可能起重要作用。     

恶性肿瘤中TGF-β1信号传递分子DPC4／Smad4的研究进展

DPC4／Smad4基因是新近被鉴定的一个肿瘤抑制基因。其编码的DPC4／Smad4蛋白是TGF-β信号传导通路中的重要传导蛋白，是TGF-β配体、受体结合后后续信号传导的胞质递质，参与TGF-β受体激活后的信号传导。DPC4／smad4调控的下游目的基因有p21^WAF3、uPA、PAL-1、VEGF、TSP-1。转化生长因子-β(transforming growth factor beta,TGF-β)信号传导通路的配体、受体、胞内信号传导分子Smad蛋白及其调控的下游目的基因等组成一个肿瘤生长的负性调节，通路中任何一个元件的异常都可引起信号传导紊乱，导致肿瘤发生。     

人胰腺癌组织中DPC4/Smad4、p21wafI、p16蛋白表达的检测

背景与目的：近一半的胰腺癌存在DPC4／Smad4失活,使肿瘤细胞增殖的抑制作用丧失;p21^warI是Smad4调控的下游靶基因,而PC4和p16基因在胰腺癌的发生中可能有协同作用。本研究拟通过研究DPC4／Smad4、p21^wafI、p16蛋白在人胰腺癌中的表达情况,探讨三者之间的关系及它们的胰腺癌中的可能作用机制。方法：用免疫组化技术检测56例石蜡包埋人胰腺癌组织Smad4,p21^wafI,p16的蛋白表达情况。结果;用石蜡包埋人胰腺癌组织免疫组化显示Smad4,p21^wafI和p16阳性率分别为58．93％,48．21％和42．86％,对应癌旁非癌胰腺组织阳性率分别为89．29％,87．55和76．79％;P3,P4,P7人胰腺腺癌细胞系DPC4／Smad4的原位杂交,免疫组化及Western blot均为阳性,而1,P2均为阴性。统计学分析显示胰腺癌及癌旁非癌胰腺之间3种蛋白表达均有显著性差异（P＜0．05）,胰腺癌中Smad4与p21^wafI表达之间有一定相关性（P＜0．05）,Smad4与p16表达之间有一定相关性（P＜0．05）,但p21^wafI与p16表达之间无显著相关（P＞0．05）。结论：胰腺癌与正常胰腺相比,Smad14,p21^wafI,p16蛋白表达明显下降,其改变在胰腺癌的发生发展中可能起重要作用。     

大肠癌中DPC4蛋白表达及与临床病理特征的关系

[目的]探讨大肠癌组织中DPC4蛋白的表达及其与患者临床病理特征的关系.[方法]免疫组化Elivison二步法检测60例大肠癌手术切除标本中DPC4蛋白的表达,并探讨其与患者组织学类型、浸润深度、淋巴结转移和远处转移等临床病理特征的关系.并取40例癌旁正常大肠组织作对照.[结果] DPC4蛋白主要在大肠癌和癌旁正常大肠组织的胞浆表达,呈棕黄色细颗粒.60例大肠癌标本中DPC4的阳性表达为21例(35.0％),其中强阳性为4例(6.7％).40例癌旁正常大肠组织中DPC4蛋白表达均为阳性,其中强阳性34例(85.0％).大肠癌组织中DPC4蛋白阳性表达率明显低于癌旁正常大肠组织(x2=42.62,P＜0.01).大肠癌组织中DPC4蛋白表达水平随组织分化程度的增加而增加(P＜0.01),随原发病灶的浸润深度增加、淋巴结转移和远处转移的出现而下降(P＜0.01).[结论]且DPC4蛋白表达降低或缺失在大肠癌的发生发展过程起重要作用,有望成为大肠癌基因诊断和治疗的新靶点.     

DPC4 基因在肺癌中的表达及其与微血管形成和凋亡的关系

 目的 探讨DPC4（deleted in pancreatic carcinoma locus 4，DPC4）基因在非小细胞肺癌（nonsmall cell lung carcinoma，NSCLC）中的表达及其与微血管形成和凋亡的关系。方法 利用免疫组织化学S-P法检测52例NSCLC组织、19例相应的癌旁正常肺组织中DPC4、VEGF的表达，用CD34标记血管内皮细胞并计算微血管密度MVD值，应用TUNEL技术对细胞凋亡情况进行了检测并计算凋亡指数。结果 DPC4在肺癌原发灶中的阳性表达率为63．5％（33／52），与癌旁正常肺组织中的阳性表达率89．5％（17／19）相比，DPC4阳性表达水平显著降低（P〈0．05）DPC4与组织学类型、肿瘤细胞分化程度无关（P〉0．05），但与淋巴结转移显著相关（P〈0．05）。52例NSCLC中，DPC4的表达与VEGF、MVD值均呈负相关（r=-0．303，P=0．020）。DPC4阳性组凋亡指数（apoptotic index，AI）值明显高于DPC4阴性组（P〈0．05）。结论 DPC4的低表达可能是肺癌发生过程的早期事件，并可通过直接或间接的作用促进肺癌血管生成，从而促进肺癌的淋巴结转移，DPC4的高表达可能促进细胞的凋亡。     

恶性肿瘤中TGF-β1信号传递分子DPC4/Smad4的研究进展

DPC4/Smad4基因是新近被鉴定的一个肿瘤抑制基因 ,其编码的DPC4/Smad4蛋白是TGF β信号传导通路中的重要传导蛋白 ,是TGF β配体、受体结合后后续信号传导的胞质递质 ,参与TGF β受体激活后的信号传导。DPC4/Smad4调控的下游目的基因有p2 1WAF1、uPA、PAI 1、VEGF、TSP 1。转化生长因子 -β(transforminggrowthfactorbeta ,TGF β)信号传导通路的配体、受体、胞内信号传导分子Smad蛋白及其调控的下游目的基因等组成一个肿瘤生长的负性调节 ,通路中任何一个元件的异常都可引起信号传导紊乱 ,导致肿瘤发生     

在非小细胞肺癌组织中DPC4和P21WAF1/CIP1蛋白的表达

目的 探讨DPC4、P21WAF1/CIP1在非小细胞肺癌组织中的表达及与肺癌生物学行为及预后的关系.方法 利用免疫组组织化学S-P法检测60例非小细胞肺癌组织及30例癌旁正常肺组织中DPC4及P21WAF1/CIP1蛋白的表达.结果 DPC4在肿瘤组织中阳性表达率为65%(39/60),与癌旁正常肺组织的阳性表达率90%(27/30)相比,DPC4阳性表达显著降低,差异有统计学意义(P＜0.05);DPC4与淋巴结转移、临床分期相关(P＜0.05),而与病理类型、组织学分级无关(P＞0.05).P21WAF1/CIP1在肿瘤组织中阳性表达率为68.3%(41/60),与癌旁正常肺组织的阳性表达率6.7%(2/30)相比,差异有统计学意义(P＜0.05);P21WAF1/CIP1与组织学分类、临床分期、是否有淋巴结转移等无关(P＞0.05).结论 DPC4、P21WAF1/CIP1异常表达可能参与了NSCLC的发生发展,联合检测二者有助于判断肺癌的恶性程度及预后.     

基因突变与胰腺癌

胰腺癌的发病率在我国呈逐年上升趋势。由于其起病隐匿，恶性程度高。早期诊断困难，出现临床症状时多属晚期，因此患者的预后较差。近年来随着分子生物学技术的发展，对胰腺癌发生机制的研究已进入基因水平，研究表明胰腺癌的发生是多基因异常改变的结果。就p16基因，p53基因，DPC4基因，Ras基因及MMR基因与胰腺癌的关系作一综述。     

Comparative genomic hybridization analysis of genetic aberrations associated with development and progression of biliary tract carcinomas

BACKGROUND: Little is known about genetic aberrations associated with development and progression of biliary tract carcinomas. METHODS: To study chromosomal aberrations associated with development and progression of biliary tract carcinomas, the authors used comparative genomic hybridization to examine 50 such carcinomas. RESULTS: Gains in part or in whole of chromosomes 1q, 8q, and 20q and losses of 5q, 8p, 9p, and 18q were detected frequently in early stage (T1/T2 classification) biliary tract carcinomas (> or = 40% of 19 early stage tumors), and they also were found in advanced stage (T3/T4 classification) tumors. In particular, loss of 9p was the most frequently observed aberration in both early stage (15 of 19; 78%) and advanced stage tumors (21 of 31; 68%). The frequencies of gains of 7p12-p14 (P < 0.003), 7p21-pter (P < 0.007), and 7q31 (P < 0.01) differed significantly between biliary tract carcinoma with and without distant metastasis. Also, gains of 5p and 19q13 and loss of 6q14-q16 were more frequent in tumors with lymph node metastasis than in those without it (P < 0.02). CONCLUSIONS: It is likely that loss of 9p is one of the genetic aberrations critical for the development of biliary tract carcinoma, whereas gains of 5p, 7p, 7q, and 19q and loss of 6q are considered later events associated with tumor progression and are thought to confer metastatic potential to biliary tract carcinomas.     

Promoter hypermethylation of DAP-kinase is associated with poor survival in primary biliary tract carcinoma patients

To clarify the clinicopathological significance of promoter hypermethylation of tumor suppressor and tumor-related genes in biliary tract carcinomas, we examined the promoter methylation status of multiple genes in primary biliary tract carcinomas. These consisted of carcinomas of the bile duct, gallbladder, and duodenal ampulla. Surgical specimens were obtained from a total of 37 patients with biliary tract carcinoma. The cohort consisted of 23 patients with bile duct carcinoma, 9 patients with gallbladder carcinoma, and 5 patients with ampullary carcinoma. The methylation status of CHFR, DAP-kinase, E-cadherin, hMLH1, p16, RASSF1A, and RUNX3 was examined by methylation-specific polymerase chain reaction (MSP). The correlation between methylation status and clinicopathological characteristics was then assessed. The methylation frequencies of CHFR, DAP-kinase, E-cadherin, hMLH1, p16, RASSF1A, and RUNX3 genes were 16.2%, 21.4%, 27.0%, 8.1%, 24.3%, 27.0%, and 56.8%, respectively, in primary biliary tract carcinomas. The number of methylated genes per sample was 2.17 +/- 0.28 (average +/- SD) in bile duct carcinomas, 1.80 +/- 0.97 in ampullary carcinomas, and 0.89 +/- 0.35 in gallbladder carcinomas, with a statistically significant difference between bile duct carcinomas and gallbladder carcinomas (P = 0.02). As for clinicopathological significance, patients with a methylated RUNX3 promoter were significantly older than those with unmethylated RUNX3 (P = 0.01), and DAP-kinase methylation was more frequent in poorly differentiated tumors than in well to moderately differentiated ones (P = 0.04). The overall survival rate was significantly lower in patients with methylated DAP-kinase (P = 0.009) or RUNX3 (P = 0.034) compared to those with unmethylated genes. Furthermore, DAP-kinase methylation-positive status was independently associated with poor survival in multivariate analyses (hazard ratio = 8.71, P = 0.024). A significant proportion of primary biliary tract carcinomas exhibited promoter hypermethylation of tumor suppressor and tumor-related genes, although bile duct carcinomas are more prone to being affected by promoter methylation than are gallbladder carcinomas. Hypermethylation of DAP-kinase appears to be a significant prognostic factor in primary biliary tract carcinomas.     

DPC4/SMAD4 mediated tumor suppression of colon carcinoma cells is associated with reduced urokinase expression.

We recently identified DPC4/Smad4 as a candidate tumor suppressor gene mutated or lost in one half of pancreatic carcinomas and in a subset of colon and biliary tract carcinomas. DPC4 plays a key role in signal transduction of the TGF-beta superfamily of molecules and inactivation of TGF-beta mediated growth inhibition is supposed to be the driving force for DPC4 inactivation in human tumors. However, DPC4 mediated tumor suppression by reconstitution of defective cells has not yet been reported. Here we show suppression of tumorigenicity in nude mice by stable reexpression of DPC4 in SW480 colon carcinoma cells. In vitro growth of DPC4-transfected cells was not affected and resistance towards TGF-beta mediated growth inhibition was retained. Instead, cells exhibited morphological alterations and adhesion and spreading were accelerated. These phenotypic changes were associated with reduced expression levels of the endogenous urokinase-type plasminogen activator (uPA) and plasminogen-activator-inhibitor-1 (PAI-1) genes, the products of which are implicated in the control of cell adhesion and invasion. In patients, high expression levels of uPA and PAI-1 correlate with poor prognosis. Thus, reduced expression of uPA and PAI-1 is consistent with suppression of tumorigenicity in DPC4 reconstituted cells. These results demonstrate DPC4's tumor suppressive function and suggest a potential role for DPC4 as a modulator of cell adhesion and invasion.     

Prognostic significance of aquaporins in human biliary tract carcinoma

Aquaporins (AQPs) are important in controlling bile formation, however, the exact role of AQPs in human biliary tract carcinogenesis has not been clearly defined. In this study, we analyzed AQP-1, -4, -5 and -8 expression immunohistochemically using tissue microarrays (TMAs) in 81 samples. (45 gallbladder carcinomas and 36 bile duct carcinomas). The survival of patients with high AQP-5 expression was longer compared to that of patients with low AQP-5 expression (P=0.017). Cox's proportional hazard model revealed that AQP-5 expression was an independent prognostic factor (RR, 0.38; P=0.025). Chi-square analysis revealed that high AQP-5 expression correlated to small tumor size in biliary tract carcinoma patients (P=0.006). With regard to the expression of other AQPs, depth of tumor invasion, histological type and serum carbohydrate antigen 19-9 (CA19-9) were associated with high AQP-1 expression (P=0.039, 0.011 and 0.032). However, AQP-4 and AQP-8 expression had no association with clinicopathological factors. Among the 10 patients who underwent gemcitabine (GEM) plus S-1 postoperative chemotherapy, the group of patients (n=5) with high AQP-5 expression were associated with higher rates of both overall and disease-free survival (log-rank P=0.033, 0.002). In conclusion, the results of this study suggest that AQP-5 expression may be associated with prognosis and drug sensitivity in biliary tract carcinoma.     

Radiation therapy of carcinoma of gallbladder and biliary tract.

Fourteen patients with carcinoma of the gallbladder of biliary tract were treated with radiation therapy. Some patients received definite palliative benefit and there were several long term survivors. Patients with bile duct carcinomas responded more often (50%) than did those with gallbladder carcinomas (20%). Only one patient was treated following total gross removal of the tumor, and he is a 6-year survivor. A plea is made for utilizing planned radiotherapy and chemotherapy for tumors arising in the biliary tract.     

Activation of telomerase and its diagnostic application in biopsy specimens from biliary tract neoplasms.

BACKGROUND: Telomerase activity has been reported to have potential as a useful diagnostic marker for cancer in various organs. The authors previously reported that telomerase activity in pancreatic juice differentiates pancreatic ductal carcinoma from adenoma and pancreatitis. In the current study, the usefulness of semiquantitatively determined telomerase activity in the diagnosis of malignant biliary tract neoplasms was investigated. METHODS: The samples examined included 61 surgically resected biliary tract tissues (11 gallbladder carcinomas, 5 bile duct carcinomas, 1 gallbladder adenoma, 30 cholecytitis cases, 7 cholesterol polyps, 1 normal gallbladder, and 6 normal common bile duct tissues), 42 bile samples from patients with biliary tract or pancreatic disease (19 cases of malignant biliary tract disease, 11 cases of benign biliary tract disease, 10 cases of malignant pancreatic disease, and 2 cases of benign pancreatic disease), and 14 bile duct biopsy specimens collected by percutaneous transhepatic choledochoscopy or endoscopic retrograde cholangiopancreatography (8 bile duct carcinoma specimens, 1 bile duct adenoma specimen, and 5 hepatolithiasis specimens). RESULTS: In biliary tract tissues, a telomerase ladder was detected in 73% of gallbladder carcinomas, 40% of bile duct carcinomas, and none of the other biliary tract tissues. One gallbladder adenoma showed a weak telomerase ladder. The telomerase ladder was detected in the bile sample from 1 patient (5.3%) with malignant biliary tract disease, none of the patients with benign biliary tract disease, 5 patients (50%) with malignant pancreatic disease, and none of the patients with benign pancreatic disease. In biopsy specimens, the telomerase ladder was detected in 75% of patients with bile duct carcinoma but not in any of the patients with hepatolithiasis. The median value of relative telomerase activity in the patients with bile duct carcinoma was significantly higher than that in the patients with hepatolithiasis. The diagnosis of bile duct carcinoma was confirmed preoperatively by histopathologic examination in only 25% of the biopsy specimens. CONCLUSIONS: The results of the current study indicate that telomerase is highly activated in biliary tract carcinomas and that the detection of a telomerase ladder in biopsy samples is an excellent tool for the diagnosis of bile duct carcinomas.     

Induction of Extrahepatic Biliary Carcinoma by N-Nitrosobis(2-oxopropyl)amine in Hamsters Given Cholecystoduodenostomy with Dissection of the Common Duct

The methods we used to produce a carcinoma in the extrahepatic bile duct and gallbladder in hamsters are described along with the characteristics of the induced tumors. Female Syrian golden hamsters were first subjected to Cholecystoduodenostomy with dissection of the extrahepatic bile duct on the distal end of the common duct (CDDB) and were, 4 weeks later, treated with weekly subcutaneous injections of N-nitrosobis(2-oxopropyl)amine (BOP) at a dose of 10 mg/kg body weight for 9 weeks. The animals were killed at the 12th, 16th and 20th week after the initiation of BOP treatment. Extrahepatic bile duct carcinoma developed in 16%, 24% and 41% and gallbladder carcinoma occurred in 58%, 81% and 82% of the hamsters, respectively, at the corresponding times of killing. The incidences were significantly higher than those in sham-operated controls ( P <0.01). The induced extrahepatic bile duct carcinomas were predominantly of the polypoid type and gallbladder carcinomas were of the papillary type in growth form, being morphologically similar to early stage biliary carcinoma in humans. Immunohistochemical staining using bromodeoxynridine and anti-bromo-deoxyuridine monoclonal antibody demonstrated that the CDDB procedure greatly accelerated the cell kinetic activity of the biliary epithelium, and this was considered to be a major factor promoting the development of biliary carcinomas in this hamster model. In conclusion, this new model provides a high incidence of tumor development at the extrahepatic biliary tract and is expected to be useful for clarifying the characteristics of this highly malignant tumor.     

Analysis of the DPC4 Gene in Gastric Carcinoma

Allelic loss on chromosome 18q is involved in the progression of gastric carcinoma. Recently, DPC4 (deleted in pancreatic carcinoma, locus 4), a candidate tumor suppressor gene, has been localized at 18q21.1. This gene is inactivated in nearly one half of pancreatic carcinomas. We tested for DPC4 gene mutations and allelic status at 18q21 in 30 primary gastric carcinomas and 5 gastric carcinoma cell lines. Polymerase chain reaction single-strand conformation polymorphism and sequencing analyses revealed no DPC4 mutations in any of the primary tumors or cell lines. Homozygous deletion ofDPC4 was observed in only 1 (MKN-45) of the 5 (20%) cell lines. This suggests that the target gene for loss on 18q is not DPC4. The true tumor suppressor gene, encoded near DPC4 , has yet to be identified.     

K-ras mutations in duodenal aspirate without secretin stimulation for screening of pancreatic and biliary tract carcinoma.

BACKGROUND: K-ras mutations at codon 12 (KRM) have been detected in over 80% of tissues and pure pancreatic juice (PPJ) samples from patients with pancreatic carcinoma (PCa) and are promising genetic tumor markers. Aspirating PPJ not only requires technical skill, but is also exhausting for patients. The authors attempted to evaluate whether the detection of KRM in the duodenal aspirate (DA) obtained immediately after endoscopic retrograde cholangiopancreatography (ERCP), an easier sample-collecting method than collecting PPJ, could be useful for the diagnosis of PCa and biliary tract carcinoma (BTCa). METHODS: DA was collected endoscopically without secretin stimulation immediately after the ERCP procedure from 160 patients: 38 patients with PCa, 38 with chronic pancreatitis (CP), 22 with BTCa, 20 with adenomyomatosis of the gallbladder (AGB), 22 with cholecystolithiasis (CCL), and 20 control subjects. Mutant allele specific amplification (MASA), which is a highly sensitive method for detecting KRM, was performed, with the DNAs extracted from these samples by phenol-chloroform. RESULTS: The incidence of KRM in DA by MASA was 25 (66%) of the 38 PCa cases, 12 (32%) of the 38 CP cases, and 12 (55%) of the 22 BTCa cases. There was no patient with positive KRM in DA among the 20 cases of AGB, 22 of CCL, and 20 control subjects. The sensitivity was 62% and the specificity 88% in this study design. The KRM incidence was found to be relatively high for the patients with PCa and BTCa by MASA, which is a highly sensitive method, although the incidence of KRM in DA from the patients with PCa was not as high as the incidence in their PPJ with secretin stimulation. CONCLUSIONS: MASA showed a relatively high incidence of KRM even in the DA, which was easily obtained from the patients with PCa and BTCa without secretin stimulation immediately after ERCP. These results suggest that the detection of KRM in the DA by MASA is useful for the screening of both PCa and BTCa.     

Differing rates of loss of DPC4 expression and of p53 overexpression among carcinomas of the proximal and distal bile ducts

BACKGROUND: Biliary tract carcinomas are clinically heterogeneous. It is not known if molecular heterogeneity underlies the clinical differences. METHODS: The authors evaluated 128 bile duct carcinomas, 88 of the distal common bile duct and 40 of more proximal origin (28 perihilar carcinomas, 12 intrahepatic carcinomas), immunohistochemically for abnormalities in the expression of the products of the DPC4 and p53 tumor-suppressor genes. Prognostic factors were evaluated in the series of distal bile duct carcinomas for which follow-up information was available. RESULTS: The authors found that a significantly higher percentage of distal bile duct carcinomas (55%) demonstrated loss of DPC4 expression than did the proximal bile duct carcinomas (15%; P < 0.001). They also found that a significantly higher percentage of the distal tumors abnormally expressed the p53 gene product (51% vs. 26%; P < 0.001). Among the distal common bile duct carcinomas, the presence of poorly differentiated histology correlated with decreased survival in multivariate analysis, while labeling for p53 or Dpc4, margin status, lymph node status, and tumor dimension did not correlate significantly with survival. CONCLUSIONS: These results demonstrate that abnormalities in DPC4 and p53 gene expression are frequent in distal common bile duct carcinomas, just as they are in pancreatic ductal adenocarcinoma, suggesting that these two tumor types might share a similar molecular pathogenesis. They also show that proximal and distal bile duct carcinomas have different patterns of inactivation of tumor-suppressor genes, indicating that they often arise through different molecular mechanisms likely reflecting their differing etiologies.