scholarly journals Efficient Generation of P53 Biallelic Mutations in Diannan Miniature Pigs Using RNA-Guided Base Editing

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1417
Author(s):  
Honghui Li ◽  
Wenmin Cheng ◽  
Bowei Chen ◽  
Shaoxia Pu ◽  
Ninglin Fan ◽  
...  
Keyword(s):  
Disease Model ◽  
P53 Gene ◽  
P53 Mutation ◽  
P53 Mutations ◽  
P53 Expression ◽  
Base Editing ◽  
System A ◽  
Reconstructed Embryos ◽  
Monoallelic Mutation ◽  
Biallelic Mutations

The base editing 3 (BE3) system, a single-base gene editing technology developed using CRISPR/Cas9n, has a broad range of applications for human disease model construction and gene therapy, as it is highly efficient, accurate, and non-destructive. P53 mutations are present in more than 50% of human malignancies. Due to the similarities between humans and pigs at the molecular level, pig models carrying P53 mutations can be used to research the mechanism of tumorigenesis and improve tumor diagnosis and treatment. According to pathogenic mutations of the human P53 gene at W146* and Q100*, sgRNAs were designed to target exon 4 and exon 5 of the porcine P53 gene. The target editing efficiencies of the two sgRNAs were 61.9% and 50.0%, respectively. The editing efficiency of the BE3 system was highest (about 60%) when C (or G) was at the 5th base. Puromycin screening revealed that 75.0% (21/28) and 68.7% (22/32) of cell colonies contained a P53 mutation at sgRNA-Exon5 and sgRNA-Exon4, respectively. The reconstructed embryos from sgRNA-Exon5-5# were transferred into six recipient gilts, all of which aborted. The reconstructed embryos from sgRNA-Exon4-7# were transferred into 6 recipient gilts, 3 of which became pregnant, resulting in 14 live and 3 dead piglets. Sequencing analyses of the target site confirmed 1 P53 monoallelic mutation and 16 biallelic mutations. The qPCR analysis showed that the P53 mRNA expression level was significantly decreased in different tissues of the P53 mutant piglets (p < 0.05). Additionally, confocal microscopy and western blot analysis revealed an absence of P53 expression in the P53 mutant fibroblasts, livers, and lung tissues. In conclusion, a porcine cancer model with a P53 point mutation can be obtained via the BE3 system and somatic cell nuclear transfer (SCNT).

Clinical and biological implication of defective p53 pathway in multiple myeloma (MM)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17516-17516
Author(s):  
W. J. Chng ◽  
T. Price-Troska ◽  
S. Van Wier ◽  
S. Jacobus ◽  
E. Blood ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Electrophoretic Pattern ◽  
P53 Mutation ◽  
Response To Treatment ◽  
Rank Test ◽  
Allelic Loss ◽  
Similar Response ◽  
Newly Diagnosed ◽  
P53 Mutations ◽  
P53 Expression

17516 Background: The p53 tumor suppressor is commonly inactivated by mutations. Even in tumors without mutations, there are defects in the response to p53 activation. In MM, the prognostic significance of p53 mutation is unknown, while there has been no systematic study of p53 function. We seek to address these issues in this study. Methods: p53 mutation was studied by conformation sensitive gel electrophoresis with primers encompassing exons 1 to 10 followed by sequencing of DNA fragments with altered electrophoretic pattern in newly diagnosed MM patients entered into ECOG E9486 trial where patients were randomized to receive variations of melphalan-based conventional chemotherapy (VBMCP). Fisher’s exact tests were used to compare variables between patients. Kaplan-Meier survival curves were compared using the log-rank test. To investigate p53 function, we analyzed the expression of p53, and 3 of its transcriptional targets, APAF1, p21 and MDM2, in a separate cohort of 15 normal plasma cells (PC), 14 MGUS, 13 smoldering myeloma (SMM) and 101 MM (73 new and 28 relapsed) from the Mayo Clinic who had gene expression profiling performed on the Affymetrix U133A chip (Santa Clara, Ca). Results: Two hundred and sixty-eight patients had enough materials for study and were included in the analysis. The prevalence of p53 mutation was 3% (n = 9). Five of the 9 patients (56%, p = 0.001) with mutations also had p53 deletion (studied by fluorescent in-situ hybridization) resulting in bi-allelic loss of p53. Soft tissue plasmacytomas (37% v 7%, p = 0.018), and among the common translocations, t(4;14) and t(14;16) (50% v 18%) were more common in patients with p53 mutations. Despite similar response to treatment, those with p53 mutation had very short OS (16.7 v 41.4 months, p < 0.001). There was induction of p53 expression in MGUS and SMM with concurrent induction of APAF1, p21 and MDM2 whereas loss of this pattern was frequent in MM (45% in new MM and 60% in relapse MM compared to 15% in MGUS/SMM (p = 0.03)). Conclusions: p53 mutations are relatively rare in newly diagnosed MM patients but portend a short survival. However, functional abnormalities of p53 are prevalent and may be important in progression from MGUS/SMM to MM. [Table: see text]

scholarly journals p53 Abnormalities in B-Cell Prolymphocytic Leukemia

Blood ◽  
1997 ◽  
Vol 89 (6) ◽  
pp. 2015-2023 ◽  
Author(s):  
Daniela Lens ◽  
Pierre J.J.C. De Schouwer ◽  
Rifat A. Hamoudi ◽  
Munah Abdul-Rauf ◽  
Nahla Farahat ◽  
...  
Keyword(s):  
B Cell ◽  
Hematologic Malignancies ◽  
P53 Mutation ◽  
Lymphocytic Leukemia ◽  
Cathepsin G ◽  
P53 Mutations ◽  
B Cell Malignancies ◽  
Prolymphocytic Leukemia ◽  
P53 Expression ◽  
Pathologic Features

Abstract B-cell prolymphocytic leukemia (B-PLL) is an aggressive disorder of mature B cells with distinct clinical and pathologic features. To determine the incidence of abnormalities of p53, we analyzed 19 cases of B-PLL by DNA blot to assess loss of heterozygosity (LOH) at 17p13.3, by immunocytochemistry to assess p53 expression, and by direct DNA sequencing of polymerase chain reaction-amplified exons 5 to 9 of the p53 gene. LOH was detected in 10 of 19 (53%) cases, p53 expression was detected in 8 of 17 (47%), and p53 mutations were detected in 10 of 19 (53%) cases. The pattern of mutations was distinct from that observed in other B-cell malignancies. Six cases exhibited missense mutations; 4 were transversions and 2 were transitions. The G:C → A:T transition at cathepsin G dinucleotides commonly reported in p53 mutations in chronic lymphocytic leukemia (CLL) and other hematologic malignancies was observed in only 1 case of B-PLL. Three cases exhibited deletions (ranging from 3 to 35 bp in length) and one case exhibited a 2-bp insertion. In 1 case, a 27-bp deletion resulted in the expression of a p53 protein lacking 9 amino acids from the DNA binding region. All samples with p53 mutation showed loss of germline p53 sequences. However, 3 of 10 showed no LOH by Southern blot, indicating a localized deletion around the p53 locus at 17p13.1. Five of the 10 cases with p53 mutation exhibited detectable p53 expression, including 4 cases with p53 missense mutation and 1 case with deletion. Two of 7 cases with no detectable mutation of p53 nevertheless overexpressed p53. Therefore, there was no correlation between protein expression and p53 mutation in B-PLL. Our data indicate that the overall abnormalities of p53 occurred in 14 of 19 (75%) cases of B-PLL. The frequency of p53 mutation (53%) in B-PLL is the highest reported in B-cell malignancies and may be responsible for the frequent resistance to therapy of this disease. In addition, the pattern of p53 mutation was different from that observed in CLL and other hematologic malignancies and may indicate that a distinct pathogenic mechanism operates in B-PLL.

scholarly journals p53 mutations as fingerprints of environmental carcinogens

2000 ◽  
Vol 72 (6) ◽  
pp. 995-999 ◽  
Author(s):  
Rengul Cetin-Atalay ◽  
Mehmet Ozturk
Keyword(s):  
Great Majority ◽  
P53 Gene ◽  
Suppressor Gene ◽  
Protein Product ◽  
P53 Mutation ◽  
P53 Mutations ◽  
Environmental Carcinogens ◽  
Molecular Fingerprints ◽  
Human Cancers ◽  
Mutation Spectra

Mutations of the p53 tumor suppressor gene occur in a great majority of human cancers. The protein product of p53 gene is involved in DNA damage response. Consequently, p53 gene may be a preferred target for environmental carcinogens, which also act as DNA-damaging agents. This is probably why p53 mutations are frequent in cancers linked to environmental carcinogens. Moreover, these carcinogens leave molecular fingerprints on the p53 gene. Thus, the study of p53 mutation spectra has been a useful approach to implicate suspected carcinogens to different human cancers. This review provides further insight into the significance of p53 mutation spectra in ten common human malignancies (skin, liver, lung, bladder, breast, head and neck, esophagus, stomach and colorectal cancers, and hematological malignancies), in relation with environmental carcinogens.

scholarly journals Nonhereditary p53 mutations in T-cell acute lymphoblastic leukemia are associated with the relapse phase

Blood ◽  
1994 ◽  
Vol 83 (10) ◽  
pp. 2922-2930 ◽  
Author(s):  
MH Hsiao ◽  
AL Yu ◽  
J Yeargin ◽  
D Ku ◽  
M Haas
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
P53 Gene ◽  
Tumor Formation ◽  
Missense Mutations ◽  
P53 Mutations ◽  
P53 Expression ◽  
Cell Acute Lymphoblastic Leukemia

Abstract We have previously reported that greater than 60% of human leukemic T- cell lines possess mutations in the p53 tumor suppressor gene. To determine whether T-cell acute lymphoblastic leukemia (T-ALL) patient samples possess p53 mutations, we screened peripheral blood-and bone marrow-derived leukemia samples, taken at diagnosis and at relapse, for p53 mutations. Exons 4 through 9 and selected intron regions of the p53 gene were analyzed using polymerase chain reaction-single-strand conformation polymorphism and direct sequencing. p53 mutations were found in 0 of 15 T-ALL diagnosis samples, as compared with 10 of 36 (28%) T-ALL relapse samples. To determine whether p53 mutations play a role in the recurrence (relapse) of T-ALL, two special groups of T-ALL patients were studied: (1) a group of 8 relapse patients whose disease was refractory to chemotherapeutic treatment, and (2) a group of 6 “paired” T-ALL cell samples from patients for whom we possess both diagnosis and relapse samples. Three of 8 relapsed patients (37.5%) whose disease was refractory to the reinduction of remission by chemotherapy possessed missense mutations of the p53 gene. All 3 cases had mutations in exon 5. Among the paired samples, 3 of 6 patients harbored p53 mutations at disease recurrence, but possessed only wild- type p53 alleles at diagnosis. One case had mutation on exon 4, 1 case in exon 5, and 1 case in exon 8 with loss of heterozygosity. These data clearly indicate that recurrence of T-ALL is associated with missense mutations in p53. Our results indicate that (1) mutations of p53 do occur in T-ALL in vivo, and such mutations are associated with the relapse phase of the disease; and (2) p53 mutation is involved in the progression of T-ALL. This conclusion is supported by our observation that the introduction of T-ALL-derived mutant p53 expression constructs into T-ALL cell lines further increases their growth rate in culture, enhances cell cloning in methylcellulose, and increases tumor formation in nude mice.

Characterization of p53 Abnormalities in CLL Patients in Relation to IGVH Mutation Status and Previous Treatment.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2947-2947
Author(s):  
M. Trbusek ◽  
V. Kuhrova ◽  
J. Malcikova ◽  
J. Smardova ◽  
H. Francova ◽  
...  
Keyword(s):  
Hot Spots ◽  
Direct Sequencing ◽  
P53 Protein ◽  
Alkylating Agents ◽  
Previous Treatment ◽  
P53 Gene ◽  
P53 Mutation ◽  
P53 Mutations ◽  
Mutation Status ◽  
P53 Inactivation

Abstract Background: Although the defects in the p53 gene predispose CLL patients for inferior outcome, little is known about the reasons leading to inactivation of this tumor-suppressor. The p53 abnormalities were reported to be associated with unmutated IgVH subtype and may thus arise as a consequence of its more aggressive behaviour, but some reports point also to potentially damaging chemotherapy including alkylating agents. Aims: The aims of the study were to determine the spectrum of p53 mutations in CLL patients treated or monitored at our center and to correlate the data to mutation status of IgVH and to the previous treatment. Methods: We analyzed the status of the p53 gene in 144 patients diagnosed with CLL of all stages using functional analysis in yeasts (FASAY) supplemented by Western-blotting detection of p53 protein expression and I-FISH detection of p53 deletions. We used PCR and direct sequencing to analyze the IgVH rearrangements and mutation status. Results: Our comprehensive approach for monitoring of p53 abnormalities provided us the overall frequency of inactivation within the expected range (14%; usually reported between 10–15%). We noticed a very good overlap between the mutation of one and deletion of the second allele (93%) and between the mutation and corresponding p53 protein over-expression (92%). All the identified mutations in the p53 gene were unambigously determined by direct sequencing from yeast colonies harboring mutated phenotype. We did not find any p53 mutation (n=15) more than once and thus we do not see in our population neither the hot-spots published for CLL in p53 mutation database IARC (codons 248 and 273) nor the hot-spots reported in literature (codons 209 and 143). Inactivation of p53 ocurred markedly more frequently in subtype with unmutated IgVH compared to mutated one (16.7% vs. 5.3%). Moreover, two of the three IgVH mutated cases harbored just p53 deletion without accompanying mutation, slightly over background level. We noticed a very low frequency of the immunoglobulin gene VH3-21 (4.3% in our study vs. 11.2% reported by Tobin et al., Blood2002; 99: 2262–2264), which was recently reported to be mostly mutated and to be associated with p53 inactivation. Four of the six our cases manifested unmutated IgVH, with two of them showing deletions of p53 or ATM (p53-regulatory kinase), respectively. The overall treatment, which included alkylating agents in 43/48 cases, was markedly more frequent within the subgroup with germ-line IgVH (in 49% of patients) compared to group harboring mutated IgVH (in 7% of patients - none of them with p53 inactivation). In the former subgroup the p53 inactivation in the untreated and treated patients was very similar (17% vs. 20%). Conclusions: The spectrum of p53 mutations in our population is different from those reported in other studies. The inactivation of the p53 was in our study associated with unmutated IgVH locus and does not seem to be primarily the consequence of previous chemotherapy including alkylating agents. Supported by grants NR8445-3/2005, NR8443-3/2005 and NR8448-3/2005 provided by IGA of Ministry of Health of the Czech Republic.

scholarly journals Role of Stat3 in Regulating p53 Expression and Function

2005 ◽  
Vol 25 (17) ◽  
pp. 7432-7440 ◽  
Author(s):  
Guilian Niu ◽  
Kenneth L. Wright ◽  
Yihong Ma ◽  
Gabriela M. Wright ◽  
Mei Huang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Tumor Development ◽  
P53 Gene ◽  
P53 Mutations ◽  
Oncogenic Signaling ◽  
P53 Expression ◽  
And Function ◽  
Oncogenic Signaling Pathways

ABSTRACT Loss of p53 function by mutation is common in cancer. However, most natural p53 mutations occur at a late stage in tumor development, and many clinically detectable cancers have reduced p53 expression but no p53 mutations. It remains to be fully determined what mechanisms disable p53 during malignant initiation and in cancers without mutations that directly affect p53. We show here that oncogenic signaling pathways inhibit the p53 gene transcription rate through a mechanism involving Stat3, which binds to the p53 promoter in vitro and in vivo. Site-specific mutation of a Stat3 DNA-binding site in the p53 promoter partially abrogates Stat3-induced inhibition. Stat3 activity also influences p53 response genes and affects UV-induced cell growth arrest in normal cells. Furthermore, blocking Stat3 in cancer cells up-regulates expression of p53, leading to p53-mediated tumor cell apoptosis. As a point of convergence for many oncogenic signaling pathways, Stat3 is constitutively activated at high frequency in a wide diversity of cancers and is a promising molecular target for cancer therapy. Thus, repression of p53 expression by Stat3 is likely to have an important role in development of tumors, and targeting Stat3 represents a novel therapeutic approach for p53 reactivation in many cancers lacking p53 mutations.

p53 Gene Status as a Predictor of Tumor Response to Induction Chemotherapy of Patients With Locoregionally Advanced Squamous Cell Carcinomas of the Head and Neck

2000 ◽  
Vol 18 (2) ◽  
pp. 385-385 ◽  
Author(s):  
Stéphane Temam ◽  
Antoine Flahault ◽  
Sophie Périé ◽  
Guy Monceaux ◽  
Florence Coulet ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Odds Ratio ◽  
Objective Response ◽  
P53 Gene ◽  
Tumor Stage ◽  
Squamous Cell Carcinomas ◽  
P53 Mutations ◽  
P53 Expression ◽  
Major Response ◽  
Gene Status

PURPOSE: To determine whether p53 gene status predicts tumor responses to platinum- and fluorouracil-based induction chemotherapy in locoregionally advanced squamous cell carcinomas of the head and neck. PATIENTS AND METHODS: Tumor responses of 105 patients were measured at the primary tumor site. Objective response and major response were defined by a 50% and 80% reduction in tumor size, respectively. All coding parts of p53 gene were directly sequenced. p53 expression in tumor cells was determined by immunohistochemistry. Human papillomavirus infection was detected by polymerase chain reaction. Odd ratios were adjusted by stepwise logistic regression analysis. RESULTS: p53 mutations, p53 expression, and tumor stage were sufficient to explain the variation in tumor responses to chemotherapy in multivariate models. p53 mutation was the only variable to significantly predict objective response (odds ratio, 0.23; 95% confidence interval, 0.10 to 0.57; P = .002) and was the strongest predictor of major response (odds ratio, 0.29; 95% confidence interval, 0.11 to 0.74; P = .006). p53 expression (odds ratio, 0.39; 95% confidence interval, 0.16 to 0.98) and tumor stage (odds ratio, 0.31; 95% confidence interval, 0.10 to 0.96) also predicted major response. Specific mutations (contact mutations) accounted for much of the reduction in the risk of major response associated with overall mutations. In complementary analyses, p53 expression was weakly predictive of major response in the subgroup with wild-type p53, and p53 mutations also predicted histologic response. CONCLUSION: p53 gene mutations are strongly associated with a poor risk of both objective and major responses to chemotherapy. Contact mutations are associated with the lowest risk of major response to chemotherapy.

Beyond Li Fraumeni Syndrome: Clinical Characteristics of Families With p53 Germline Mutations

2009 ◽  
Vol 27 (8) ◽  
pp. 1250-1256 ◽  
Author(s):  
Kelly D. Gonzalez ◽  
Katie A. Noltner ◽  
Carolyn H. Buzin ◽  
Dongqing Gu ◽  
Cindy Y. Wen-Fong ◽  
...  
Keyword(s):  
Family History ◽  
Diagnostic Testing ◽  
P53 Gene ◽  
Germline Mutations ◽  
P53 Mutation ◽  
Family Characteristics ◽  
P53 Mutations ◽  
Li Fraumeni Syndrome ◽  
Li Fraumeni ◽  
Associated Family

Purpose A clinical testing cohort was used to gain a broader understanding of the spectrum of tumors associated with germline p53 mutations to aid clinicians in identifying high-risk families. Patients and Methods Full sequencing of the coding exons (2 to 11) and associated splice junctions of the p53 gene was performed on 525 consecutive patients whose blood samples were submitted for diagnostic testing. Clinical features of p53 germline carriers in this cohort were characterized, clinical referral schemes based on reported p53-associated family phenotypes were evaluated, and practical mutation prevalence tables were generated. Results Mutations were identified in 91 (17%) of 525 patients submitted for testing. All families with a p53 mutation had at least one family member with a sarcoma, breast, brain, or adrenocortical carcinoma (ACC). Every individual with a choroid plexus tumor (eight of eight) and 14 of 21 individuals with a childhood ACC had a mutation regardless of family history. Based on reported personal and family history, 95% of patients (71 of 75) with a mutation met either classic Li Fraumeni syndrome (LFS) or Chompret criteria. A simplified prevalence table provides a concise summary of individual and family characteristics associated with p53 mutations. Conclusion This is, to our knowledge, the largest single report of diagnostic testing for germline p53 mutations, yielding practical mutation prevalence tables and suggesting clinical utility of classic LFS and Chompret criteria for identifying a subset of cancer-prone families with p53 germline mutations, with important implications for diagnosis and management.

p53 Alterations Predict Tumor Response to Neoadjuvant Chemotherapy in Head and Neck Squamous Cell Carcinoma: A Prospective Series

2000 ◽  
Vol 18 (7) ◽  
pp. 1465-1473 ◽  
Author(s):  
Arnauld Cabelguenne ◽  
Hélène Blons ◽  
Isabelle de Waziers ◽  
Françoise Carnot ◽  
Anne-Marie Houllier ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Neoadjuvant Chemotherapy ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
P53 Gene ◽  
P53 Mutations ◽  
P53 Antibodies ◽  
Response To Chemotherapy ◽  
P53 Status ◽  
Response To Neoadjuvant Chemotherapy

PURPOSE: The tumor suppressor gene p53 plays a crucial role in cell cycle control and apoptosis in response to DNA damages. p53 gene mutations and allelic losses at 17p are one of the most common genetic alterations in primary head and neck squamous cell carcinoma (HNSCC). Alterations of the p53 gene have been shown to contribute to carcinogenesis and drug resistance. PATIENTS AND METHODS: In this prospective series, patients with HNSCC were treated with cisplatin-fluorouracil neoadjuvant chemotherapy. p53 status was characterized in 106 patients with HNSCC (p53 mutations, allelic losses at p53 locus, and plasma anti-p53 antibodies) to determine the existence of a relationship between p53 gene status and response to neoadjuvant chemotherapy. RESULTS: Exons 4 to 9 of the p53 gene were analyzed, and mutations were found in 72 of 106 patients with HNSCC. p53 mutations were associated with loss of heterozygosity at chromosome 17p (P < .001). The prevalence of p53-mutated tumors was higher in the group of patients with nonresponse to neoadjuvant chemotherapy than in the group of responders (81% v 61%, respectively; P < .04). When compiling p53 mutations and anti-p53 antibodies in plasma, the correlation between p53 status and response to chemotherapy was significant (87% v 57%, respectively; P = .003). A multivariate analysis showed that p53 status is an independent predictive factor of response to chemotherapy. CONCLUSION: This prospective study suggests that p53 status may be a useful indicator of response to neoadjuvant chemotherapy in HNSCC.

Regulators of Apoptosis in Cholangiocarcinoma

2005 ◽  
Vol 129 (4) ◽  
pp. 481-486
Author(s):  
Nirag C. Jhala ◽  
Selwyn M. Vickers ◽  
Pedram Argani ◽  
Jay M. McDonald
Keyword(s):  
Bile Duct ◽  
Biliary Tract ◽  
P53 Gene ◽  
Tumor Location ◽  
Biliary Duct ◽  
Early Event ◽  
Tumor Differentiation ◽  
P53 Gene Mutation ◽  
P53 Expression ◽  
Poorly Differentiated

Abstract Context.—Dysregulation of mediators of apoptosis is associated with carcinogenesis. For biliary duct cancers, p53 gene mutation is an important contributor to carcinogenesis. Mutations in the p53 gene affect transcription of the Fas gene, resulting in lack of Fas expression on cell membrane. It has been previously shown that cloned Fas-negative but not Fas-positive human cholangiocarcinoma cells are resistant to anti–Fas-mediated apoptosis and develop tumors in nude mice. In addition, interferon gamma induces Fas expression in Fas-negative cholangiocarcinoma cells and makes them susceptible to apoptosis. Therefore, it becomes important to characterize immunophenotypic expression of p53 and Fas in normal and neoplastic human tissues of the biliary tract to further understand the pathogenesis of the disease. To date, human studies to characterize differences in immunophenotypic expression of the Fas protein between intrahepatic and extrahepatic biliary duct cancers and in their precursor lesions have not been performed. Objective.—To report the immunophenotypic expression of p53 and Fas expression in various stages in the development of bile duct cancers (intrahepatic and extrahepatic tumor location) and their association with tumor differentiation. Design.—Thirty bile duct cancer samples (13 intrahepatic and 17 extrahepatic) from 18 men and 12 women who ranged in age from 44 to 77 years (mean age, 65.6 years) were retrieved from the surgical pathology files. Hematoxylin-eosin–stained slides were evaluated for the type and grade of tumor and dysplastic changes in the biliary tract epithelium. Additional slides were immunohistochemically stained with p53 and anti–Fas mouse monoclonal antibody. The pattern of Fas distribution and percentage of cells positive for p53 and Fas expression were determined. Results.—The percentage of Fas-expressing cells is significantly (P = .01) more frequently noted in extrahepatic tumors compared with intrahepatic tumors. Furthermore, Fas expression decreased from dysplastic epithelium to cholangiocarcinoma (P = .01), and this decreasing trend continued from well to poorly differentiated tumors. Nuclear p53 expression was not identified in normal and dysplastic epithelium but was noted in 30% of carcinomas (P = .02). Conclusion.—Fas expression is an early event in pathogenesis of bile duct cancers. Immunophenotypic expression of Fas is associated with well to moderately differentiated tumors but not with poor tumor differentiation.

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