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 Exon 5 of the p53 gene is a target for deletions in ovarian cancer

1998 ◽  
Vol 44 (1) ◽  
pp. 72-77 ◽  
Author(s):  
Katerina Angelopoulou ◽  
Michael A Levesque ◽  
Dionyssios Katsaros ◽  
Rob Shipman ◽  
Eleftherios P Diamandis
Keyword(s):  
Ovarian Cancer ◽  
Human Cancer ◽  
Insertion Site ◽  
Point Mutations ◽  
Pcr Amplification ◽  
P53 Gene ◽  
Suppressor Gene ◽  
Protein Product ◽  
The Other ◽  
Chromosome 17

Abstract Missense point mutations, leading to inactivation of the p53 tumor suppressor gene product, are currently the most frequent alterations in human cancer. Little, however, is known about small intragenic deletions or insertions occurring in this locus of chromosome 17. We have analyzed 56 primary ovarian tumors for the presence of such abnormalities. The analysis was based on multiplex PCR amplification of exons 1 through 11 of the p53 gene and fragment analysis of the generated PCR products. Mutations were detected in 14% (8 of 56) of the tumors. Deletions were much more prevalent than insertions (seven vs one). Six of the deletions and the insertion affected exon 5, and the other deletion was in exon 7. Two deletions and the insertion did not disrupt the reading frame; the protein product was expressed in the tumor at high concentrations in all three cases. The other five deletions generated a frameshift, which is predicted to result in the production of a truncated protein product. In the case of the deletions, a 2–5-bp repeat was present close to the detected deletion, whereas the insertion duplicated the sequence immediately upstream of the insertion site. Overall our findings indicate that small intragenic p53 deletions/insertions are not rare events in ovarian cancer, and that p53 exon 5 is the target in the vast majority (88%) of the cases.

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).

Mutation of the p53 Gene Is Not a Typical Feature of Hodgkin and Reed-Sternberg Cells in Hodgkin’s Disease

Blood ◽  
1999 ◽  
Vol 94 (5) ◽  
pp. 1755-1760 ◽  
Author(s):  
Manuel Montesinos-Rongen ◽  
Axel Roers ◽  
Ralf Küppers ◽  
Klaus Rajewsky ◽  
Martin-Leo Hansmann
Keyword(s):  
Hodgkin's Disease ◽  
Cell Clone ◽  
Hodgkin’S Disease ◽  
Single Cells ◽  
Point Mutations ◽  
P53 Gene ◽  
Suppressor Gene ◽  
Typical Feature ◽  
P53 Mutations ◽  
Technical Problems

Point mutations of the p53 tumor suppressor gene are a frequent finding in human carcinomas and are thought to be an important oncogenic event. In non-Hodgkin lymphomas, p53 mutations occur in a minor fraction of cases. However, conclusive data are still lacking for Hodgkin’s disease (HD) where the analysis meets technical problems. The neoplastic tumor cell clone in HD is represented by the large Hodgkin and Reed-Sternberg (HRS) cells, which account for only a minority of all cells in the tumor tissue (often <1%). To identify putative HRS cell-specific mutations, single HRS cells were micromanipulated from frozen tissue sections of HD biopsy specimens. Exons 4 to 8 of the p53 gene (in which more than 90% of p53 mutations associated with human neoplasms occur) were amplified from these single cells and sequenced. Mutations of p53 were not found in HRS cells of any of 8 cases of HD analyzed. We conclude that mutation of the p53 gene is only rarely, if at all, involved in the pathogenesis of HD.

Mutation of the p53 Gene Is Not a Typical Feature of Hodgkin and Reed-Sternberg Cells in Hodgkin’s Disease

Blood ◽  
1999 ◽  
Vol 94 (5) ◽  
pp. 1755-1760 ◽  
Author(s):  
Manuel Montesinos-Rongen ◽  
Axel Roers ◽  
Ralf Küppers ◽  
Klaus Rajewsky ◽  
Martin-Leo Hansmann
Keyword(s):  
Hodgkin's Disease ◽  
Cell Clone ◽  
Hodgkin’S Disease ◽  
Single Cells ◽  
Point Mutations ◽  
P53 Gene ◽  
Suppressor Gene ◽  
Typical Feature ◽  
P53 Mutations ◽  
Technical Problems

Abstract Point mutations of the p53 tumor suppressor gene are a frequent finding in human carcinomas and are thought to be an important oncogenic event. In non-Hodgkin lymphomas, p53 mutations occur in a minor fraction of cases. However, conclusive data are still lacking for Hodgkin’s disease (HD) where the analysis meets technical problems. The neoplastic tumor cell clone in HD is represented by the large Hodgkin and Reed-Sternberg (HRS) cells, which account for only a minority of all cells in the tumor tissue (often &lt;1%). To identify putative HRS cell-specific mutations, single HRS cells were micromanipulated from frozen tissue sections of HD biopsy specimens. Exons 4 to 8 of the p53 gene (in which more than 90% of p53 mutations associated with human neoplasms occur) were amplified from these single cells and sequenced. Mutations of p53 were not found in HRS cells of any of 8 cases of HD analyzed. We conclude that mutation of the p53 gene is only rarely, if at all, involved in the pathogenesis of HD.

Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma.

1994 ◽  
Vol 12 (5) ◽  
pp. 925-930 ◽  
Author(s):  
J F McIntyre ◽  
B Smith-Sorensen ◽  
S H Friend ◽  
J Kassell ◽  
A L Borresen ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
P53 Gene ◽  
Predictive Testing ◽  
Germline Mutations ◽  
Suppressor Gene ◽  
P53 Mutations ◽  
P53 Tumor Suppressor ◽  
P53 Tumor Suppressor Gene ◽  
First Degree Relatives

PURPOSE We investigated the possibility that a significant proportion of children with osteosarcoma harbor germline mutations of the p53 tumor suppressor gene and, therefore, this subgroup of pediatric cancer patients should be considered for large-scale predictive testing. PATIENTS AND METHODS Genomic DNA extracted from peripheral-blood leukocytes from 235 unselected children with osteosarcoma from 33 institutions were screened for the presence of germline p53 mutations using constant denaturant gel electrophoresis (CDGE). Exons 5 through 8 were evaluated in all patients and exon 2 and exon 9 were analyzed in 59 and 95 patients, respectively. Those samples that showed aberrant migration on CDGE were sequenced or analyzed by restriction enzyme digestion of polymerase chain reaction (PCR) products to confirm the nature of the gene alteration. RESULTS In 18 samples, CDGE showed fragments of the p53 gene with altered electrophoretic mobilities compared with wild-type p53. DNA sequencing showed that 11 samples had an identical, previously described polymorphism. The other seven contained heterozygous p53 mutations located in exon 5 (n = 3), exon 6 (n = 1), exon 7 (n = 1), and exon 8 (n = 2). Six alterations were missense mutations and one was a nonsense mutation. Three of these patients had first-degree relatives with cancer. One of these three kindreds had a family history consistent with Li-Fraumeni syndrome (LFS). CONCLUSION We identified germline p53 mutations in seven of 235 (3.0%) children with osteosarcoma. Four of these mutations were found in patients who did not have first-degree relatives with cancer. Although genetic transmission of the altered p53 gene could not be tested in this survey because of how it was designed, it is possible that predictive testing for p53 mutations could identify unaffected relatives of gene carriers who also have a high risk for the development of cancer. This study provides evidence for the importance of considering children with osteosarcoma for predictive testing for germline p53 mutations.

scholarly journals Gain-of-function mutant p53 in cancer progression and therapy

2020 ◽  
Vol 12 (9) ◽  
pp. 674-687 ◽  
Author(s):  
Cen Zhang ◽  
Juan Liu ◽  
Dandan Xu ◽  
Tianliang Zhang ◽  
Wenwei Hu ◽  
...  
Keyword(s):  
Cancer Progression ◽  
P53 Gene ◽  
Amino Acid Difference ◽  
Protein Accumulation ◽  
Mutant P53 ◽  
P53 Mutations ◽  
Wild Type ◽  
Gain Of Function ◽  
Human Cancers ◽  
Wild Type P53

Abstract p53 is a key tumor suppressor, and loss of p53 function is frequently a prerequisite for cancer development. The p53 gene is the most frequently mutated gene in human cancers; p53 mutations occur in &gt;50% of all human cancers and in almost every type of human cancers. Most of p53 mutations in cancers are missense mutations, which produce the full-length mutant p53 (mutp53) protein with only one amino acid difference from wild-type p53 protein. In addition to loss of the tumor-suppressive function of wild-type p53, many mutp53 proteins acquire new oncogenic activities independently of wild-type p53 to promote cancer progression, termed gain-of-function (GOF). Mutp53 protein often accumulates to very high levels in cancer cells, which is critical for its GOF. Given the high mutation frequency of the p53 gene and the GOF activities of mutp53 in cancer, therapies targeting mutp53 have attracted great interest. Further understanding the mechanisms underlying mutp53 protein accumulation and GOF will help develop effective therapies treating human cancers containing mutp53. In this review, we summarize the recent advances in the studies on mutp53 regulation and GOF as well as therapies targeting mutp53 in human cancers.

scholarly journals Mutation status of p53 gene in oral squamous cell carcinoma

2009 ◽  
Vol 56 (4) ◽  
pp. 171-175 ◽  
Author(s):  
Branka Popovic ◽  
Biljana Jekic ◽  
Drago Jelovac ◽  
Ivana Novakovic
Keyword(s):  
Cell Cycle ◽  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Point Mutation ◽  
Squamous Cell ◽  
Cell Cycle Control ◽  
P53 Gene ◽  
Suppressor Gene ◽  
Protein Product

Introduction. p53 gene is the most common tumor suppressor gene involved in pathogenesis oral squamous cell carcinoma (OSCC). Protein product of p53 gene contributes to cell cycle control and apoptosis. p53 gene mutations may lead to uncontrolled cell growth. The aim of this study was to determine the incidence of mutation in DNA-binding domain of p53 gene. Materials and Methods. In the 60 specimens, the presence of point mutation in exons 5, 6, 7 and 8 was detected using PCR-SSCP method. To confirm the presence of p53 mutation found by SSCP method, five samples were analyzed by sequencing of exon 5. Results. Point mutation affecting exons 5, 6, 7 and 8 were found in 60% of analyzed samples. A higher incidence of mutation was detected in exon 7 and 8 (60%), than in exon 5 and 6. Sequencing of exon 5, confirmed the presence of mutations revealed by SSCP method. Study of associations showed an increase of p53 mutations in poor differentiated and carcinoma of higher clinical stages. Conclusion. p53 gene is one of major factor in control of cell cycle and has important role in pathogenesis of oral squamous cell carcinoma.

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.

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.

The specificity of p53 mutation spectra in sunlight induced human cancers

1995 ◽  
Vol 28 (2) ◽  
pp. 115-124 ◽  
Author(s):  
Leela Daya-Grosjean ◽  
Nicolas Dumaz ◽  
Alain Sarasin
Keyword(s):  
P53 Mutation ◽  
Human Cancers ◽  
Mutation Spectra
Sign in / Sign up

Export Citation Format

Share Document