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Query: UMLS:C0027651 (tumor)
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The frequent occurrence of TF gene involvement in translocations associated with leukemia is remarkable, although not yet explained. The wide variety of TFs involved in these translocations and the different stages of cellular maturation argue against a unifying mechanism. Recombinases, active during B-cell and T-cell development, have been implicated in gene arrangements involving TCR genes and in the SIL/SCL rearrangement, which involves two genes not normally rearranged. However, other mechanisms must clearly be active in generating these molecular abnormalities and perhaps they relate to the multistep maturation and differentiation processes and continuous cell turnover seen in hematopoietic cells. The difficulties in obtaining human solid tumor samples may make it more difficult to identify translocations involving TF genes in solid tumors. Recently, the cytogenetic analysis of solid tumors has improved and specific cytogenetic abnormalities have been associated with specific types of tumors. With advanced techniques, such as fluorescent in situ hybridization (a technique that does not depend on cell growth) and PCR, abnormalities involving TF genes will be discovered. Abnormalities of TF genes, other than translocations, have been seen in a broad variety of nonhematopoietic malignancies. The p53 protein has been shown to bind DNA in a sequence-specific fashion and interact with a variety of DNA tumor virus oncoproteins. The broad range of cell types that harbor p53 abnormalities suggests that TF abnormalities will likely be implicated in many solid tumors. We have detailed several examples of how gene rearrangements that accompany chromosomal translocations in acute leukemia can alter the expression or activity of cellular TFs. Several translocations generate fusion RNA transcripts and fusion TF proteins with altered functional characteristics. Other translocations result in the expression of a gene not normally detectable in hematopoietic cells or alter the level of its expression, or affect the promoter usage or exon structure of the gene (Table 2). Studies are underway in many laboratories to characterize the biologic activity of these abnormal TFs and it remains to be proven that these molecular abnormalities are directly linked with leukemogenesis. The identification of abnormal fusion transcripts and proteins may allow specific therapies to be directed against "tumor-specific" DNA, mRNA, or protein targets. Therapeutic strategies based on antisense or ribozyme technology may be used to turn off expression of these genes and inhibit leukemia cell growth. Immunologic methods can also be used to direct therapy against the malignant cells.
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PMID:Transcription factors, translocations, and leukemia. 136 70

The human T-cell lymphotropic virus type I (HTLV-I) is capable of inducing adult T-cell leukemia/lymphoma (ATLL). However, the long latency period between infection and development of ATLL, as well as the small fraction of the infected population that actually develops this disease, suggest that additional factors are involved in its pathogenesis. Therefore, we performed a molecular analysis of 10 cases of ATLL presenting in a nonendemic area that were shown to have HTLV-I sequences by polymerase chain reaction as well as clonal T-cell receptor beta gene rearrangements. We analyzed these cases for alterations in some of the oncogenes and tumor suppressor genes frequently involved in hematopoietic neoplasia. Specifically, we used a single-strand conformation polymorphism assay to determine the presence of mutations in the p53 tumor suppressor gene, as well as the K-RAS, N-RAS, H-RAS, and c-myc oncogenes. In addition, we studied the c-myc gene for rearrangements by Southern blotting and assessed expression of the retinoblastoma (Rb) and p53 genes by immunostaining. Analysis of the c-myc gene and the RAS family of oncogenes did not show any alterations. Also, the Rb gene was expressed in all cases analyzed. However, we found mutations of the p53 gene in 3 of the 10 cases and these results were confirmed by sequence analysis. In two of these cases, we showed by restriction fragment length polymorphism analysis of chromosome 17p sequences that the p53 mutations were accompanied by a loss of heterozygocity. Also, these mutations correlated with an altered pattern of p53 expression. Thus, mutations in the p53 locus may be a cofactor for the development of ATLL in some cases, whereas the c-myc, Rb, and RAS genes do not appear to be involved in these neoplasms.
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PMID:Structural and functional analysis of oncogenes and tumor suppressor genes in adult T-cell leukemia/lymphoma shows frequent p53 mutations. 136 72

Cytogeneticists first proposed that the karyotypic abnormalities identified on chromosomes 1, 3, 6, 11, 13, 16, 17, and 18 supported a genetic basis for breast cancer. Such abnormal banding patterns, however, may represent either loss-of-function or gain-of-function molecular events. RFLP analyses have since confirmed that 20-60% of primary and spontaneous human breast tumors exhibit allelic losses on these same chromosomes, although the exact genes involved at these chromosomal sites remain largely unknown. Knowledge gained about the Rb-1 and p53 tumor suppressor genes at 13q14 and 17p13 in breast and other human tumors supports the paradigm that for any chromosomal locus, allelic loss associated with a mutation in the remaining tumor allele signifies an involved tumor suppressor gene. Given this paradigm, there are nearly a dozen putative breast tumor suppressor genes under active investigation, with most investigators now focusing on various chromosome 17 loci. Among the known proto-oncogenes found activated in breast cancer, amplification of c-erbB-2 at 17q21 is the most widely studied and clinically significant gain-of-function event uncovered to date, occurring in about 20% of all primary breast tumors. The involvement of this overexpressed membrane receptor has engendered interest in related tyrosine kinase receptors, such as EGFR, IR, and IGF-I-R, as well as their respective ligands, which may be overexpressed in a greater fraction of tumors, contributing to the autocrine and paracrine regulation of breast cancer growth and metastasis. New attention is being given to the potentially oncogenic function of structurally altered nuclear transactivating steroid hormone receptors, such as ER, whose overexpression has long been used to determine endocrine therapy and prognosis for individual breast cancer patients. While c-myc was one of the first known proto-oncogenes to be found amplified and overexpressed in human breast cancers, the actual incidence and clinical significance of its activation remain disputed and in need of further study. Lastly, we can expect greater clarification about the importance of various 11q13 genes found coamplified in nearly 20% of primary breast cancers, and pursuit into the intriguing possibility that a cyclin-encoding gene represents the overexpressed locus of real interest in this amplicon. Virtually all of these important genetic abnormalities identified thus far are associated with but not restricted to human breast cancers. The absence of identifiable molecular defects relating to the tissue specificity of this malignancy must be considered a substantial gap in our basic understanding of breast carcinogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Activated oncogenes and putative tumor suppressor genes involved in human breast cancers. 136 56

In this present study, we report the mutation of the p53 gene in vivo in human primary carcinomas of cervix and cervical intraepithelial neoplasia (CIN). The association of the HPV subtypes with the tumors was determined by multiplex primer polymerase chain reaction (PCR) amplification. The mutation of the p53 gene was detected using PCR amplification of the p53 exons followed by SSCP (single strand conformation polymorphism) and DNA sequencing analysis. The p53 mutation was detected in two out of two HPV-33 positive carcinomas but was absent in the HPV-16/-18 positive carcinomas (0 out of 8 cases). The p53 mutation was also detected in one out of four HPV-negative cervical carcinomas. No mutation of the p53 gene was detected in the CIN specimens (0 out of 7 cases). The two mutations in the HPV-33 associated cervical carcinoma were detected at codon 273 (CGT to TGT; arginine to cysteine) and intron 5 (24 base pair downstream of the 3' end of exon 5). The p53 mutation at codon 273 has been previously reported in one of the HPV-negative cervical carcinoma cell line (C33A). Our results indicate that mutation of the p53 gene is not a common event in human cervical cancers (3/14), and may be related to the infection of HPV-16/18 in the tumor. However, mutation of the p53 gene was detected in cervical carcinomas associated with HPV-33 and may be an important genetic event in this subgroup of carcinomas.
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PMID:Presence of p53 mutation in human cervical carcinomas associated with HPV-33 infection. 136 12

The diagnostic and prognostic implications of p53 immunostaining have been investigated in 59 pulmonary neuroendocrine tumors, including typical carcinoids (n = 15), so-called "atypical carcinoids" (n = 22), and small cell lung carcinomas (SCLCs; n = 22). Immunocytochemistry was performed on formalin-fixed, paraffin-embedded samples using the monoclonal antibody PAb1801, which has been shown to be suitable for staining fixed and embedded tissue sections. p53 immunoreactivity was restricted to atypical carcinoids (45% of the cases being immunoreactive) and to SCLCs (which were positively stained in 59% of the cases), whereas it was consistently lacking in typical carcinoid tumors. When the group of the so-called "atypical carcinoids" was further reclassified, p53 immunostaining was strictly confined to those cases belonging to the histologically more aggressive subsets (well differentiated neuroendocrine carcinoma subsets II and III). Within the same tumor type, however, p53 immunoreactivity did not correlate with the clinical outcome of the disease and was not predictive of the length of survival. The data indicate that abnormal p53 expression (which is strictly dependent on structural abnormalities of the p53 gene) is detectable in the majority of neuroendocrine carcinomas of the lung and might represent a useful adjunct in the differential diagnosis of pulmonary neuroendocrine neoplasms, particularly in routinely fixed and embedded small bronchoscopic biopsies.
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PMID:Abnormal p53 expression in lung neuroendocrine tumors. Diagnostic and prognostic implications. 136 72

The complex process of cell immortalization and transformation is likely to involve the inactivation of growth regulatory genes. Mutations (deletions, missense mutations) in the p53 gene are the most frequently observed genetic alteration in human tumors, making p53 a candidate for a cellular protein involved in the control of cell growth. Two recent studies have examined the role of p53 in immortalization and tumorigenesis. In the first study, p53 expression was examined in both mortal and immortal chick embryo fibroblasts. All mortal clones expressed p53 but the loss of wild-type p53 expression was observed in every immortal cell line examined. In the second study, a line of mice carrying two null p53 alleles has been created and characterized. Although these mice develop normally, they show a predisposition to develop a variety of neoplasms at an early age (< 6 months). Although it is unclear whether p53 regulates the same, different, or overlapping pathways in the two experimental systems, these data demonstrate that p53 function is critical for the maintenance of normal growth control and support the current classification of p53 as a growth suppressive or tumor suppressor gene.
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PMID:p53 loss of function: implications for the processes of immortalization and tumorigenesis. 136 9

Many diverse tumors contain cells that select for mutations at the p53 gene locus. This appears to be the case because the p53 gene product can act as a negative regulator of cell division or a tumor suppressor. These mutations then eliminate this activity of the p53 gene product. The simian virus 40 (SV40) large T antigen binds to p53 and acts as an oncogene to promote cellular transformation and initiate tumors. If the binding of T antigen to the p53 protein inactivated its tumor suppressor activity, there would be no selection pressure for p53 mutants to appear in tumors. To test this idea, transgenic mice that carried and expressed the SV40 large T-antigen gene were created. Expression of the T antigen was directed to the liver, using the albumin promoter, and the choroid plexus, using the SV40 enhancer-promoter. A large number of papillomas (indicated in parentheses) of the choroid plexus (14), hepatocellular carcinomas (5), liver adenomas (10), and tumors of clear-cell foci (5) were examined for mutant and wild-type p53 genes and gene products. In all cases, the tumor extracts contained readily detectable T-antigen-p53 protein complexes. A monoclonal antibody specifically recognizing the wild-type p53 protein (PAb246) reacted with p53 in every tumor extract. A monoclonal antibody specifically recognizing mutant forms of the p53 protein (PAb240) failed to detect p53 antigens in these extracts. Finally, p53 partial cDNAs were sequenced across the regions of common mutations in this gene, and in every case only the wild-type sequence was detected. These results strongly support the hypothesis that T antigen inactivates the wild-type p53 tumor-suppressing activity and there is no need to select for mutations at the p53 locus.
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PMID:p53 mutations are not selected for in simian virus 40 T-antigen-induced tumors from transgenic mice. 137 May 52

Cytogenetic analysis of a cemento-ossifying fibroma from a patient with nonfamilial bilateral multicentric retinoblastoma revealed three reciprocal translocations with the karyotype 46,XY,t(1;18)(q21;q21.3),t(3;10)(p13;q22),t(6;11)(p22;p15). Routine and high-resolution cytogenetic analysis of peripheral blood leukocytes showed an apparently normal, 46,XY chromosome pattern with no deletion of chromosome 13. Molecular analysis demonstrated no gross differences in the retinoblastoma gene or the TP53 gene between constitutional and tumor DNA. This is the first cytogenetic analysis of a cemento-ossifying fibroma and the first report of this tumor in a retinoblastoma patient. The data may be added to the small, but growing literature on cytogenetic aberrations in benign tumors and may lend insight into genes involved in cell proliferation and neoplastic transformation.
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PMID:Cytogenetic abnormalities in an ossifying fibroma from a patient with bilateral retinoblastoma. 137 15

Overexpression of the p53 protein, resulting from gene mutations that increase protein stability, has been detected in greater than 25% of primary human breast cancers. In addition, approximately 10% of breast cancer patients have circulating antibodies to the p53 protein. In this study, the anti-p53 humoral response is correlated with the presence and type of mutant p53 protein expressed in the tumor. In a series of 60 breast cancer patients, 0 of 30 tumors with normal, low-level p53 expression induced anti-p53 antibodies, whereas 7 (23%) of 30 tumors with p53 overexpression elicited a specific anti-p53 antibody response. These 7 patients had anti-p53 antibodies that recognized wild-type p53 and a variety of mutant p53 proteins. A comparison of p53 mutations revealed that antibody-negative tumors had mutations exclusively in exons 7 and 8, whereas antibody-positive tumors had mutations primarily in exons 5 and 6. Moreover, all antibody-eliciting tumors contained complexes between p53 and a 70-kDa heat shock protein, whereas none of the antibody-negative tumors contained this complex. This study implicates a 70-kDa heat shock protein in the antigenic presentation of p53.
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PMID:Immune response to p53 is dependent upon p53/HSP70 complexes in breast cancers. 137

Mutations affecting the p53 gene have been found associated with many human malignancies, but little is as yet known about multiple myeloma. We investigated p53 gene alterations in 10 human myeloma cell lines (HMCL), half of these being dependent upon exogenous interleukin 6 (IL-6) for in vitro growth, similar to freshly explanted myeloma cells. Using a polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) approach, eight of the 10 HMCL were found to bear a mutated p53 gene. All the mutations were single base substitutions with a predominance of G:C to A:T transitions. There was no apparent relation between the presence of a mutation and IL-6 requirement of the cell line. Interestingly, in two cell lines (XG-2 and XG-4) the SSCP pattern showed the presence of both the wild-type and the mutated allele and, upon reverse PCR on RNA, both alleles were found to be concomitantly expressed at the RNA level. Moreover, three freshly explanted tumor samples had the same p53 gene status (mutated versus wild type) as the HMCL that were derived from them. These results show that p53 mutations are frequent in HMCL. Although no apparent relation could be evidenced with the loss of exogenous IL-6 requirement, it may prove interesting to investigate further potential relations between the presence of a mutated p53 allele and gradual autonomy for cell growth.
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PMID:Mutations of the p53 gene in human myeloma cell lines. 137 72


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