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Mutational myriad of tumor suppressor p53 in Filipino breast cancer: results and perspectives in molecular pathology and epidemiology

Abstract

The p53 tumor suppressor is by far the most widely mutated gene in human cancers. p53 encodes a 53-kDa phosphoprotein, transcription-activator whose targets include genes and gene products that orchestrate genomic stability, cellular response to DNA damage, cell cycle progression apoptosis and aging (senescence). Analysis of the p53 gene profile has previously resulted in identifying several cancer-causative factors in the human setting, as well as, in creating a unique molecular profile of a tumor useful in the design of tailored-therapies for individual cancer patients. Our results in screening for p53 abnormalities in 140 Filipino patients with primary breast lesions confined from 1997-1998 in 5 major hospitals in Manila reveal that p53 plays an important role in the development and progression of breast cancer in at least 48% of all cases. Two methods of p53 analysis are employed, enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction-temporal temperature gradient electrophoresis (PCR-TTGE). Inter-comparisons of method exhibit 63.3% concordance in 21 fresh breast carcinoma samples, with ELISA demonstrating 14% false-positives and 10% false-negatives. Only mutations in exon 7 (p=0.063) in the tumor samples how significant correlation with abnormal cellular elevation of p53. PCR-TTGE screening in a large series of 140 patients show that most  More>>
Publication Date:
Apr 01, 2000
Product Type:
Thesis/Dissertation
Report Number:
INIS-PH-014
Reference Number:
EDB-01:089701
Resource Relation:
Other Information: TH: M.S. Molecular Biology and Biotechnology; 155 refs, 7 figs, 8 tabs; PBD: Apr 2000
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; CARCINOMAS; DIAGNOSTIC TECHNIQUES; ENZYME IMMUNOASSAY; EPIDEMIOLOGY; GENE MUTATIONS; MAMMARY GLANDS; NEOPLASMS; NUMERICAL DATA; PATHOLOGY; PATIENTS; PHILIPPINES; POLYMERASE CHAIN REACTION
OSTI ID:
20194800
Research Organizations:
University of the Philippines, Quezon City (Philippines). College of Science, National Institute of Molecular Biology and Biotechnology
Country of Origin:
Philippines
Language:
English
Other Identifying Numbers:
TRN: PH0100006046476
Availability:
Available from INIS in electronic form; Also available from PNRI library
Submitting Site:
INIS
Size:
69 pages
Announcement Date:
Oct 17, 2001

Citation Formats

Deocaris, Custer C. Mutational myriad of tumor suppressor p53 in Filipino breast cancer: results and perspectives in molecular pathology and epidemiology. Philippines: N. p., 2000. Web.
Deocaris, Custer C. Mutational myriad of tumor suppressor p53 in Filipino breast cancer: results and perspectives in molecular pathology and epidemiology. Philippines.
Deocaris, Custer C. 2000. "Mutational myriad of tumor suppressor p53 in Filipino breast cancer: results and perspectives in molecular pathology and epidemiology." Philippines.
@misc{etde_20194800,
title = {Mutational myriad of tumor suppressor p53 in Filipino breast cancer: results and perspectives in molecular pathology and epidemiology}
author = {Deocaris, Custer C}
abstractNote = {The p53 tumor suppressor is by far the most widely mutated gene in human cancers. p53 encodes a 53-kDa phosphoprotein, transcription-activator whose targets include genes and gene products that orchestrate genomic stability, cellular response to DNA damage, cell cycle progression apoptosis and aging (senescence). Analysis of the p53 gene profile has previously resulted in identifying several cancer-causative factors in the human setting, as well as, in creating a unique molecular profile of a tumor useful in the design of tailored-therapies for individual cancer patients. Our results in screening for p53 abnormalities in 140 Filipino patients with primary breast lesions confined from 1997-1998 in 5 major hospitals in Manila reveal that p53 plays an important role in the development and progression of breast cancer in at least 48% of all cases. Two methods of p53 analysis are employed, enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction-temporal temperature gradient electrophoresis (PCR-TTGE). Inter-comparisons of method exhibit 63.3% concordance in 21 fresh breast carcinoma samples, with ELISA demonstrating 14% false-positives and 10% false-negatives. Only mutations in exon 7 (p=0.063) in the tumor samples how significant correlation with abnormal cellular elevation of p53. PCR-TTGE screening in a large series of 140 patients show that most genetic lesions are localized in exons 5 (41% of the total cases) and 6 (27% of the total cases). No mutations are, however, detected in the transactivation (exons 2-4) and oligomerization (exons 10-11) domains. Invasive carcinomas (stages II and III) are characterized with more frequent and diverse genetic alterations compared with benign tumors, most significantly at exon 5B (p=0.066) and at independently multiple sites (p=0.066). Earlier-onset cases (age of diagnosis < 50 yrs), known to be more clinico-pathologically aggressive, are diagnosed harboring more frequent p53 mutations centered at exon 7 (p=0.093) as compared to late-presenting tumors (age of diagnosis {>=} 50 yrs.). Incidentally, exon 7 encodes the L3 domain of p53 that interacts with the DNA minor groove while forming a stabilized complex with zinc and its mutations are correlated with poor prognosis and resistance to radiotherapy and chemotherapy, specifically, but not limited to, doxorubicin and cisplatinum (Aas et al., 1997). Whereas, residency in rural or urban regions fail to elicit any significantly disparate mutational profile, women from Manila have slightly higher p53 mutation rates (43% of the total cases) when compared with those referred from provincial hospitals (33% of the total cases). Social class appears to affect p53 at exons 6 (p=0.050: biased to the 'high-income' bracket) and 8 (p=0.052): biased to the 'low-income' bracket). The mutational myriad of tumor suppressor p53 in Filipino breast cancer in this thesis underscores the important fine-structured biophysical correlates of the p53 core domain (exons 5-8) with that of the neoplasm's cell biology, pathology and epidemiology. In future studies, p53 analysis will be used to identify the underlying causes of the unusually high breast cancer incidence in Manila by offering a possible glimpse into the temporal interactions of genetics (WT, GST, NMT, MSH1/2, PTEN, BRCA1/2, ETC), hormonal and environmental cues leading to a tumor phenotype). (Author)}
place = {Philippines}
year = {2000}
month = {Apr}
}