The p53 Gene in Breast Cancer: Prognostic Value of Complementary DNA Sequencing Versus Immunohistochemistry

Sjögren, S.; Inganäs, M.; Norberg, Torbjörn; Lindgren, Anders; Nordgren, Hans; Holmberg, Lars; Bergh, Jonas

doi:10.1093/jnci/88.3-4.173

Cited by 348 publications

(265 citation statements)

References 23 publications

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“…Immunohistochemistry is reasonably sensitive and easy to implement in diagnostic laboratories. However, truncated forms of p53 resulting from frameshift and nonsense mutations are not reliably detected by this approach (Hall and Lane, 1994;SjoÈ gren et al, 1996). Furthermore, wild-type p53 can be overexpressed without mutations (Moll et al, 1992;Cesarman et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

High frequency of p53 mutations in human oral epithelial dysplasia and primary squamous cell carcinoma detected by yeast functional assay

et al. 1997

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To determine the timing and actual incidence of p53 mutations in oral epithelial lesions, we examined 33 primary squamous cell carcinomas (SCCs), 14 dysplasias and six hyperplasias from Japanese patients by a combination of yeast functional assay and DNA sequencing. The assay detects mutations of p53 mRNA between codons 67 and 347 on the basis of the DNAbinding activity of the protein. Twenty-six SCCs (79%) and ®ve dysplasias (36%) were positive for p53 mutation, while all six hyperplasias were negative for the mutation. Human papillomavirus type 16 E6 mRNA was detected in one of seven p53 mutation-negative SCCs by reverse transcription polymerase chain reaction (RT ± PCR). We further examined p53 mutations in 17 Sri Lankan oral SCCs using the yeast functional assay and the singlestrand conformation polymorphism analysis of PCRampli®ed DNA fragments (PCR ± SSCP) of exon 5 ± 8. The mutations were con®rmed by DNA sequencing and the detection sensitivity was compared between the two methods. Six samples (35%) were positive for p53 mutation in PCR ± SSCP analysis, while nine samples (53%) were positive in yeast functional assay. This suggests that the incidence of p53 mutations has been considerably underestimated in the conventional SSCP analysis. The present data indicate that p53 mutations are extremely frequent in oral cancers in the Japanese, and suggest that the timing and signi®cance of p53 mutation in oral tumor progression vary in di erent ethnic populations and areas.

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Section: Introductionmentioning

confidence: 99%

High frequency of p53 mutations in human oral epithelial dysplasia and primary squamous cell carcinoma detected by yeast functional assay

et al. 1997

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“…For example, nonsense mutations will not cause protein accumulation, so these cells will be negative by immunohistochemical staining. In keeping with this, the presence of p53 mutations in the breast cancer was shown to be associated with decreased disease free survival as well as overall survival (5-9, 31), but the presence of p53 protein detected immunohistochemically in the tumor has not consistently been associated with a worse prognosis (7,8,42). As molecular analysis of p53 may provide prognostic and treatment information for patients with breast cancer, ThinPrep aspirate is a suitable alternative to the paraffin-embedded tissue as a source of cells for this type of analysis in patients who will receive neoadjuvant chemotherapy or have unresectable tumors.…”

Section: Discussionmentioning

confidence: 89%

“…Experimental studies have shown that functional p53 is required for the in vitro cytotoxic action of some chemotherapeutic agents (2) The presence of p53 mutations is associated with an increased chemoresistance to doxorubicin in breast cancer patients (3) and may be involved in the development of multidrug resistance (4). Clinical studies have shown that breast cancers that contain p53 gene mutations are associated with decreased disease-free and overall survival (3,(5)(6)(7)(8)(9). These results suggest that the presence of p53 mutations might provide prognostic information and influence the treatment of the breast cancer.…”

mentioning

confidence: 99%

Correlation of p53 Mutations in ThinPrep-Processed Fine Needle Breast Aspirates with Surgically Resected Breast Cancers

Pollett

Bédard

et al. 2000

Modern Pathology

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Mutations of the p53 gene are one of the most common genetic changes found in cancer; their presence may be prognostic and even influence treatment for breast cancer. In this study, we investigated whether DNA could be extracted from the residual cells left in ThinPrep-processed breast fine-needle aspirates and whether p53 gene changes could be detected in the DNA. The results were then correlated with DNA extracted from the matched formalin-fixed, paraffin-embedded, surgically resected breast cancer when available. DNA was successfully extracted from 54 of 62 aspirates and all 31 surgical specimens. p53 gene mutations were detected in 10 of the 54 cytology specimens (18.5%) and consisted of base pair substitutions or deletions. Silent or intronic p53 changes were found in five additional aspirates. One of the aspirates had two gene alterations, resulting in a total of six gene changes. Five of these changes were located in introns 6 or 9 and the sixth was a silent (no amino acid change) change in exon 6. p53 Polymorphisms were detected in nine aspirates (16.3%) and were located in codon 47 (one aspirate), codon 72 (six aspirates), and codon 213 (two aspirates). All cases with surgical material available showed identical p53 mutations, alterations, and polymorphisms in the resected tumors compared with those detected in the corresponding aspirates. The results of this study show that DNA suitable for analysis of p53 gene sequence changes can be successfully extracted from ThinPrep-processed breast fine-needle aspirates, and that identical alterations are detected in both the cytology and surgical specimens.

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“…Immunohistochemistry is inferior to sequencing, as the latter has been shown to yield better prognostic information in patients with breast cancer. 30 An adenoviral expression vector system was chosen because of its established safety in clinical trials and its organotropism, 34 -40 and because of its capability to effect wt p53 gene transfer in vitro and in preclinical animal models. 27,32 Unlike retroviruses, integration into the cell genome is not an obligate part of the adenoviral life cycle; rather, adenovirus DNA functions in the extrachromosomal portion of the cell's nucleus.…”

Section: Discussionmentioning

confidence: 99%

“…6 Currently, it is known that IHC gives false-positive rates of up to 30% and false-negative rates of up to 10%, and that sequencing for p53 status is the more accurate method. 30,31 However, when this study was planned, these findings were not generally accepted. Because the primary objective of this study was transgene expression and safety, and immunohistochemistry is a rapid test and was readily available at all study sites, patients were enrolled based on IHC rather than the more stringent technology of gene sequencing.…”

Section: Patientsmentioning

confidence: 96%

Biological activity and safety of adenoviral vector-expressed wild-type p53 after intratumoral injection in melanoma and breast cancer patients with p53-overexpressing tumors

et al. 2000

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p53 mutations are common genetic alterations in human cancer. Gene transfer of a wild-type (wt) p53 gene reverses the loss of normal p53 function in vitro and in vivo. A phase I dose escalation study of single intratumoral (i.t.) injection of a replication-defective adenoviral expression vector containing wt p53 was carried out in patients with metastatic melanoma or breast cancer with increased p53 protein immunoreactivity in pretreatment tumor biopsies. The biological activity of the injected wt p53 was assayed by reverse transcriptase-polymerase chain reaction in tumor tissue. A total of six (five melanoma and one breast adenocarcinoma) patients were treated at dose levels dependent upon tumor size/dose escalation sequence. Five of six patients became positive for the transfer of wt p53 into tumor tissue 2 days after injection of the vector. Of the four patients assayed, all developed anti-adenoviral antibodies. Adverse reactions associated with i.t. injection were mild, with no obvious correlation between the incidence, severity, or relationship of the events and drug dose. p53 gene therapy by i.t. injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective (with respect to transduction frequency) in patients with either metastatic melanoma or breast cancer.

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The p53 Gene in Breast Cancer: Prognostic Value of Complementary DNA Sequencing Versus Immunohistochemistry

Abstract: Use of a cDNA-based sequencing method to determine the status of the p53 gene in primary breast cancers yielded better prognostic information than IHC performed with the Pab 1801 monoclonal antibody.

Cited by 348 publications

References 23 publications

High frequency of p53 mutations in human oral epithelial dysplasia and primary squamous cell carcinoma detected by yeast functional assay

High frequency of p53 mutations in human oral epithelial dysplasia and primary squamous cell carcinoma detected by yeast functional assay

Correlation of p53 Mutations in ThinPrep-Processed Fine Needle Breast Aspirates with Surgically Resected Breast Cancers

Biological activity and safety of adenoviral vector-expressed wild-type p53 after intratumoral injection in melanoma and breast cancer patients with p53-overexpressing tumors

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