p53 mutations are confined to comedo type ductal carcinoma in situ of the breast. Immunohistochemical and sequencing data
Department of Pathology, Vanderbilt University, Nashville, Tennessee. Laboratory Investigation
(Impact Factor: 3.68).
Mutations in the p53 tumor suppressor gene have been identified in breast and many other carcinomas. It is not clear, however, when these mutations occur during breast carcinogenesis. Overexpression of 53 protein has been reported in some ductal carcinoma in situ (DCIS) lesions. To further study the overexpression of p53 in DCIS of the breast and correlate these findings with changes at the molecular level, we performed p53 immunostaining and direct sequencing in noncomedo and comedo DCIS.
Archival blocks were obtained on cases of noncomedo DCIS, (including encysted, noninvasive papillary carcinoma) and comedo DCIS. Immunohistochemical staining with the p53 antibody DO7 was performed on all cases. Polymerase chain reaction (PCR) amplification of exons 5, 6, and 7 of the p53 gene was performed and the PCR products were directly sequenced. Four comedo DCIS cases that were p53 immunopositive were further screened for p53 mutations by PCR/single strand conformation polymorphism in exons 8 and 9 of the p53 gene. One of these cases showing a mobility shift was directly sequenced.
We examined 39 lesions including comedo DCIS (N = 12) and noncomedo DCIS (N = 27), the latter including 17 encysted noninvasive papillary carcinomas. Immunostaining with DO7 was positive in 4 of 12 comedo DCIS lesions (33%) while all noncomedo lesions including encysted noninvasive papillary carcinomas were negative. Direct sequencing of PCR products confirmed wild-type DNA in exons 5 and 6 in all noninvasive papillary carcinomas, 3 randomly selected noncomedo DCIS lesions, and 4 p53 antibody-positive comedo DCIS lesions. In these latter 4 cases, wild-type DNA sequences were preserved in exon 7 for all cases. A single case had a conformational shift in exon 8 within the four cases screened in exons 8 and 9. Direct DNA sequencing of this exon revealed a G to A point mutation resulting in an arginine-to-histidine substitution at codon 273 of the protein.
Our results suggest that mutant p53 protein accumulation in preinvasive lesions is limited to comedo (high grade) DCIS and that p53 positivity by immunohistochemistry does not correlate in all cases with specific p53 mutations in exons 5 to 9, the most highly conserved regions of this gene.
Available from: Simonetta Monti
- "Regarding LN, there is scarcity of data: in two studies, no p53 immunoreactivity was demonstrated in LN lesions (Siziopikou et al. 1996; Sapino et al. 2000), whereas a more recent study on LCIS reported p53 immunoreactivity in one fifth of cases (Mohson et al. 2005). p53 mutations/accumulation are present in a significant percentage of DCIS cases (Lebeau et al. 2003; Poller et al. 1993), especially in the comedo type (O'Malley et al. 1994). However, the clinical significance of p53 accumulation remains still elusive; although it has been found to influence the proliferation rate (Rudas et al. 1997), a recent study showed that it does not affect the proliferation rate of the DCIS lesion per se (Lebeau et al. 2003). "
Available from: Geoffrey C Kabat
- "Although p53 mutations can occur at different locations in the p53 gene, most mutations tend to occur in the DNA-binding motifs within exons 5–8 [4, 6–11]. p53 mutations and/or p53 protein accumulation have been reported in 13% to 70% of invasive intraductal carcinomas of the breast [5, 15–23] and have also been detected in ductal carcinoma in situ [5, 20–22], in benign breast disease [24–28], in normal-appearing breast tissue , and in women at high risk of breast cancer . Taken together, these findings suggest that p53 changes may play a role in the pathogenesis of breast cancer. "
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ABSTRACT: Mutations in the p53 tumor suppressor gene and accumulation of its protein in breast tissue are thought to play a role in breast carcinogenesis. However, few studies have prospectively investigated the association of p53 immunopositivity and/or p53 alterations in women with benign breast disease in relation to the subsequent risk of invasive breast cancer. We carried out a case-control study nested within a large cohort of women biopsied for benign breast disease in order to address this question. After exclusions, 491 breast cancer cases and 471 controls were available for analysis. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). Neither p53 immunopositivity nor genetic alterations in p53 (either missense mutations or polymorphisms) was associated with altered risk of subsequent breast cancer. However, the combination of both p53 immunopositivity and any p53 nucleotide change was associated with an approximate 5-fold nonsignificant increase in risk (adjusted OR 4.79, 95% CI 0.28-82.31) but the confidence intervals were extremely wide. Our findings raise the possibility that the combination of p53 protein accumulation and the presence of genetic alterations may identify a group at increased risk of breast cancer.
Available from: Theodoros N Sergentanis
- "p53 mutations/accumulation are present in a significant percentage of DCIS [107-111], especially in the comedo type . However, the clinical significance of p53 accumulation remains still elusive; although it has been found to influence the proliferation rate , a recent study showed that it does not affect the proliferation rate of the DCIS lesion per se . "
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ABSTRACT: Precursors and preinvasive lesions of the breast include atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and lobular neoplasia (LN). There is a significant debate regarding the classification, diagnosis, prognosis and management of these lesions. This review article describes the current theories regarding the pathogenesis and molecular evolution of these lesions. It reviews the implication of a variety of molecules in the continuum of breast lesions: estrogen receptors (ER-alpha and ER-beta), c-erb-B2 (Her2/neu), p53, Ki-67, bcl-2, E-cadherin, transforming growth factor-beta (TGF-beta), p27 (Kip1), p16 (INK4a), p21 (Waf1), vascular endothelial growth factor (VEGF). With respect to the aforementioned molecules, this article reviews their pathophysiological importance, and puts the stress on whether they confer additional risk for invasive breast cancer or not. This knowledge has the potential to be of importance in the therapeutic decisions presenting in the common clinical practice.
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