UMLS:C0007124 - FACTA Search

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Query: UMLS:C0007124 (ductal carcinoma in situ)
3,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have optimized a technique that allows the study of numerous chromosomal loci (n = 20-50) from single paraffin-embedded tissue sections by microsatellite length polymorphism analysis. DNA samples from normal and breast cancerous tissue can be obtained from the same section by means of microdissection. This technique was further improved by subjecting DNA to several cycles of amplification with a degenerate (universal) primer and then with specific microsatellite primers. This amplified DNA was also used to screen for mutations in the p53 gene by means of PCR-SSCP. In addition adjacent tissue sections were used to assess specific chromosome copy number by interphase cytogenetic analyses (chromosome in situ hybridization) and to analyze expression of specific genes such as p53 and ERBB2. As an example of the use of our approach we performed a detailed chromosome 17 allelotypic analysis in 22 breast tumors (5 ductal carcinomas in situ, 13 invasive ductal carcinomas, and 4 invasive lobular carcinomas). We detected mutations in the p53 gene by PCR-SSCP in 36% of the samples. Samples with significant levels of p53 protein accumulation detected by immunohistochemistry were also positive for mobility shifts in the SSCP analysis. We observed that chromosome 17 allelic losses and imbalance occurred at as early a stage as ductal carcinoma in situ (DCIS). Although in some cases we observed allelic losses or imbalance affecting the 17p13 region, close to the p53 locus, several of the tumors showed dissociation between such loss or imbalance and p53 mutation. Lobular carcinomas were predominantly disomic for chromosome 17 in contrast with ductal tumors, which often showed polysomy for chromosome 17. This comprehensive approach correlating the tumor subtype, its allelotype, with specific chromosome copy number and specific gene mutations and expression in preinvasive or early invasive breast cancer lesions will potentially provide information of relevance for a better understanding of the multistep mechanisms of breast carcinogenesis.
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PMID:Technical approach for the study of the genetic evolution of breast cancer from paraffin-embedded tissue sections. 887 26

A panel of 36 cases of preinvasive breast lesions, including 35 cases of ductal carcinoma in situ (DCIS), has been examined for mutation of TP53, allelic imbalance (AI) on 17p13, and expression of TP53, in a number of cases, has been studied using immunohistochemistry. Areas of DCIS, with or without adjacent invasive or benign cells, have been separately microdissected from paraffin-embedded sections and analysed by PCR for genetic changes to chromosome 17p13. TP53 mutations and AI on 17p have been identified in cases of 'pure' DCIS as well as those with associated invasive carcinoma and, furthermore, have been identified in well-differentiated lesions as well as poorly differentiated ones.
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PMID:Mutation of the TP53 gene and allelic imbalance at chromosome 17p13 in ductal carcinoma in situ. 893 38

The p53 gene is altered in approximately 50% of human cancers and is considered to be important in the pathogenesis of these malignancies. The p53 protein product regulates the transition from G1 to S phase of the cell cycle and entry to the DNA damage repair pathway. As alterations in this pathway appear to be important in a variety of human cancers, downstream effector proteins of p53 are potential sites for somatic alterations. WAF1/Cip1, also known as WAF1, Cip1, sdi1, or CAP20, codes for a 21-kd protein (p21WAF1/Cip1), which was recently described as a universal inhibitor of cyclins and is thus critical in cell cycle control. Mutations in WAF1/Cip1 are potentially important in human malignancies because they could affect the control of the cell cycle. To understand whether mutations of WAF1/Cip1 occur in cancer, we screened 53 cases of invasive breast carcinoma, 35 cases of ductal carcinoma in situ (DCIS), 53 ovarian carcinomas, and 47 endometrial carcinomas in the second exon of WAF1/Cip1 (90% of the open reading frame). p21WAF1/Cip1 expression was characterized with immunohistochemistry. Cells from the blood of 21 normal individuals were also characterized using single-strand conformational polymorphism analysis, DNA sequencing and restriction analysis. Single-strand conformational polymorphism analysis demonstrated an altered mobility pattern for exon 2 in 12 invasive breast cancers (22.6%), 5 DCIS of the breast (14%), 8 invasive ovarian carcinomas (15%), and 9 endometrial carcinomas (19%). In total, 209 samples were screened, and 38 cases (18.2%) had an altered codon 31. Each case with altered single-strand conformational polymorphism, analyzed by DNA sequencing and/or restriction analysis, showed the same alteration of codon 31, a C to A transversion encoding a change in amino acid sequence from serine to arginine (31Ser-->31Arg). DNA from the blood of 21 normal individuals showed the same alteration in WAF1/Cip1 in 4 cases (19%). Furthermore, paired normal tissue was available for 3 of 20 breast carcinomas with the Ser31Arg transversion. Normal DNA from all 3 cases showed the same 31Arg alteration as found in the tumor tissue. These results indicate that codon 31 is a polymorphic site and that the serine to arginine shift is a polymorphism. p21WAF1/Cip1 expression, identified by immunohistochemistry, was found to vary in a pattern that depended both on the tissue type and on the presence or absence of the codon 31 polymorphism. Using pair-wise comparisons in breast DCIS, we found higher protein expression in tumor nuclei as compared with benign stromal cell nuclei (P = 0.002) or normal ductal epithelium (P = 0.005). Invasive breast cancer specimens showed a trend in p21WAF1/Cip1 immunostaining similar to DCIS but did not reach statistical significance (P = 0.12). However, when cases with extensive desmoplastic reaction were excluded, a statistically significant association (P = 0.019) similar to that in DCIS was noted. In contrast to the breast tumors, ovarian carcinomas exhibited significantly greater p21WAF1/Cip1 expression in the benign stromal (fibroblast) nuclei surrounding the tumor than in the carcinoma cell nuclei (P = 0.016). Endometrial carcinoma revealed no difference in staining when comparing benign tissue with carcinoma (P = 0.99); however, unlike breast and ovarian carcinomas in which there was no correlation between p21WAF1/Cip1 expression and the presence or absence of the alteration at the 31st codon, endometrial carcinomas showed an increased percentage of immunopositive nuclei associated (P = 0.056) with 31Arg. These results demonstrate tissue-specific expression patterns of WAF1/Cip1 in different tumors which appears to be characteristic of the tumor type.
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PMID:WAF1/Cip1 gene polymorphism and expression in carcinomas of the breast, ovary, and endometrium. 900 33

Many anticipate that application of findings in molecular genetics will help to achieve greater precision in defining high-risk populations that may benefit from chemopreventive interventions. We must recognize, however, that genetic susceptibility, environmental factors, and complex gene-environment interactions are all likely to be risk determinants for most cancers. Cohort studies of twins and cancer indicate that having "identical" genes is generally not a very accurate predictor of cancer incidence. Data from twin studies support the suggestion that environmental factors such as tobacco use significantly influence cancer risk. The complexities of the genetic contribution to disease risk are exemplified by the development of Duchenne muscular dystrophy in only one of monozygotic twin girls, hypothesized to be the result of X chromosome inactivation, with the distribution patterns of the X chromosome being skewed to the female X in the manifesting twin and to the male X in the normal twin. Evidence from transgenic and genetic-environmental studies in animals support the possibility of genetic-environmental interactions. Calorie restriction modifies tumor expression in p53 knockout mice; a high-fat, low-calcium, low-vitamin D diet increases prepolyp hyperplasia formation in Apc-mutated mice; and calorie restriction early in life influences development of obesity in the genetically obese Zucker rat (fafa). Such environmental modulation of gene expression suggests that chemoprevention has the potential to reduce risk for both environmentally and genetically determined cancers. In view of the growing research efforts in chemoprevention, the NCI has developed a Prevention Trials Decision Network (PTDN) to formalize the evaluation and approval process for large-scale chemoprevention trials. The PTDN addresses large trial prioritization and the associated issues of minority recruitment and retention; identification and validation of biomarkers as intermediate endpoints for cancer; and chemopreventive agent selection and development. A comprehensive database is being established to support the PTDN's decision-making process and will help to determine which agents investigated in preclinical and early phase clinical trials should move to large-scale testing. Cohorts for large-scale chemoprevention trials include individuals who are determined to be at high risk as a result of genetic predisposition, carcinogenic exposure, or the presence of biomarkers indicative of increased risk. Current large-scale trials in well-defined, high-risk populations include the Breast Cancer Prevention Trial (tamoxifen), the Prostate Cancer Prevention Trial (finasteride), and the N-(4-hydroxyphenyl) retinamide (4-HPR) breast cancer prevention study being conducted in Milan. Biomarker studies will provide valuable information for refining the design and facilitating the implementation of future large-scale trials. For example, potential biomarkers are being assessed at biopsy in women with ductal carcinoma in situ (DCIS). The women are then randomized to either placebo, tamoxifen, 4-HPR, or tamoxifen plus 4-HPR for 2-4 weeks, at which time surgery is performed and the biomarkers reassessed to determine biomarker modulation by the interventions. For prostate cancer, modulation of prostatic intraepithelial neoplasia (PIN) by 4-HPR and difluoromethylornithine is being investigated; similar studies are being planned for oltipraz, dehydroepiandrosterone, and vitamin E plus selenomethionine. The validation of biomarkers as surrogate endpoints for cancer incidence in high-risk cohorts will allow more agents to be evaluated in shorter studies that use fewer subjects to achieve the desired statistical power.
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PMID:Cancer risk factors for selecting cohorts for large-scale chemoprevention trials. 902 95

In the last 6 years a number of non-randomized, predominantly single institutional trials of breast conservation therapy (BCT) with DCIS, have demonstrated that it constitutes a very heterogeneous group of diseases with markedly different risks of local recurrence and invasive transformation. There has been a consensus that DCIS, which exhibits a "comedo" morphology, generally defines a high risk group. Most studies, moreover, have identified the same two features, nuclear grade and necrosis, as contributing most significantly to prognosis. Nuclear grade and necrosis have been identified as independent prognostic variables in several studies. High nuclear grade DCIS which exhibits comedo necrosis defines the majority of all DCIS which will result in local recurrence and invasive transformation after BCT. Studies utilizing image cytometry, to determine ploidy and S-phase fraction and immunohistochemical studies of proliferation and oncogene distribution have shown a significant association with morphologically identified high nuclear grade and aneuploidy, high S-phase fraction or proliferation rate, presence of HER-2/neu and P53 oncogenes and absence of estrogen receptors. Generally the inverse of this association is seen with low nuclear grade DCIS. However, initial hopes that these adjunctive studies would identify subsets within the high nuclear grade group which might be more likely to recur have not been fulfilled.
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PMID:Classification of duct carcinoma in situ (DCIS) with a characterization of high grade lesions: defining cohorts for chemoprevention trials. 902 6

Abnormalities in p53 gene expression have been implicated in many inherited and sporadic forms of malignancies in humans. Immunohistochemical staining using monoclonal antibody D0-7 for the p53 protein expression was performed in 81 cases of pure DCIS, 14 benign breast lesions and 2 cases with normal breast tissue. Expression of p53 protein was detected in 15 (18.5%) cases of pure DCIS. Thirteen (25%) of the 52 comedo type DCIS showed p53 protein expression compared with 2 (6.9%) of the 29 non-comedo types (P < 0.02). p53 protein expression was also associated with high nuclear grade (P < 0.001) and high mitotic index (P < 0.05). The pattern of p53 protein staining was diffuse in one comedo type DCIS, regional in 6 comedo types, and focal in the remaining 8 cases (6 comedo type and 2 micropapillary type DCIS). The patient with comedo type DCIS showing diffuse staining has a family history of breast cancer in the first and second degree relatives (sister and maternal aunt). Clinical follow-up data was available in 52 cases. Follow-up period ranged from 9 to 55 months. Three patients, who were primarily treated by local excision, have had a documented local recurrence in the form of residual tumor within a short interval of 5 to 11 months. In all these three patients both the original and the recurrent tumors are negative for p53 protein expression. The difference in the local recurrence rate between p53 positive (0/15) and p53 negative (3/37) cased does not reach statistical significance (p > 0.05). We interpret that the local tumor recurrence in these three cases within a short period after primary excision is due to the presence of residual tumor at the excision site and is independent of the p53 gene alteration. It is concluded that p53 protein expression in DCIS is associated with comedo subtype, high nuclear grade, and high mitotic index, and is a promising new parameter to evaluate the cellular biology and prognosis of DCIS.
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PMID:p53 protein expression in ductal carcinoma in situ (DCIS) of the breast. 906 12

p53 and c-erbB-2 expression, and their correlation with cell proliferation and steroid hormone receptors, were investigated in 121 carcinomas, 23 lobular in situ carcinomas (LCIS), 74 intraductal carcinomas (DCIS) and 24 minimal invasive carcinomas. DCIS were classified according to the EORTC classification. All markers were measured immunohistochemically on paraffin sections. None of the LCIS, 9 DCIS and 9 minimal invasive cancers showed nuclear positivity for p53. A strong association between histological type and p53 expression was found. Proliferation rates correlated with p53 expression. c-erbB-2 positivity was found in 1 LCIS, 27 DCIS and 12 minimal invasive cancers. There was a significant correlation between p53 expression and c-erbB-2. Both parameters were associated with high proliferation rate and negativity for steroid hormone receptor status. Nuclear pleomorphism could become a comparable prognostic marker in DCIS as it is for infiltrating carcinomas.
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PMID:p53 protein expression, cell proliferation and steroid hormone receptors in ductal and lobular in situ carcinomas of the breast. 947 Aug 56

Immunocytochemically detectable MT and p53 have been found more commonly in comedo DCIS of the breast with high-grade cytology. The aim of this study is to confirm these findings and to investigate the relationship between MT and p53 in a single large series of cases of DCIS of the breast. To this end, 127 cases of DCIS were classified histologically according to architecture, cytonuclear differentiation (grade), presence and extent of intraduct necrosis, and using the Van Nuys system. Sections were immunostained for p53 and MT (E9) using established techniques, and the extent and intensity of staining were assessed semi-quantitively. The results confirmed that there was generally more MT and p53 positivity in poorly differentiated (grade 3) DCIS with extensive necrosis and that MT expression was greater in grade 2 lesions than p53 expression. However, overall there was no statistically significant correlation between p53 and MT staining. The results indicate that MT and p53 overexpression may arise from independent mechanisms in early breast neoplasia.
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PMID:Immunoreactive p53 and metallothionein expression in duct carcinoma in situ of the breast. No correlation. 917 27

The expression of c-erbB-2 oncogene and p53 tumor suppressor gene was studied in methacarn-fixed, paraffin-embedded biopsy specimens from 58 benign breast lesions and 129 sporadic breast carcinomas, using the supersensitive monoclonal antibodies CB 11 and BP 53-12-1 and the biotin-streptAvidin-amplified methodology. None of the benign lesions studied, which included 36 fibrocystic lesions with mild or florid epithelial hyperplasia, 12 fibrocystic lesions with ADH or ALH and 10 fibroadenomas, demonstrated membrane staining for c-erbB-2 or nuclear immunoreactivity for p53. Overall, 48.06% of primary breast carcinomas showed membrane expression of c-erbB-2, while 28.68% were p53 positive. Those showing p53 immunoreactivity displayed a nuclear and/or cytoplasmic staining type. A significant correlation was seen between c-erbB-2 and p53 expression (r = 0.213, p < 0.05), as well as between c-erbB-2 status and PSNA score (r = 0.221, p < 0.05). In addition, c-erbB-2 and p53, separately or in combination, correlated significantly with the prognostic index. In conclusion, immunohistochemistry of c-erbB-2 and p53 immunohistochemistry allows a better definition of intraductal proliferative lesions and assists in the differentiation between ADH and DCIS. It provides additional clues with regard to the biologic behavior of invasive ductal carcinomas (NOS and medullary).
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PMID:Expression of c-erbB-2 oncogene and p53 tumor suppressor gene in benign and malignant breast tissue: correlation with proliferative activity and prognostic index. 922 49

Ductal carcinoma in situ (DCIS) represents a heterogeneous group of diseases. There is no generally accepted classification for the different cytological and architectural types of DCIS. A recent study (Scott et al, 1995) indicates that over 90% of DCIS can be easily classified into the following five categories: high grade (HG), intermediate grade (IG), low grade (LG), pure micropapillary (M), and pure apocrine (A). The aim of this study was to determine if there is a relationship between lesion size and the immunohistochemical expression of p53, c-erb B2, bcl-2, and ki67 with this reproducible categorization of DCIS. Seventy cases of DCIS diagnosed between 1984 and 1995 were obtained from the Departments of Pathology at two teaching hospitals in London, Ontario. The original sections were reviewed, classified according to Scott et al (1995), and representative sections were cut for immunohistochemical (IHC) studies. IHC stains were scored using a previously described semiquantitative scoring system (Allred et al, 1993). Size was taken from the gross measurement if the lesion was palpable or recorded as the largest dimension, as measured on the histological slide, for nonpalpable cases. Of the 70 DCIS cases, 17 (24.3%) were HG, 23 (32.9%) were IG, 21 (30%) were LG, seven (10%) were pure micropapillary cases, and two (2.9%) were pure apocrine DCIS. The mean size of the DCIS for each subcategory was statistically significantly different (P = .008). In particular, the micropapillary DCIS cases were largest (mean size, 17 mm). The mean immunohistochemical scores for c-erb B2 for each category were also statistically different (P = .007), whereas the mean scores for p53 and ki67 for each category trended toward significance (P = .073, P = .062, respectively). There were no significant differences between bcl-2 mean scores and each subcategory. Size of DCIS and c-erb B2 positivity are known to be associated with more aggressive clinical behavior and more advanced histologic features, respectively. Because this combined histological cytological classification system is predictive of size and c-erb B2 positivity, our results support the clinical relevance of this classification system.
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PMID:Relationship of a new histological categorization of ductal carcinoma in situ of the breast with size and the immunohistochemical expression of p53, c-erb B2, bcl-2, and ki-67. 926 21

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