The 4th Copenhagen Workshop "Carcinoma in situ Germ Cell and Testicular Cancer: Molecular and Endocrine Aspects" was held in Copenhagen, Denmark, May 18-21, 1997. This paper discusses the major themes that emerged during the workshop and summarises the most important contributions.
To compare men with prostate disease with those from the general population regarding polymorphisms in the androgen receptor gene and in the 5alpha-reductase II (SRD5A2) gene.
The SRD5A2 polymorphisms A49T, V89L and R227Q, the androgen receptor CAG and GGN repeats and sex hormone status was investigated in men with prostate cancer (CaP) (n=89), benign prostate hyperplasia (n=45) and healthy military conscripts (n=223).
The SRD5A2 high-activity allele variants A49T AT and V89L LL were more frequent in CaP-patients compared to general population, p=0.026 and p=0.05, respectively. CaP progression was, however, independent of SRD5A2 variants. In contrary, men with GGN
BACKGROUND: 8-Hydroxydeoxyguanosine (8-oxodG) is the commonly used marker of oxidative stress-derived DNA damage. 8-OxodG formation is regulated by local antioxidant capacity and DNA repair enzyme activity. Earlier studies have reported contradictory data on the function of 8-oxodG as a prognostic factor in different cancer types. METHODS: We assessed pre-operative serum 8-oxodG levels with an enzyme-linked immunosorbent assay in a well-defined series of 173 breast cancer patients. 8-OxodG expression in the nuclei of cancer cells from 150 of these patients was examined by immunohistochemistry. RESULTS: The serum 8-oxodG levels and immunohistochemical 8-oxodG expression were in concordance with each other (P
Estrogens have an important role in the development and progression of breast cancer. 17beta-Hydroxysteroid dehydrogenase type 1 (17HSD1), type 2 (17HSD2), and type 5 (17HSD5) are associated with sex steroid metabolism in normal and cancerous breast tissue. The mRNA expressions of the 17HSD1, 17HSD2, and 17HSD5 enzymes were analyzed in 794 breast carcinoma specimens by using tissue microarrays and normal histologic sections. The results were correlated with the estrogen receptor alpha (ER-alpha) and beta (ER-beta), progesterone receptor, Ki67, and c-erbB-2 expressions analyzed by immunohistochemical techniques and with the Tumor-Node-Metastasis classification, tumor grade, disease-free interval, and survival of the patients. Signals for 17HSD1 mRNA were detected in 16%, 17HSD2 in 25%, and 17HSD5 in 65% of the breast cancer specimens. No association between the 17HSD1, 17HSD2, and 17HSD5 expressions was detected. A significant association was observed between ER-alpha and ER-beta (P = 0.02; odds ratio, 1.96) expressions. There was also a significant inverse association between ER-alpha and 17HSD1 (P = 0.04; odds ratio, 0.53), as well as ER-alpha and 17HSD5 (P = 0.001; odds ratio, 0.35). Patients with tumors expressing 17HSD1 mRNA or protein had significantly shorter overall and disease-free survival than the other patients (P = 0.0010 and 0.0134, log rank). The expression of 17HSD5 was significantly higher in breast tumor specimens than in normal tissue (P = 0.033; odds ratio, 5.56). The group with 17HSD5 overexpression had a worse prognosis than the other patients (P = 0.0146). ER-alpha also associated with survival (P = 0.045). Cox multivariate analyses showed that 17HSD1 mRNA, tumor size, and ER-alpha had independent prognostic significance.
Human epidermal growth factor receptor 2 expression in osteosarcoma and its relationship to prognosis have been the subject of several conflicting reports, most of them relying on immunohistochemical studies. Because the urgent need of prognostic markers and effective new treatment options for osteosarcoma patients, we evaluated the role of human epidermal growth factor receptor 2 in 2 well-characterized sets of pretherapeutic osteosarcoma samples (46 paraffin-embedded and 46 fresh-frozen biopsy samples) using immunohistochemistry with 2 different antibodies [DAKO A0485 (Glostrup, Denmark) and Novocastra CB11 (Newcastle, UK)] as well as fluorescence in situ hybridization, real-time polymerase chain reaction, and SNP array analyses and correlated our findings with clinicopathological parameters. However, our study failed to detect unequivocal evidence of human epidermal growth factor receptor 2 gene amplification or overexpression of human epidermal growth factor receptor 2 messenger RNA or protein in any of the investigated tumors. Only in a small subset of samples, a moderate increase in messenger RNA levels (13.6%) or focal membranous immunoreactivity (8.7%; A0485) was detected but did not correlate with survival or response to chemotherapy. Cytoplasmic staining was identified more frequently (63%; CB11) but again did not show any association with clinicopathological parameters. In conclusion, our study does not support a role for human epidermal growth factor receptor 2 as a prognostic marker in osteosarcoma.
Increased synthesis and degradation of extracellular matrix components are associated with breast cancer development. This study evaluated type I and type III procollagen mRNA expression and the corresponding protein synthesis and maturation, as well as the tissue distribution of these collagens, in benign breast lesions, infiltrating ductal carcinomas, and their metastases by in situ hybridization and immunohistochemistry. In the benign lesions, the type I and type III collagen bundles were regularly organized and the expression of the corresponding mRNA was weak, indicating a relatively slow collagen turnover. In the malignant tumours, increased expression of type I and type III procollagen mRNAs was observed in the fibroblastic cells of the stroma; the malignant epithelial cells did not participate. The staining of corresponding newly-synthesized pN-collagens showed aberrant bundles in the invasive front of the malignant tumours. Newly-synthesized type I and type III procollagens were occasionally observed in fibroblastic cells, particularly in grade 2 and grade 3 tumours. Metastases of breast carcinoma resembled poorly differentiated primary tumours with respect to their collagen synthesis and deposition. The increased synthesis of fibrillar type I and type III procollagens may serve as a pathway for tumour invasion. The enhanced synthesis is associated with the formation of aberrant collagen bundles, which may be more readily degradable and may thus facilitate breast tumour invasion.
The majority of oral squamous cell carcinomas (OSCCs) are preceded by visible changes in the oral mucosa, most often white patches. Although the histological finding of dysplasia in oral white patches signals increased risk of developing OSCC, this may also occur in non-dysplastic lesions. However, no reliable markers exist to predict the occurrence of OSCC in these patients. From a total of 263 patients diagnosed with oral white patches, biopsies from 45 patients were selected on the criteria that the patients had lesions histologically proven to be non-dysplastic. The lesions were analyzed with respect to their DNA content. The clinical outcome of the patients was known from the Cancer Registry of Norway, and these data were compared to the DNA content of their lesions. Among the 45 patients, five cases (11%) later developed an OSCC. Four of the cases that subsequently developed an OSCC were among the five aneuploid (abnormal) cases (P=0.001). One aneuploid lesion did not develop a carcinoma during a follow-up time of 120 months. The fifth case that subsequently developed an OSCC was diploid (normal), and developed into an OSCC after an observation time of 73 months (P=0.001). In conclusion, aberrant DNA content reliably predicts the occurrence of OSCC in patients that otherwise would be regarded as at very low risk. Normal DNA content indicates low risk.
To test whether academic centers (ACs) are more successful than nonacademic centers (NACs) in immunohistochemistry (IHC) external quality assessment challenges in the Canadian Immunohistochemistry Quality Control (CIQC) program.
Results of 9 CIQC challenges for breast cancer marker (BM) and various non-breast cancer marker (NBM) tests were examined. Success rates were compared between AC/NAC laboratories and those located in small or large cities. Performance was also correlated with annual IHC case volumes.
There was no statistically significant difference in performance in any of the comparisons. However, overall performance on BM was significantly better (P
Renal cell carcinoma (RCC) encompasses different histologic subtypes. Distinguishing between the subtypes is usually made by morphologic assessment, which is not always accurate.
Our aim was to identify microRNA (miRNA) signatures that can distinguish the different RCC subtypes accurately.
A total of 94 different subtype cases were analysed. miRNA microarray analysis was performed on fresh frozen tissues of three common RCC subtypes (clear cell, chromophobe, and papillary) and on oncocytoma. Results were validated on the original as well as on an independent set of tumours, using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis with miRNA-specific primers.
Microarray data were analysed by standard approaches. Relative expression for qRT-PCR was determined using the ??C(T) method, and expression values were normalised to small nucleolar RNA, C/D box 44 (SNORD44, formerly RNU44). Experiments were done in triplicate, and an average was calculated. Fold change was expressed as a log(2) value. The top-scoring pairs classifier identified operational decision rules for distinguishing between different RCC subtypes and was robust under cross-validation.
We developed a classification system that can distinguish the different RCC subtypes using unique miRNA signatures in a maximum of four steps. The system has a sensitivity of 97% in distinguishing normal from RCC, 100% for clear cell RCC (ccRCC) subtype, 97% for papillary RCC (pRCC) subtype, and 100% accuracy in distinguishing oncocytoma from chromophobe RCC (chRCC) subtype. This system was cross-validated and showed an accuracy of about 90%. The oncogenesis of ccRCC is more closely related to pRCC, whereas chRCC is comparable with oncocytoma. We also developed a binary classification system that can distinguish between two individual subtypes.
MiRNA expression patterns can distinguish between RCC subtypes.
We measured activity and content of cathepsin B in tumor tissues, liver, and spleen in mice with Lewis adenocarcinoma and LS-lymphosarcoma. Cathepsin B activity in Lewis adenocarcinoma cells was lower than in LS-lymphosarcoma cells, which was probably related to differences in their metastatic properties. Antitumor therapy increased activity and content of cathepsin B in tumor tissues. Changes in the content and activity of cathepsin B in tumor tissues can serve as a prognostic criterion for tumor regression during therapy. Cathepsin B is probably involved in apoptosis of tumor cells during chemotherapy of lymphosarcoma-LS with cyclophosphamide.