Summary The importance of polymorphism in the glutathione S-transferase GSTM1, GSTT1 and, cytochrome P450, CYP2D6 loci in the pathogenesis of epithelial ovarian cancer has been assessed in two studies; firstly, a case-control study designed to determine the influence of these genes on susceptibility to this cancer, and secondly, the putative role of these genes in the protection of host cell DNA has been studied by comparing p53 expression in patients with different GSTM1, GSTT1 and CYP2D6 genotypes. The frequencies of GSTM1, GSTT1 and CYP2D6 genotypes in 84 cases and 325 controls were not different. Immunohistochemistry was used to detect p53 expression in 63 of these tumours. Expression was found in 23 tumours. Of the patients demonstrating immunopositivity, 20 (87%) were GSTM1 null. The frequency distributions of GSTM1 genotypes in p53-positive and -negative samples were significantly different (P= 0.002) and those for GSTT1 genotypes approached significance (exact P=0.057). The proportion of patients with both GSTM1 null and GSTT1 null was also significantly greater in the immunopositive (4/22) than in the immunonegative group (1/40) (P=0.0493). Single-strand conformational polymorphism (SSCP) analysis was used to detect mutations in the 23 tumour samples demonstrating p53 positivity. A shift in electrophoretic mobility of amplified fragments was found in 11 patients (exons 5, 6, 7 and 8) and these exons were sequenced. In eight samples a mutation was found. No SCCP variants were identified in the other 12 immunopositive patients. Sequencing of exons 4-9 of p53 from these tumours resulted in the detection of mutations in two patients (exons 5 and 7). Thus, in 23 patients who demonstrated immunopositivity, p53 mutations were found in nine patients with GSTM1 null (90.0%). In the 13 patients in whom no mutations were identified, 11 were GSTM1 null (84.6%). The data show that overexpression of p53 is associated with the GSTM1 null genotype. We propose the data are compatible with the view that GSTM1 and GSTT1 are critical in the detoxification of the products of oxidative stress produced during the repair of the ovarian epithelium. Thus, failure to detoxify products of this stress may result in damage to various genes in the host cell, including to p53, resulting in persistent expression of mutant protein. In other patients, oxidative stress effects damage to various genes, but not including p53, resulting in overexpression of wild-type p53.

SummaryThe expression of cyclin D1 protein in tumour sections from 81 patients with epithelial ovarian cancer was analysed using immunohistochemistry. The tumours that overexpressed cyclin D1 in more than 10% of neoplastic cells were considered positive. Thus overexpression of cyclin D1 was observed in 72/81 (89%) of the cases examined. Protein was detected in both the nucleus and the cytoplasm in 24/81 (30%) and localized exclusively in the cytoplasm in 48/81 (59%) of the tumours. Cyclin D1 was overexpressed in both borderline and invasive tumours. There was no association between protein overexpression and tumour stage and differentiation. Furthermore, no correlation between cyclin D1 expression and clinical outcome was observed. However, in tumours overexpressing cyclin D1 (n = 72), the proportion displaying exclusively cytoplasmic localization of protein was higher in those with serous compared with non-serous histology (P = 0.004, odds ratio 4.8, 95% confidence interval 1.4-19.1). Western analysis using a monoclonal antibody to cyclin D1 identified a 36 kDa protein in homogenates from seven tumours displaying cytoplasmic only and one tumour demonstrating both nuclear and cytoplasmic immunostaining. Using restriction fragment length polymorphism polymerase chain reaction and PCR-multiplex analysis, amplification of the cyclin D1 gene (CCNDI) was detected in 1/29 of the tumours demonstrating overexpression of cyclin D1 protein. We conclude that deregulation of CCND1 expression leading to both cytoplasmic and nuclear protein localization is a frequent event in ovarian cancer and occurs mainly in the absence of gene amplification.

Aims:To determine ifthere is any correlation between vascular invasion and prognosis in non-small cell carcinoma of the lung; and to look specifically at invasion of vascular channels by tumour cells. Methods: Eighty seven patients undergoing lobectomy or pneumonectomy for adenocarcinoma or squamous carcinoma were followed up for five years. The histological sections were studied for evidence of vascular invasion using an elastic van Gieson stain. The incidence of intimal fibrosis in arteries and veins was noted and the proportion with vascular invasion evaluated using a scoring system. The presence or absence of lymphatic permeation and tumour necrosis were noted. Survival data were analysed using the log rank test. Results: The overall five year survival was 32%. There were 64 squamous cell carcinomas and 23 adenocarcinomas. Vascular invasion was seen in 77% of patients and lymphatic invasion in 44%. Neither the presence nor absence nor the proportion of blood vessels showing vascular invasion showed any relation to prognosis. Intimal fibrosis and tumour necrosis were unrelated to prognosis. Patients with lymphatic permeation had recurrence and died earlier than those without. Conclusion: The presence of arterial or venous invasion by adenocarcinoma or squamous carcinoma of the lung was unrelated to survival; lymphatic permeation was associated with poor prognosis. The two common non-small cell lung cancers behaved differently from other solid tumours, where vascular invasion was a significant factor in determination of prognosis. This study was undertaken to see if there was a similar correlation between vascular invasion and prognosis in carcinoma of the lung and to look specifically at invasion of vascular channels by tumour cells, rather than combining both vascular and lymphatic channels under the same broad heading. MethodsEighty seven patients who had resections for lung cancer between 1979 and 1983, and for whom there was complete follow up data, were studied retrospectively. The operations were all carried out by a single surgeon (RAML) and in each there was no clinical or radiological evidence of metastasis at the time of surgery. The number of histological blocks taken from each tumour ranged between two and six (mean four). In most of the cases studied at least one tumour block had some adjacent lung tissue in the histological section.Slides from each block were stained conventionally with haematoxylin and eosin and elastic van Gieson to permit clear visualisation of blood vessel laminae. " Only patients with squamous cell and adenocarcinoma were studied as it is well recognised that small cell tumours invade the pulmonary vasculature early. "' Undifferentiated tumours were also not considered as it was felt that they comprise a very mixed group and should be studied separately. Lymphatic invasion was recorded as being present only if tumour cells were seen within areas which had a definite and clearly identifiable endothelial lining.Vascular invasion was identified if tumour was seen with...

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We have investigated the influence of CCND1 genotype on clinical outcome in 138 women with epithelial ovarian cancer. CCND1 genotypes were identified from peripheral blood DNA by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. Patient CCND1 genotypes were compared with clinical details including FIGO tumor stage, residual tumor volume, tumor histology and differentiation, response to chemotherapy, progression free interval, and survival. We observed no association between patient CCND1 genotypes and tumor characteristics or response to chemotherapy. There was no significant difference in overall survival and progression free interval (PFI) among women with different CCND1 genotypes. However, analysis of data from patients who responded to postoperative chemotherapy revealed that women with CCND1 AA genotype were associated with early disease progression (P = 0.020, HR 4.58, 95% CI 1.27-16.48) and reduced survival (P = 0.026, HR 4.48, 95% CI 1.19-16.79) compared with those with CCND1 AG and GG genotypes. These data show that CCND1 genotype does not influence overall prognosis in a cohort of epithelial ovarian cancer patients, however, it is associated with disease progression in a subgroup of patients following initial response to chemotherapy.