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A substantial proportion of women with breast cancer exhibit an abnormally high radiosensitivity as measured by the frequency of chromatid breaks induced in G[SUB2]-phase, PHA stimulated lymphocytes. Chromatid break frequencies were compared for a cohort of previously) untreated sporadic breast cancer patients and hospital outpatient controls. In the breast cancer group 46% showed high radiosensitivity compared to 14% of controls (P < 0.001). Comparison of those breast cancer patients with a high G[SUB2] radiosensitivity (G[SUB2]RS) versus those with a low G[SUB2]RS showed no difference in menopausal status or age but the high G[SUB2]RS group had on average a lower score on the Nottingham Prognostic Index. Predicted survival in the high G[SUB2]RS group at 15 years was 55% compared to 36% for the low G[SUB2]RS group. Furthermore, 81% of tumours from the high G[SUB2]RS were oestrogen receptor positive compared to 45% from the low G[SUB2]RS group. Thus high G[SUB2]RS identifies a sub-population of patients with distinctive tumour characteristics and with a predicted improved prognosis as compared with those in the low G[SUB2]RS group. Our findings imply that besides influencing risk of breast cancer the genetic factors determining G[SUB2]radiosensitivity also influence the tumour characteristics and prognosis in these patients. [ABSTRACT FROM AUTHOR]

Allele imbalance on chromosome 11 loci in ovarian cancer is a frequent event, suggesting the presence of tumour-suppressor genes for ovarian carcinogenesis on this chromosome. Ten highly polymorphic (CA) repeat microsatellites were used to determine allele imbalance in 60 primary ovarian tumours, including 47 epithelial ovarian cancers (EOCs). Forty EOCs (85%) showed allele imbalance at one or more loci, and in 39 of these (83%) the data suggested subchromosomal deletions: eight of 11p only; six of 11q only; and 25 of both 11p and 11q. Three consensus regions of deletion were indicated at 11p15.5-p15.3, 11q12-q22 and 11q23.3-q24.1. Allele imbalance at the 11q subtelomeric region (D11S912) correlated significantly with adverse survival, while imbalance at 11q14.3 and retention of heterozygosity at 11q22 (close to the site of the progesterone receptor gene) were associated with favourable clinicopathological features. The findings allow development of a preliminary model for the molecular evolution of epithelial ovarian cancer.

p53 gene aberrations are common in human malignancies, and recent studies suggest that in cervical carcinoma p53 function is inactivated either by complex formation with human papillomavirus (HPV) E6 product or by gene mutation. Using polymerase chain reaction (PCR) followed by denaturing gradient gel electrophoresis (DGGE), we examined the mutational status of the four 'hotspot' regions of the p53 gene in 47 primary cervical carcinomas. HPV status was determined, also by PCR. In 20 of these cases, we examined for loss of heterozygosity (LOH) on chromosome 17p13. In the 47 carcinomas, and in a further 68 biopsy specimens from normal, premalignant and malignant cervix, we investigated aberrant immunocytochemical expression of p53. Immunocytochemically, abnormal p53 expression was detected in 13 of 115 cases (8/57 carcinomas). Somatic mutation in p53 was detected in 1 of 47 cervical carcinomas; 36 were positive for HPV 16, 18 or 33. A low level of allele loss (3 out of 20 cases) was detected on chromosome 17p, occurring in both HPV-positive and HPV-negative cases, and in cases with and without p53 mutations. We conclude that somatic mutation in the hotspot regions of the p53 gene occurs infrequently in cervical carcinomas; that immunocytochemically detectable levels of p53 are also infrequent; and that there is no consistent correlation between p53 mutational status, LOH on chromosome 17p or HPV status in these cancers.

Transforming growth factor-beta 1 (TGF-beta 1) is inhibitory for breast epithelial cells in vitro and treatment of breast cancer cell lines with tamoxifen results in a rise in TGF-beta 1 mRNA expression with associated inhibition of cell growth. To study whether these findings apply in vivo we examined TGF-beta 1 mRNA expression in an oestrogen-dependent mouse xenograft system following systemic treatment of the mice with tamoxifen. In agreement with in vitro studies. TGF-beta 1 mRNA expression was sustained at high levels and associated with a reduction in tumour size. A subsequent study of breast tumour tissue from 56 patients demonstrated high levels of TGF-beta 1 mRNA in 45 of the tumours. High expression was found to correlate with premenopausal status, but not with tumour oestrogen receptor content or other parameters. In a subgroup of 11 patients who had received tamoxifen therapy for 3 to 6 months prior to surgery, unexpectedly high levels of TGF-beta 1 mRNA were demonstrated in tumours increasing in size and unresponsive to tamoxifen. Data from this study indicate that in patients with breast cancer, TGF-beta 1 in the tumour may not behave as in vitro and xenograft studies have suggested. We speculate that failure of tamoxifen therapy may be due to failure of the autocrine inhibitory functions of TGF-beta 1 either alone or in combination with paracrine stimulation of stromal cells or angiogenesis and localised immunosuppression. Further studies of active TGF-beta 1, TGF-beta receptors and the interactions with other growth factors will be required to elucidate the precise role of TGF-beta 1 in human breast cancer and in the failure of tamoxifen therapy.

In a study of DNAs from 100 breast cancer patients and 100 controls, there were no differences in the frequencies of common or rare alleles at the Harvey ras (c-Ha-ras) locus on chromosome 11. However, one Ha-ras allele was deleted from the tumour DNA in 14 of 65 informative patients. Loss of a Ha-ras allele correlates with paucity of oestrogen receptor protein and with increased tumour size at presentation, but is not associated with microscopic evidence of lymph node invasion. The findings on Ha-ras and other informative loci are consistent with the possibility that a tumour suppressor gene involved in the early stages of breast cancer is located on the short arm of chromosome 11.