The results suggest that survival for carriers of a BRCA1 mutation may be similar, or worse than, that for breast and ovarian cancer in general. This finding is in accordance with the adverse histopathologic features observed in BRCA1 tumors and underlines the need for surveillance in families that carry a BRCA1 mutation.

Summary Survival in squamous cell carcinoma of the head and neck (HNSCC) was compared with overexpression and mutation of the p53 gene. Archival tissue from 77 tumours was analysed for protein expression using immunohistochemistry (IHC) with the monoclonal antibody Do-7, and for the presence of mutation in exons 5-8 using single-stranded conformation polymorphism (SSCP), followed (4/19) or low protein expression (4/33). Fifty-eight patients were eligible for survival analysis. There was a strong correlation between p53 mutation and cause-specific survival; median survival among mutated cases was 12.5 months compared with >160 months among non-mutated patients (P < 0.005). There was no correlation between p53 overexpression and survival. The results suggest that p53 mutation status is an important prognostic factor in HNSCC, and that IHC analysis of protein overexpression is an inadequate measure of gene mutation in these tumours.

BACKGROUND:The combined effect from the androgen receptor (AR) CAG and GGC length polymorphisms on testosterone levels has not been studied in young women. METHODS: Testosterone levels were measured in blood drawn on both menstrual cycle days 5-10 and 18-23 in 258 healthy women, aged £40 years, from high-risk breast cancer families. CAG and GGC length polymorphisms were analysed by PCR and fragment analyses. All women completed a questionnaire including information on oral contraceptive (OC) use and reproductive factors. RESULTS: OC users had lower median testosterone levels than non-users during cycle days 5-10 and 18-23 (P £ 0.005 for both). The BRCA mutation status was associated neither with testosterone levels nor with CAG or GGC length polymorphism. The CAG length polymorphism was not associated with testosterone levels. The cumulative number of long GGC alleles (³17 repeats) was significantly associated with lower testosterone levels in OC users during cycle days 5-10 (P trend =0.014), but not during cycle days 18-23 or in non-users. The interaction between the GGC length polymorphism and OC status was highly significant during cycle days 5-10 (P = 0.002) and near-significant during days 18-23 (P = 0.07). Incident breast cancer was more common in women with two short GGC alleles (log-rank P = 0.003). CONCLUSION: The GGC repeat length was the only significant genetic factor modifying the testosterone levels in current OC users from high-risk families. Homozygosity for the short GGC allele may be linked to the increased risk of early-onset breast cancer after OC exposure in high-risk women.

© 2 0 0 2 L a n d e s B i o s c i e n c e . N o t f o r d i s t r i b u t i o n .[Cancer Biology & Research PaperA Naturally Occurring Allele of BRCA1 Coding for a TemperatureSensitive Mutant Protein ABSTRACT Recent evidence suggests that the breast and ovarian cancer susceptibility gene product BRCA1 is involved in at least two fundamental cellular processes: transcriptional regulation and DNA repair. However, the mechanism of action of BRCA1 in either of these processes is still unknown. Here, we report the characterization of a disease-predisposing allele of BRCA1, identified in a family with several cases of ovarian cancer, coding for a protein that displays temperature-sensitive activity in transcriptional activation. The mutant protein differs from the wild type protein at a single amino acid, R1699W that occurs in a region at the N-terminal BRCT domain that is highly conserved among BRCA1 homologs. When the C-terminus of the mutant protein (aa 1560-1863) was fused to a heterologous GAL4 DNA-binding domain and expressed in yeast or mammalian cells, it was able to activate transcription of a reporter gene to levels observed for wild type BRCA1 at the permissive temperature (30˚C) but exhibited significantly less transcription activity at the restrictive temperature (37˚C or 39˚C). Our results indicate that the transcriptional activity of the R1699W mutant can be modulated as a function of temperature and provide a novel experimental approach which can be utilized to dissect the molecular mechanism(s) of BRCA1 in processes related to transcription.

In previous studies in southern Sweden, early use of oral contraceptives has been found to be accompanied by an increased risk of developing premenopausal breast cancer, and the tumors developing in these patients have shown a more aggressive behavior. In the present study, amplification of the proto-oncogenes Her-2/neu (also known as ERBB2) and INT2 was studied in primary tumor specimens from 72 premenopausal women and was related to starting age of oral contraceptive use and other reproductive risk factors. Amplification of Her-2/neu was more common among early oral contraceptive users (i.e., those starting at less than or equal to 20 years of age) than among nonusers or late users (odds ratio [OR], 5.3; 95% confidence interval [CI], 1.6-16.7), whereas INT2 amplification did not differ significantly among those groups (OR, 0.9; 95% CI, 0.1-5.0). The likelihood of INT2 amplification was greater among users of progestins and those with a history of abortions before the first full-term pregnancy (OR, 9.0; 95% CI, 1.3-51.7; and OR, 18.6; 95% CI, 2.2-165.8, respectively). No significant relationships were found between proto-oncogene amplification and the variables of parity, age at first full-term pregnancy, or late abortion. The increased ORs persisted after adjustment for age at diagnosis and other risk factors. The findings suggest that the higher rate of Her-2/neu amplification among early oral contraceptive users is an effect of the oral contraceptive use per se rather than of the relative youth of the users. Moreover, the relationship between progestin use and early abortion and amplification of the INT2 gene is biologically plausible.