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A C to T transition within the 3' untranslated region of the prohibitin gene alters mRNA function, and an association between the T allele and an increased risk of breast cancer has been reported in North American women, specifically in those aged under 50 years with a first-degree family history of breast cancer. We did a population-based case-control study to assess whether this association existed in Australian women. We did not note such an association in our sample of 1446 patients and 786 controls (odds ratio 0.96, 95% CI 0.80-1.16; p=0.7), or in subgroups defined by age or family history, or both. Hence, our results do not lend support to the hypothesis that this polymorphism contributes to risk of breast cancer

The enzyme 5alpha-reductase type II (SRD5A2) converts testosterone to its more active form 5alpha-dihydroxytestosterone. The 3' untranslated region of the gene contains a (TA)(n) length polymorphism. The (TA)(9) allele has been reported to be associated with higher serum prostate-specific antigen levels in breast tumors and lower risk of relapse in breast cancer patients and more recently has also been reported to be linked to the codon 89 valine variant, which is itself associated with higher serum prostate-specific antigen levels in breast tumors and a more favorable breast cancer prognosis. We investigated whether the SRD5A2 (TA)(n) polymorphism was associated with risk of breast or ovarian cancer in Australian women by studying 946 breast cancer cases and 509 age-matched controls, and 544 ovarian cancer cases and 298 controls of similar age distribution. The (TA)(9) allele frequency was similar in breast cancer cases (0.110), breast cancer controls (0.125), ovarian cancer cases (0.106), and ovarian cancer controls (0.117). There was no difference in genotype distribution between breast cancer cases and controls (P = 0.5), ovarian cancer cases and controls (P = 0.7), or between the two control groups (P = 0.9). Genotypes containing at least one (TA)(9) allele were not significantly associated with risk of breast cancer overall (odds ratio, 0.86; 95% confidence interval, 0.67-1.12; P = 0.3) or in women stratified by age, menopausal status, or family history. Similarly, the (TA)(9) allele was not associated with risk of ovarian cancer (odds ratio, 0.87; 95% confidence interval, 0.61-1.23; P = 0.4) or with ovarian tumor behavior (invasive or low malignant potential), histology, stage, or grade. Given that this study had sufficient power to detect altered risks in the order of 1.4- to 1.7-fold, our results suggest that the SRD5A2 (TA)(9) allele is unlikely to be associated with moderate alterations in breast or ovarian cancer risk.

BACKGROUND: Women with extensive dense breast tissue visible on a mammogram have a risk of breast cancer that is 1.8 to 6.0 times that of women of the same age with little or no density. Menopausal status, weight, and parity account for 20 to 30 percent of the age-adjusted variation in the percentage of dense tissue. METHODS: We undertook two studies of twins to determine the proportion of the residual variation in the percentage of density measured by mammography that can be explained by unmeasured additive genetic factors (heritability). A total of 353 pairs of monozygotic twins and 246 pairs of dizygotic twins were recruited from the Australian Twin Registry, and 218 pairs of monozygotic twins and 134 pairs of dizygotic twins were recruited in Canada and the United States. Information on putative determinants of breast density was obtained by questionnaire. Mammograms were digitized, randomly ordered, and read by a blinded investigator. RESULTS: After adjustment for age and measured covariates, the correlation coefficient for the percentage of dense tissue was 0.61 for monozygotic pairs in Australia, 0.67 for monozygotic pairs in North America, 0.25 for dizygotic pairs in Australia, and 0.27 for dizygotic pairs in North America. According to the classic twin model, heritability (the proportion of variants attributable to additive genetic factors) accounted for 60 percent of the variation in density (95 percent confidence interval, 54 to 66) in Australian twins, 67 percent (95 percent confidence interval, 59 to 75) in North American twins, and 63 percent (95 percent confidence interval, 59 to 67) in all twins studied. CONCLUSIONS: These results show that the population variation in the percentage of dense tissue on mammography at a given age has high heritability. Because mammographic density is associated with an increased risk of breast cancer, finding the genes responsible for this phenotype could be important for understanding the causes of the disease

Breast cancers arising in women with and without a germline mutation in the BRCA1 or BRCA2 gene display different histological features, which suggests unique mechanisms of molecular pathogenesis: We used a molecular pathological analysis to define the genetic abnormalities relevant to these specific pathogeneses. Tumor material was studied from 40 women with breast cancer diagnosed before 40 years of age, sampled from a population-based study and stratified by BRCA1 and BRCA2 germline mutation status. Cases were not selected for family history or ethnic origin, and none were known to be genetically related. Thus, germline mutation itself is likely to impact on the molecular pathogenesis of these tumors, with no substantial influence due to modifying genetic or environmental factors. Breast cancers occurring in BRCA1 mutation carriers had significantly higher levels of p53 expression, including the preinvasive (carcinoma in situ) stage of disease, compared with cancers occurring in BRCA2 mutation carriers or women with no detectable germline mutation. These cancers also had a higher proliferation rate as measured by Ki-67 antibody. Expression of the prognostic factors c-erbB-2, cyclin D1, and estrogen receptor was significantly less common in BRCA1 mutation carriers. Lower levels of cyclin D1 were also found in cancers from BRCA2 mutation carriers compared with non-mutation carriers. Direct p53 mutation analysis revealed mutations in 18% of all of the early-onset breast cancers within the study and included rare insertion and deletional mutations in cancers from BRCA1 mutation carriers. Our data indicate that a BRCA1 breast cancer phenotype may be recognized by an exceptionally high proliferation rate and early and frequent p53 overexpression but infrequent selection for overexpression of several other prognostic factor proteins known to be involved in breast oncogenesis. In contrast, breast cancers arising in BRCA2 mutation carriers have a more heterogeneous phenotypic profile.

The purpose of this study was to examine the relationship between androgenetic alopecia (AA) and prostate cancer with particular emphasis on early age at diagnosis and higher grade tumors. We conducted an age-stratified, population-based case-control study in Australia of men who were diagnosed before 70 years of age during 1994-1997 with histopathology-confirmed adenocarcinoma of the prostate, excluding well-differentiated tumors. Controls were selected from the electoral rolls, and the frequency was matched on age. After excluding subjects with missing values, the analysis was based on 1446 cases and 1390 controls of whom direct observations were made of their pattern of AA during face-to-face interviews. Our data suggest an association between prostate cancer and vertex baldness; compared with men who had no balding, the adjusted odds ratio (OR) was 1.54 (1.19-2.00). No associations were found between prostate cancer and frontal baldness or when frontal baldness was present concurrently with vertex baldness. The ORs were 0.98 (0.79-1.23) and 1.14 (0.90-1.45), respectively. The highest ORs were for high-grade disease in men 60-69 years of age: 1.80 (1.02-3.16) for frontal baldness; 2.91 (1.59-5.32) for vertex baldness; and 1.95 (1.10-3.45) for frontal and vertex baldness. This association between the pattern of AA and prostate cancer points to shared androgen pathways that are worthy of additional investigation