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Background: The cytochrome P450c17alpha enzyme functions in the steroid biosynthesis pathway, and altered endogenous steroid hormone levels have been reported to be associated with a T to C polymorphism in the 5' promoter region of the CYP17 gene. Because steroid hormone exposure is known to influence breast cancer risk, we conducted a population-based, case-control-family study to assess the relationship between the CYP17 promoter polymorphism and early-onset breast cancer.Methods: Case subjects under 40 years of age at diagnosis of a first primary breast cancer, population-sampled control subjects, and the relatives of both case and control subjects were interviewed to record family history of breast cancer and other risk factors. CYP17 genotype was determined in 369 case subjects, 284 control subjects, and 91 relatives of case subjects. Genotype distributions were compared by logistic regression, and cumulative risk was estimated by a modified segregation analysis. All statistical tests were two-tailed.Results: Compared with the TT genotype (i.e., individuals homozygous for the T allele), the TC genotype was not associated with increased breast cancer risk (P: =.7). Compared with the TT and TC genotypes combined, the CC genotype was associated with a relative risk of 1. 81 (95% confidence interval [CI] = 1.15-2.86; P: =.01) before adjustment for measured risk factors and 1.63 (95% CI = 1.00-2.64; P: =.05) after adjustment. There was an excess of CC genotypes in case subjects who had at least one affected first- or second-degree relative, compared with control subjects unstratified by family history of breast cancer (23% versus 11%; P: =.006), and these case subjects had a threefold to fourfold higher risk than women of other groups defined by genotype and family history of breast cancer. Analysis of breast cancer in first- and second-degree relatives of case subjects with the CC genotype, excluding two known carriers of a deleterious mutation in BRCA1 or BRCA2, gave a relative hazard in women with the CC genotype of 3.48 (95% CI = 1.13-10.74; P: =.04), which is equivalent to a cumulative risk of 16% to age 70 years.Conclusions: The CC genotype may modify the effect of other familial risk factors for early-onset breast cancer. [ABSTRACT FROM AUTHOR]

Background: A recent meta-analysis of 23 studies supported the empirically derived hypothesis that women who lack one of the four common minisatellite alleles at the HRAS1 locus are at increased risk of breast cancer. These studies relied on visual sizing of alleles on electrophoretic gels and may have underreported rare alleles. We determined whether this hypothesis applied to early-onset breast cancer by using a new method to size minisatellite alleles.Methods: We conducted a population-based, case-control-family study of 249 Australian women under 40 years old at diagnosis of a first primary breast cancer and 234 randomly selected women, frequency matched for age. We sized HRAS1 minisatellite alleles with an Applied Biosystems model 373 automated DNA sequencer and GENESCAN(TM) software. All P values are two-sided.Results: We found no association of rare alleles with breast cancer, before or after adjustment for risk factors and irrespective of how their effects were modeled (crude odds ratio = 1.04; 95% confidence interval [CI] = 0.071-1.53; P =.8). The rare allele frequency was 0. 173 (95% CI = 0.149-0.197), three times the pooled estimate of 0.058 (95% CI = 0.050-0.066) from previous studies (P<.001), and was similar for case subjects, 0.177 (95% CI = 0.143-0.221), and control subjects, 0.169 (95% CI = 0.135-0.203) (P =.7).Conclusion: There was no support for an association between rare HRAS1 alleles and the risk of early-onset breast cancer, despite 80% power to detect effects of the magnitude of those associations (1.7-fold) previously suggested.Implications: The question of whether cancer risk is associated with rare minisatellite HRAS1 alleles needs to be revisited with the use of new methods that have a greater ability to distinguish rare alleles from similarly sized common alleles. [ABSTRACT FROM AUTHOR]

Background: The estrogen receptor (ER) protein is believed to play a role in the development and progression of breast cancer. In a previously published U.S. clinic-based study, a polymorphism in the ER gene (codon 325, CCC --> CCG) was found to be more common in 34 case subjects with a family history of breast cancer than in 154 case subjects without such a history (mean allele frequencies +/- standard error = 0.28+/-0.05 versus 0.11+/-0.02; P<.001). To determine whether this polymorphism is a risk factor for early-onset breast cancer, we conducted a population-based, case-control-family study in Australia.Methods: Case subjects under the age of 40 years with a first primary breast cancer and control subjects, frequency-matched to the case subjects on the basis of age, and their relatives were interviewed to assess the family history of breast cancer. Polymorphism status of the ER gene was determined for 388 case subjects and 294 control subjects. All statistical tests were two-tailed.Results: There was no association between ER gene polymorphism status and breast cancer, before or after adjustment for risk factors. There was no difference in allele frequencies between case subjects and control subjects (0.232+/-0.015 versus 0.209+/-0.017; P = .4) or between women with and without a family history of breast cancer (P = .3), irrespective of case-control status. The findings were not altered when different definitions of family history of breast cancer were used and when allele frequencies were adjusted for residence and country of birth.Conclusion: We found no evidence that the ER codon 325 polymorphism is associated with breast cancer before the age of 40 years or with a family history of breast cancer, despite ample power to detect effects half the magnitude of those previously reported. [ABSTRACT FROM AUTHOR]

Incidence and mortality rates for oral and pharyngeal cancers have been reported to be increasing in Europe and the United States, with particularly large increases in mortality in central and eastern Europe. Such increases have been noted to be birth cohort-based, primarily affecting young and middle-aged men. In this report oral and pharyngeal cancer incidence data from New South Wales, Australia has been analysed for the period 1972-90. Although an increase in the incidence of oral and pharyngeal cancer occurred during the mid-1970s and early 1980s, it did not continue. This pattern is consistent with Australian trends in per capita consumption of tobacco, alcohol, fruit and vegetables. Individual regions within metropolitan Sydney showed substantial geographical variation with age-specific rates of oral and pharyngeal cancers (combined) in middle-aged men being at least three times higher in the city of Sydney than in New South Wales as a whole. Given the preventable nature of the disease, such high rates need not occur. [ABSTRACT FROM AUTHOR]

Objective: To examine whether childhood brain tumors (CBTs) are associated with a family history of brain tumors or other cancers in an international case-control study., Methods: Cancers in children's first- and second-degree relatives were ascertained by interview with parents of 620 children with astroglial tumors, 255 with primitive neuroectodermal tumors, 324 with other CBTs, and 2,218 controls from Australia, Canada, France, Israel, Italy, Spain, and the US. These were used with histories of neurofibromatosis or tuberous sclerosis to exclude in subanalyses children with Li-Fraumeni or other hereditary syndromes predisposing to brain tumors., Results: A first- or second-degree relative of 4% of children with astroglial tumors, 6% with PNET, 5% with other CBTs, and 5% of controls had had a brain tumor. Any potential differences were statistically non-significant, including when focusing on relatives diagnosed in childhood. In the US, where anatomical sites of relatives' other cancers were known, CBT occurrence was not associated with any other specific site. Results were not markedly altered by exclusion of children with hereditary syndromes., Conclusion: Consistent with most prior studies using these methods, we observed no strong relationship between CBT occurrence and cancers in family members.

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2 > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10(-7)). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.

Background: Only unbiased estimates of end-stage renal disease (ESRD) incidence and trends are useful for disease control-identification of risk factors and measuring the effect of intervention., Methods: Age- and sex-standardized incidences (with trends) were calculated for all-cause and diabetic/non-diabetic ESRD for persons aged 0-14, 15-29, 30-44 and 45-64 years in 13 populations identified geographically, and six populations identified by ethnicity., Results: The incidence of ESRD varied most with age, ethnicity and prevalence of diabetes. All non-Europid populations had excess ESRD, chiefly due to rates of type 2 diabetic ESRD that were greater than accounted for by community prevalences of diabetes. Their rates of non-diabetic ESRD also were raised, with contributions from most common primary renal diseases except type 1 diabetic nephropathy and polycystic kidney disease. The ESRD rates generally were low, and more similar than different, in Europid populations, except for variable contributions from type 1 (high in Finland, Sweden, Denmark and Canada) and type 2 (high in Austria and Canada) diabetes. In Europid populations during 1998-2002, all-cause ESRD declined by 2% per year in persons aged 0-44 years, and all non-diabetic ESRD by a similar amount in persons aged 45-64 years, in whom diabetic ESRD had increased by 3% per year., Conclusions: Increased susceptibility to type 2 diabetes and to kidney disease progression characterizes excess ESRD in non-Europid peoples. The decline in all-cause ESRD in young persons, and non-diabetic ESRD in the middle-aged, probably reflects improving management of progressive renal disease.

Data from 1218 cases of childhood brain tumors (CBT) diagnosed between 1976 and 1994 and 2223 matched controls from the general population were included in an analysis of maternal beauty product exposure and beauty-related employment in 9 centers in 7 countries. A 50% increased odds ratio (OR) [95% confidence interval (CI) = 1.0-2.1] for CBT was observed among children of mothers who were exposed via personal use of and/or possible ambient contact with beauty products during the 5 years preceding the index child's birth compared with children of mothers never exposed to beauty products during this time period. Overall maternal personal use of hair-coloring agents in the month before or during the pregnancy of the index child's birth was not associated with CBT (OR = 1.0, CI = 0.83-1.3) or with astroglial (OR = 1.1, CI = 0.85-1.4), PNET (OR = 1.0, CI = 0.71-1.5) and other glial subtypes (OR = 1.0, CI = 0.62-1.0). Similarly, no statistically increased ORs or discernable pattern of risk estimates were observed for period of use or for number of applications per year for maternal personal use of hair-coloring agents overall or by histologic type. Among children born on or after 1980, increased ORs for CBT were associated with maternal non-work-related exposure to any beauty products (OR = 2.6, CI = 1.2-5.9), hair-dyes (OR = 11, CI = 1.2-90), and hair sprays (OR = 3.4, CI = 1.0-11). No overall increased OR for CBT was observed among children of mothers employed in beauty-related jobs during the 5 years preceding the index child's birth compared with those who reported no beauty-related employment. In general, other specific beauty product-related exposures were not associated with increased ORs for CBT. Data from our study provide little evidence of an increased risk for CBT with mothers' exposures to beauty products.

We investigated whether there is an association between cytomegalovirus (CMV) and Epstein-Barr virus (EBV) IgG levels and risk of breast cancer before age 40 years. CMV and EBV IgG levels were measured in stored plasma from 208 women with breast cancer and 169 controls who participated in the Australian Breast Cancer Family Study (ABCFS), a population-based case-control study. CMV and EBV IgG values were measured in units of optical density (OD). Cases and controls did not differ in seropositivity for CMV (59 and 57% respectively; P=0.8) or EBV (97 and 96% respectively; P=0.7). In seropositive women, mean IgG values were higher in cases than controls for CMV (1.20 vs 0.98 OD, P=0.005) but not for EBV (2.65 vs 2.57 OD, P=0.5). The adjusted odds ratios per OD unit were 1.46 (95% CI 1.06-2.03) for CMV IgG and 1.11 (0.93-1.33) for EBV IgG. The higher mean CMV IgG levels found in women with breast cancer could be the result of a more recent infection with CMV, and may mean that late exposure to CMV is a risk factor for breast cancer.

Background: The epidemiology of androgenetic alopecia (AGA) is not fully understood. Although a strong genetic basis has long been identified, little is known of its non-genetic causes., Objectives: To estimate the prevalence of and to determine risk factors for AGA in men aged 40-69 years in Australia., Methods: Men (n = 1390) were recruited at random from the electoral rolls to serve as controls in a population-based case-control study of prostate cancer. All were interviewed in person and direct observations of AGA were made. Men were grouped into the following categories; no AGA, frontal AGA, vertex AGA and full AGA (frontal and vertex AGA). Epidemiological data collected from these men were used for an analysis of risk factors for each AGA category using unconditional logistic regression with AGA category as the response variable adjusting for age, education and country of birth., Results: The prevalence of vertex and full AGA increased with age from 31% (age 40-55 years) to 53% (age 65-69 years). Conversely, the proportion of men with only frontal AGA was very similar across all age groups (31-33%). No associations were found between pubertal growth spurt or acne, reports of adult body size at time of interview, urinary symptom score, marital status, or current smoking status or duration of smoking and the risk of any form of AGA. The consumption of alcohol was associated with a significant increase in risk of frontal and vertex AGA but not full AGA. Men with vertex AGA had fewer female sexual partners but average ejaculatory frequency did not differ between men in different AGA categories. Reported weight and lean body mass at reaching maturity at about 21 years of age were negatively associated with vertex balding (P for trend < 0.05) but not with frontal AGA or full AGA., Conclusions: Evidence for environmental influences on AGA remains very slight. Our study failed to confirm previously reported or hypothesized associations with smoking and benign prostatic hypertrophy. The associations that we found with alcohol consumption and with lean body mass at age 21 years would be worthy of further research if they were able to be replicated in other studies.

Objective: We conducted a case-control study of prostate cancer and familial risk of the disease in Australia between 1994 and 1998, a period during which the incidence of prostate cancer increased dramatically with widespread use of prostate-specific antigen (PSA) testing., Methods: 1475 cases and 1405 controls were asked about prostate cancer in their first-degree relatives. Odds ratios (OR) were calculated using logistic regression., Results: Cases were more likely to report a family history of prostate cancer than controls (OR 3.0; 95% confidence interval (CI) 2.3-3.9) and cases reporting an affected relative were younger (58.8 versus 60.9 years, p < 0.0001). The OR for an affected first-degree relative increased with increasing number of affected relatives and decreased with increasing age of the case. The OR for more than one affected first-degree relative was 6.9 (95% CI 2.7-18). The OR for an affected brother was 3.9 (95% CI 2.5-6.1) and for an affected father was 2.9 (95% CI 2.1-3.9) but these were not significantly different (p = 0.2). When analyses were repeated including only diagnoses made in relatives prior to 1992, the risks were generally similar except that the OR for an affected brother decreased to 3.1 (95% CI 1.2-3.9). When only relatives' diagnoses made after 1991 were included results were again similar to those for all relatives, although the effect for brothers was greater and the attenuation with age at diagnosis dissipated., Conclusions: The recent introduction of PSA testing that has resulted in a greater prevalence of apparent prostate cancer, does not appear to have substantially altered familial risks of disease, although effects associated with brothers may be inflated.

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: To examine the risk of smoking on histopathologically-confirmed moderate- and high-grade prostate cancer., Materials and Methods: A population-based case-control study was conducted in Melbourne, Sydney and Perth between 1994 and 1998 in men aged below 70 years. Cases were recruited from cancer registries and controls were selected from electoral registers. 1498 cases and 1434 controls were interviewed and a detailed smoking history obtained. Data were analyzed by unconditional logistic regression, adjusting for age, study center, year of recruitment, family history and country of birth., Results: The odds ratios (OR) were 1.02 (0.85-1.22) for former smoking and 0.82 (0.65-1.05) for current smoking. The respective ORs were 0.95 (0.78-1.15) and 0.76 (0.59-0.99) for moderate grade tumors, and 1.28 (0.96-1.70) and 1.00 (0.67-1.47) for high-grade tumors (P = 0.2 for test that ORs of the two grades were identical). There was no evidence of a dose-response effect for duration of smoking, amount smoked daily, pack-years of smoking and years since quitting and most ORs for these variables were close to unity., Conclusions: Smoking was not associated with the incidence of prostate cancer. The widths and upper limits of the confidence intervals for the effects of current and former smoking were consistent with weak effects at most.

Segregation analyses aim to detect genetic factors that have a major effect on an individual's risk of disease and to describe them in terms of mode of inheritance, age-specific cumulative risk (penetrance), and allele frequency. We conducted single- and two-locus segregation analyses of data from 1,476 men with prostate cancer diagnosed at age <70 years and ascertained through population registries in Melbourne, Sydney, and Perth, Australia, and from their brothers, fathers, and both maternal and paternal lineal uncles. Estimation and model selection were based on asymptotic likelihood theory and were performed through use of the software MENDEL. All two-locus models gave better fits than did single-locus models, even if lineal uncles were excluded or if we censored data (age and disease status) for relatives at 1992, when prostate-specific-antigen testing started to have a major impact on the incidence of prostate cancer in Australia. Among the genetic models that we considered, the best-fitting ones included a dominantly inherited increased risk that was greater, in multiplicative terms, at younger ages, as well as a recessively inherited or X-linked increased risk that was greater, in multiplicative terms, at older ages. The recessive and X-linked effects were strongly confounded, and it was not possible to fit them together. Penetrance to age 80 years was approximately 70% (95% confidence interval [CI] 57%-85%) for the dominant effect and virtually 100% for the recessive and X-linked effects. Approximately 1/30 (95% CI 1/80-1/12) men would carry the dominant risk, and 1/140 (95% CI 1/220-1/90) would carry the recessive risk or 1/200 (95% CI 1/380-1/100) would carry the X-linked risk. Within discussed limitations, these analyses confirm the genetic heterogeneity, of prostate cancer susceptibility, that is becoming evident from linkage analyses, and they may aid future efforts in gene discovery.

Mutations in BRCA1 and BRCA2 that cause a dominantly inherited high risk of female breast cancer seem to explain only a small proportion of the aggregation of the disease. To study the possible additional genetic components, we conducted single-locus and two-locus segregation analyses, with and without a polygenic background, using three-generation families ascertained through 858 women with breast cancer diagnosed at age <40 years, ascertained through population cancer registries in Melbourne and Sydney, Australia. Extensive testing for deleterious mutations in BRCA1 and BRCA2, to date, has identified 34 carriers. Our analysis suggested that, after other possible unmeasured familial factors are adjusted for and the known BRCA1 and BRCA2 mutation carriers are excluded, there appears to be a residual dominantly inherited risk of female breast cancer in addition to that derived from mutations in BRCA1 and BRCA2. This study also suggests that there is a substantial recessively inherited risk of early-onset breast cancer. According to the best-fitting model, after excluding known carriers of mutations in BRCA1 and BRCA2, about 1/250 (95% confidence interval [CI] 1/500 to 1/125) women have a recessive risk of 86% (95% CI 69%-100%) by age 50 years and of almost 100% by age 60 years. Possible reasons that our study has implicated a novel strong recessive effect include our inclusion of data on lineal aunts and grandmothers, study of families ascertained through women with early-onset breast cancer, allowance for multiple familial factors in the analysis, and removal of families for whom the cause (i.e., BRCA1 or BRCA2) is known. Our findings may have implications for attempts to identify new breast cancer-susceptibility genes.

Background: This study was devised to determine the prevalence of urinary symptoms among men living in the Australian cities of Melbourne, Sydney or Perth, and to identify factors associated with the presence of moderate-to-severe urinary symptoms., Methods: The study comprised a population-based sample of 1,216 men, aged 40-69 years, whose names were obtained through electoral rolls and who participated as controls in a case-control study of risk factors for prostate cancer. As part of a structured face-to-face interview, the men completed the International Prostate Symptom Score (IPSS). Men with moderate (IPSS = 8-19) or severe (IPSS > or = 20) urinary symptoms were compared with those with mild or no symptoms (IPSS < 8) using unconditional logistic regression., Results: The age-specific prevalence of moderate-to-severe urinary symptoms (IPSS > or = 8) in men aged 40-49, 50-59, 60-69 years was 16%, 23% and 28%, respectively. Compared with men with no or mild urinary symptoms (IPSS < 8), men with moderate-to-severe symptoms were more likely to report not currently living as married [odds ratio (OR) = 1.5; 95% confidence interval (CI) 1.1-2.0] and being circumcised (OR = 1.5; 95% Cl 1.2-2.0). The increased likelihood associated with drinking an average of > 60 g day(-1) of alcohol in the 2 years before interview was of marginal statistical significance (OR = 1.6; 1.0-2.6). There were no significant differences between men with IPSS > or = 8 and those with IPSS < 8 with respect to body mass index, education level, having had a vasectomy, or cigarette smoking., Conclusion: Among Australian men, being circumcised, or not currently living as married, were associated with increased prevalence of urinary symptoms.

This report notes the differences in the classification of the primary renal disease (PRD) used in different renal dialysis and transplant registries worldwide. The heterogeneity of coding systems complicates the comparative analysis of end-stage renal disease from different regions. Using data collected over two decades in the United States, Europe, and Australia/New Zealand, we present a method for reorganization of the classes of PRD that allows a straightforward comparison of retrospective data from these registries.

The average breast cancer risk for carriers of a germ-line mutation in BRCA1 or BRCA2 (penetrance) has been estimated from the multiple-case families collected by the Breast Cancer Linkage Consortium (BCLC) to be approximately 80% to age 70. However, women now being tested for these mutations do not necessarily have the intense family history of the BCLC families. Testing for protein-truncating mutations in exons 2, 11, and 20 of BRCA1 and exons 10 and 11 of BRCA2 was conducted in a population-based sample of 388 Australian women with breast cancer diagnosed before age 40. Onset of breast cancer was analyzed in the known and potential mutation-carrying first- and second-degree female relatives of cases found to carry a mutation. Of the 18 mutation-carrying cases (9 BRCA1 and 9 BRCA2), only 5 (1 BRCA1 and 4 BRCA2) had at least one affected relative, so family history of breast cancer was not a strong predictor of mutation status in this setting. The risk in mutation carriers was, on average, 9 times the population risk [95% confidence interval (CI), 4-23; P < 0.001]. Penetrance to age 70 was 40% (95% CI, 15-65%), about half that estimated from BCLC families. By extrapolation, approximately 6% (95% CI, 2-20%) of breast cancer before age 40 may be caused by protein-truncating mutations in BRCA1 or BRCA2. Breast cancer risk in BRCA1 or BRCA2 mutation carriers may be modified by other genetic or environmental factors. Genetic counselors may need to take into account the family history of the consultand.

Background: Previous studies have suggested that the frequency of cancer is higher in patients with end-stage renal disease (ESRD) than in the general population, but have not established whether this increase is confined to certain cancers or to certain categories of ESRD patients. The aim of this study was to examine the risk of cancer in a large cohort of patients treated by dialysis but not transplantation., Methods: We assembled a cohort of 831,804 patients who received dialysis during the period 1980-94 for ESRD in the USA, Europe, Australia, or New Zealand. We compared the observed frequency of cancer among these patients during 2,045,035 person-years of follow-up with the frequency of cancer in the respective background populations., Findings: During average follow-up of 2.5 years, 25,044 (3%) of 831,804 patients developed cancer compared with an expected number of 21,185 (standardised incidence ratio 1.18 [95% CI 1.17-1.20]). We observed a higher risk of cancer in patients younger than 35 years (3.68 [3.39-3.99]), and the risk gradually decreased with increasing age. High risks were observed for cancer of the kidney (3.60 [3.45-3.76]), bladder (1.50 [1.42-1.57]), and thyroid and other endocrine organs (2.28 [2.03-2.54]). Excess cancers appeared in several organs for which viruses have been suspected as causative agents, whereas cancers of the lung, colorectum, prostate, breast, and stomach were not consistently increased., Interpretation: The overall risk of cancer is increased in patients with ESRD, and the distribution of tumour types resembles the pattern seen after transplantation (although we have no data to make the comparison with skin cancer). The excess risk can largely be ascribed to effects of underlying renal or urinary-tract disease, or of loss of renal function, on the kidney and bladder, and to increased susceptibility to viral carcinogenesis. The relative risk, which is especially high in younger patients, gradually diminishes with age.

Background: We conducted a population-based, case-control-family study to determine whether androgen receptor (AR) exon 1 polymorphic CAG repeat length (CAGn) was a risk factor for early-onset breast cancer in the Australian population., Methods: Case subjects under 40 years of age at diagnosis of a first primary breast cancer and age-matched control subjects were interviewed to assess family history and other risk factors. AR CAGn length was determined for 368 case subjects and 284 control subjects. Distributions in the two groups were compared by linear and logistic regression, allowing adjustment for measured risk factors. All statistical tests were two-tailed., Results: When analyzed as either a continuous or a dichotomous variable, there was no association between CAG, length and breast cancer risk, before or after adjustment for risk factors. Mean (95% confidence interval [CI]) CAGn lengths were 22.0 (21.8-22.2) for case subjects and 22.0 (21.7-22.3) for control subjects (P = .9). The frequency (95% CI) of alleles with 22 or more CAGn repeats was 0.531 (0.494-0.568) for case subjects and 0.507 (0.465-0.549) for control subjects (P = .4). After adjustment, the average effect on log OR (odds ratio) per allele was 0.16 (95% CI = -0.03 to 0.40; P = .2), and the effect of any allele was equivalent to an OR of 1.40 (95% CI = 0.94-2.09; P = .1). Stratification by family history also failed to reveal any association. Similar results were obtained when alleles were defined by other cutoff points., Conclusion: We found no evidence for an association between AR exon 1 CAGn length and breast cancer risk in women under the age of 40, despite having 80% power to detect modest effects.

Objectives: Because the factors that influence risk of acral melanomas on the soles and palms in White populations are unknown, we investigated these in a multi-center case-control study., Methods: Cases of melanoma of the feet and hands diagnosed from 1987-93 in persons aged over 18 years were ascertained in eastern Australia and western Scotland. There were 275 cases of melanoma on the soles and palms matched to 496 controls (selected from the electoral roll) in Australia, and 36 cases matched to 72 controls (nominated by general practitioners) in Scotland., Results: Acral melanoma was strongly associated with high total body nevus counts (adjusted relative risk [RR] = 6.3, 95% confidence interval [CI] = 2.5-15.6), and with nevi on the soles (RR = 7.5, CI = 3.0-18.6). There were also significant positive associations with a penetrative injury of the feet or hands (RR = 5.0, CI = 3.0-8.6) and with heavy exposure to agricultural chemicals (RR = 3.6, CI = 1.5-8.3). Sun-sensitive complexions, cumulative sun exposure and a past history of nonmelanoma skin cancer were also associated with increased risk of acral melanoma. Current cigarette smoking was inversely related to acral melanoma (RR = 0.6, CI = 0.4-0.9)., Conclusions: Melanomas of the soles and palms resemble other cutaneous melanomas in their association with sun exposure, but are distinguished from them by their strong positive associations with nevi on the soles, previous penetrative injury, and exposure to agricultural chemicals, and by their inverse association with smoking.

The frequency, in women with breast cancer, of mutations and other variants in the susceptibility gene, BRCA1, was investigated using a population-based case-control-family study. Cases were women living in Melbourne or Sydney, Australia, with histologically confirmed, first primary, invasive breast cancer, diagnosed before the age of 40 years, recorded on the state Cancer Registries. Controls were women without breast cancer, frequency-matched for age, randomly selected from electoral rolls. Full manual sequencing of the coding region of BRCA1 was conducted in a randomly stratified sample of 91 cases; 47 with, and 44 without, a family history of breast cancer in a first- or second-degree relative. All detected variants were tested in a random sample of 67 controls. Three cases with a (protein-truncating) mutation were detected. Only one case had a family history; her mother had breast cancer, but did not carry the mutation. The proportion of Australian women with breast cancer before age 40 who carry a germline mutation in BRCA1 was estimated to be 3.8% (95% CI 0.3-12.6%). Seven rare variants were also detected, but for none was there evidence of a strong effect on breast cancer susceptibility. Therefore, on a population basis, rare variants are likely to contribute little to breast cancer incidence.

Background: Women with breast carcinoma diagnosed before age 40 years have a greater prevalence of germline BRCA1 and BRCA2 mutations than women with breast carcinoma diagnosed at older ages. Several recognizable histologic characteristics have been identified in breast carcinoma from studies of BRCA1/2 mutation carriers who belong to multiple-case families. The authors attempted to determine whether breast carcinoma occurring before age 40 years in BRCA1 or BRCA2 mutation carriers who were not selected for family history could be distinguished histologically from one another and from breast carcinoma in women of a similar age without a germline BRCA1 or BRCA2 mutation., Methods: The study undertook a histologic assessment of breast carcinomas diagnosed before age 40 years identified from a population-based study., Results: Breast carcinoma in BRCA1 mutation carriers was associated with a distinct histologic appearance; these tumors were high grade, and had exceptionally high mean mitotic counts, a syncytial growth pattern, pushing margins, and confluent necrosis. Atypical medullary carcinoma was overrepresented in BRCA1 mutation carriers. All low grade tumors and tumors with low mitotic rates belonged to the group without BRCA1 or BRCA2 mutations. Pleomorphic lobular carcinomas and extensive intraduct carcinomas were more common in BRCA2 mutation carriers., Conclusions: Breast carcinoma occurring in women with a germline BRCA1 or BRCA2 mutation have recognizable histologic phenotypes, which may be useful in identifying individuals more likely to carry germline mutations. Histologic examination of breast carcinoma should become an important part of the evaluation of women seeking genetic testing for germline mutations in these breast carcinoma susceptibility genes.

Objectives: A case-control-family study of breast cancer in women under the age of 40 was carried out in Melbourne and Sydney, Australia, from 1992 to 1995 to determine the risk factors for these women. Subjects included 467 incident cases identified by state cancer registries and 408 population-based controls., Methods: All participants completed a structured risk-factor questionnaire and family pedigree during an in-person interview. Where possible, cancers in first- and second-degree relatives were verified., Results: Multiple logistic regression analysis showed that the strongest risk factor for breast cancer was a family history of the disease -- having at least one affected first-degree relative trebled the risk (relative risk [RR] = 3.3, 95 percent confidence interval [CI] = 1.9-5.8). Risk increased with height by three percent (standard error [SE] of one percent) per cm, and after adjusting for height, there was evidence for a decreased risk in women weighing 73 kg or more. There was an increased risk of breast cancer after the first full-term birth (RR = 1.8, CI = 1.0-3.5) but this risk fell by 30 percent (SE = 11 percent) with each subsequent livebirth., Conclusions: The effects of other reproductive factors and oral contraceptive use, although not nominally significant, were in accord with published findings from similar studies in young women. This study of Australian women has indicated that some risk factors for breast cancer in women under age 40 differ from those reported for older women either in direction (e.g., weight) or relative importance (e.g., family history).

Migrant studies have taken advantage of the wide geographical variation in cancer risk. Cancer rates in migrants, obtained from routinely collected incidence or mortality statistics, are compared with those in the host country and in the country of origin; the rate of change with time since migration (or age at migration) and in subsequent generations is assessed; and the results are interpreted in the light of differences in socio-economic status and the degree of cultural assimilation. Rapid changes in cancer risk following migration imply that life-style or environmental factors are of overriding importance in aetiology. The susceptibility of fair-skinned races to ultraviolet (UV)-associated skin cancers is an example of racial differences based on inherited factors, but the long-term excess or deficit of other cancers in migrants has not yet been attributed definitively to genetic rather than persisting life-style factors. Are there racial differences in metabolism, DNA repair mechanisms or altered expression of oncogenes or tumour suppressor genes? Several genetic polymorphisms affecting the metabolism of known occupational carcinogens or hormonal factors do vary by race. While classical epidemiology has shown that the environment predominates in determining cancer incidence, molecular epidemiology has identified several examples of genetically determined differences between races.

In view of the changing trends in the incidence of melanoma at different body sites and in particular on the limbs, the detailed distributions of over 10,000 invasive melanomas diagnosed on the upper and lower limbs in residents of mainland eastern Australia between 1987 and 1993 were examined. Cancer notifications and histopathology reports from the cancer registries of Queensland, New South Wales and Victoria were searched manually, and subsites when specified were recorded as shoulder, upper arm, forearm, elbow, wrist or hand, and thigh, leg, knee, ankle or foot. On the upper limbs relative tumour densities were highest on the shoulder, approximately equal on the upper arm and forearm and least on the hand in both men and women; on the lower limbs melanomas occurred more than twice as often on the leg than on the thigh or the foot, taking account of surface area. There was a clear inverse gradient of incidence of melanoma with latitude in the three eastern Australian states studied, but little difference between the states or between sexes in distribution of histological type: the majority specified being specified as superficial spreading melanomas. In contrast to predictions based on apparent frequency of sun exposure at subsites on the upper limbs, the relative concentration of melanomas on the shoulder suggests that wearing sleeveless garments outdoors in the sun should be avoided whenever possible. Also, the similar densities of leg and forearm melanomas seems inconsistent with the relative degree of exposure of each and further suggests that women's adoption of ankle-length skirts or trousers, in preference to knee-length skirts would be a worthwhile modern control measure.

The relationships between reproductive factors, exogenous hormones and renal-cell cancer were examined in an international, multicenter, population-based, case-control study undertaken in 1989-1991. Data from 5 centers situated in Australia, Denmark, Germany, Sweden and the United States included for analysis 608 women with renal-cell cancer and 766 female controls. A significant trend in risk (p = 0.002) was associated with number of births, with an 80% excess risk for 6 or more births [RR = 1.8, 95% confidence interval (CI) = 1.1 to 2.9] compared with one birth. A decreasing risk was seen for increasing age at first birth, although this was confounded by body-mass index and number of births. A suggestive reduction of risk was also seen for increasing age at menarche. Age at menopause was unrelated to risk of renal-cell cancer. An increased risk was observed for women having had both a hysterectomy and an oophorectomy. Use of oral contraceptives in non-smoking women reduced the risk of renal-cell cancer (RR = 0.5, 95% CI = 0.4 to 0.8); this reduction increased with longer duration of use. No association was observed for estrogen replacement therapy. Our results indicate that certain hormonal and reproductive variables may be related to risk of renal-cell cancer and deserve further investigation, both epidemiologically and experimentally.

The major factor contributing to the increase in incidence of both renal and urothelial cancers has been improved detection rates. To a considerable extent, this accounts for the difference between the trends in incidence and mortality since, on the whole, the efficacy of treatment has improved only slowly. In the case of renal parenchymal cancer, the true burden of disease is rising almost everywhere, probably reflecting changes in standard of living, perhaps chiefly diet, although there will be some contribution from smoking. Where the increase in bladder cancer is not artefactual, it can be attributed in large part to smoking and perhaps to increasing industrial exposure in some localities. Trends in incidence and, to a greater degree, mortality for urothelial cancer are likely to improve substantially with implementation of policies of prevention (reduction in smoking, improvements in industrial hygiene), earlier detection (eg with monoclonal antibodies) and treatment (immunotherapy). No such optimism can be held with respect to renal parenchymal cancer, which is set to become one of the major cancers of affluent societies unless its aetiology becomes known and can be addressed.

Age-specific and cumulative incidence rates were calculated for entry into Australian end-stage renal failure programmes from 1972 to 1991, as a result of all causes, or from analgesic nephropathy, glomerulonephritis, hypertension and vascular disease, or diabetes. Three different trends were demonstrated. A rising recorded incidence of renal failure occurred throughout the period of observation in those aged 0-4 years (all causes) and in those aged 55 years and over (all categories, least in analgesic nephropathy) principally attributable to a falling fraction of patients not accepted for treatment. Falling incidence rates indicating a real reduction in the burden of disease were seen for analgesic nephropathy (at least up to the age of 64 years) and hypertension and vascular disease (only up to the age of 54 years). In young adults the unchanging incidence of renal failure due to all causes, glomerulonephritis and diabetes probably reflect nearly complete acceptance rates into end-stage renal failure programmes, and therefore approximate the true burden of disease. In end-stage renal failure, age-specific or age-standardized cumulative rates are required to distinguish rising or falling incidence of disease from trends due to changing medical practice.

Age-standardised incidence rates for cancers of the renal parenchyma, renal pelvis and bladder and for end-stage renal failure due to analgesic nephropathy for the years 1982-83 were compared between the Australian states and New Zealand, and within New South Wales (NSW), to determine whether these rates paralleled the previous prevalence of consumption of phenacetin-containing analgesics. Whereas little variation was seen within Australasia in respect of the incidence of cancer of the renal parenchyma and bladder, both cancer of the renal pelvis and end-stage renal failure due to analgesic nephropathy had higher incidence rates amongst women in NSW and Queensland than in the other states or New Zealand. Within NSW, the average annual incidence rates during 1973-82 for renal pelvic cancer in the Hunter region of 1.3 (m) and 1.6 (f) per 100,000 were the highest in the state. These high incidence rates coincided with areas known to have had a high prevalence of consumption of compound analgesics containing phenacetin. In an international comparison with populations which had published incidence rates for each of the periods 1973-77 and 1978-82, the rate for cancer of the renal pelvis in women was highest in both time periods in NSW and had increased absolutely at a faster rate.

In 1981, questionnaires seeking information about the teaching of medicine in general, and rheumatology in particular, were sent to random samples of undergraduates in Australian medical schools and trainees in the Family Medicine Programme (FMP) of the Royal Australian College of General Practitioners. Neurology rated most highly, with the majority of undergraduates considering it to be well taught and interesting; by contrast, rheumatology was perceived as being badly taught and lacking in interest. Many graduates had never attended rheumatology outpatient clinics either as undergraduates (45%) or as FMP trainees (68%). Only 40% of the graduates had ever been attached to a rheumatology inpatient service, and fewer than 50% had received any teaching about the role of physiotherapists or occupational therapists in the management of patients with arthritis.

A case-control study of cancer of the renal parenchyma (360 cases and 985 controls) investigated lifestyle and dietary risk factors by means of a questionnaire survey. A lifetime history concerning urological disease and consumption of analgesics, tobacco, and prescribed medicines, was obtained together with current dietary and demographic information. Estimates of relative risk were calculated using logistic regression. Statistically significant associations were found with phenacetin-containing analgesics, urological disease and increasing consumption of milk. No association was found with consumption of aspirin, paracetamol, prescribed medicines, tea, coffee or animal proteins other than milk, or with the type of fat or oil used for cooking or spreading. The association with tobacco just failed to reach significance.

Data from the New South Wales (NSW) Central Cancer Registry comprising all new cases of cancer registered in persons aged 15 years and over for the 10-year period 1973 to 1982 were examined using log-linear regression to determine whether the incidence of cancer had been changing in NSW. Allowing for the altered age and sex structure of the population over this period, the annual incidence rate for all sites combined increased significantly by 1.7% in men and 1.0% in women. Cancers which had increased at a rate significantly greater than that for all sites combined were those of unknown primary site (8.7% per year), lung (in women only, 5.6%), kidney (4.5%), bladder (2.7%) and rectum (2.6%) and lymphomas (2.6%). Other cancers which showed a significantly increased incidence rate per se were testis (3.5%), larynx (3.2%), prostate (2.1%), colon (1.7%), brain (1.6%), leukaemias (1.3%) and lung (in men only, 0.7%). Cancers which had decreased significantly in incidence were those of oesophagus (-2.2%), cervix uteri (-2.0%) and stomach (-1.4%). No significant change in incidence over the 10 years had occurred for cancers of the corpus uteri, breast, ovary or pancreas.

A lifetime history of analgesics and tobacco consumption was obtained by a questionnaire completed at interview from 67 patients with carcinoma of the renal pelvis (40 women, 27 men) and 180 control subjects drawn from two sources, friends of patients and persons attending a health screening clinic. Regular consumption of analgesics conferred a tenfold relative risk of renal pelvic cancer in women and in men a risk ratio of 4-8. The fraction of cases for which analgesic consumption was an attributable risk was 0.74 in women and 0.43 in men. The effect of tobacco, much less than that of analgesics, was significant only in women (risk ratio approximately four; attributable risk 0.4), and no dose-response relationship was demonstrated. Relative excess risks suggested a synergistic effect when both analgesics and tobacco had been consumed. Standardized risk ratios indicated a dose-response relationship for both phenacetin-containing and non-phenacetin analgesics: moderate consumption doubled the risk of renal pelvic cancer, and heavy consumption increased at risk to 6-16 times that for noncomsumers.

A lifetime history of analgesic consumption was recorded at interview from 91 patients (11 men, 80 women) with a secure diagnosis of renal papillary necrosis, 38 patients (5 men, 33 women) with probable renal papillary necrosis and 223 control subjects from two sources. Consumption of phenacetin-containing analgesics increased the risk of renal papillary necrosis in women some seventeen times over that for non-consumers, but analgesics containing no phenacetin did not confer an increased risk of renal papillary necrosis; in both calculations the confounding effect of taking the other type of analgesic was controlled.

Incidence data for cancers of the kidney and urinary tract (1973-83) and for end stage renal failure (ESRF) due to analgesic nephropathy (1973-86) were examined by loglinear regression to determine the effect of the withdrawal of phenacetin from analgesic preparations in New South Wales and the Australian Capital Territory. Allowing for the altered age and sex structure of the population, the incidence rate between 1973-83 for ESRF due to analgesic nephropathy, in persons aged between 5 and 54 years, decreased by 4.2% per year while that for ESRF excluding patients with analgesic nephropathy or diabetes increased annually by 1.3%. The incidence rates in persons over 14 years of age for cancer of the renal parenchyma (3.4% per year), renal pelvis (5.5%) and bladder (2.1%) increased significantly more than that for cancer at all sites (1.2%). Thus the decrease in ESRF due to analgesic nephropathy had not, by 1983, been paralleled by a decrease in renal parenchymal or urothelial cancer.