Increased cancer risks for relatives of very early-onset breast cancer cases with and without BRCA1 and BRCA2 mutations.

BACKGROUND: Little is known regarding cancer risks for relatives of women with very early-onset breast cancer. METHODS: We studied 2208 parents and siblings of 504 unselected population-based Caucasian women with breast cancer diagnosed before age 35 years (103 from USA, 124 from Canada and 277 from Australia), 41 known to carry a mutation (24 in BRCA1, 16 in BRCA2 and one in both genes). Cancer-specific standardised incidence ratios (SIRs) were estimated by comparing the number of affected relatives (50% verified overall) with that expected based on incidences specific for country, sex, age and year of birth. RESULTS: For relatives of carriers, the female breast cancer SIRs were 13.13 (95% CI 6.57-26.26) and 12.52 (5.21-30.07) for BRCA1 and BRCA2, respectively. The ovarian cancer SIR was 12.38 (3.1-49.51) for BRCA1 and the prostate cancer SIR was 18.55 (4.64-74.17) for BRCA2. For relatives of non-carriers, the SIRs for female breast, prostate, lung, brain and urinary cancers were 4.03 (2.91-5.93), 5.25 (2.50-11.01), 7.73 (4.74-12.62), 5.19 (2.33-11.54) and 4.35 (1.81-10.46), respectively. For non-carriers, the SIRs remained elevated and were statistically significant for breast and prostate cancer when based on verified cancers. CONCLUSION: First-degree relatives of women with very early-onset breast cancer are at increased risk of cancers not explained by BRCA1 and BRCA2 mutations.

BRCA1 promoter deletions in young women with breast cancer and a strong family history: a population-based study.

Women diagnosed with breast cancer before the age of 40 years who have a strong family history of breast and/or ovarian cancer were selected from an Australian population-based case-control-family study for large deletion screening within the BRCA1 promoter. Deletions within the BRCA1 promoter region are usually not detected by the methods applied in routine clinical mutation detection strategies. Fifty-one of the 66 women (77%) who met our inclusion criteria were tested for promoter deletions using linkage disequilibrium analysis of two BRCA1 polymorphic sites (C/G1802 and Pro871Leu) and multiplex ligation-dependent probe amplification. Two cases of BRCA1 promoter deletion involving exons 1A-2 and exons 1A-23 were detected. The morphology of the breast cancers arising in these women with BRCA1 promoter deletions was consistent with the morphology associated with other germline BRCA1 mutations. Large genomic deletions that involve the promoter regions of BRCA1 make up 20% (2/10) of all known BRCA1 mutations in this group of young women with a strong family history of breast and ovarian cancer. Our data support the inclusion of testing for large genomic alterations in the BRCA1 promoter region in routine clinical mutation detection within BRCA1.

Divergent trends in the incidence of end-stage renal disease due to Type 1 and Type 2 diabetes in Europe, Canada and Australia during 1998-2002.

AIMS: To describe the variation in geographical distribution of end-stage renal disease (ESRD) due to Type 1 and Type 2 diabetes, and to calculate recent trends in incidence in predominantly white populations. METHODS: Estimation of age- and sex-standardized incidence of ESRD by type of diabetes, and temporal trends, in population-based data for persons aged 30-44, 45-54 or 55-64 years newly treated for ESRD during 1998-2002 in eight countries or regions of Europe, and Non-Indigenous Canadians and Australians. RESULTS: The incidence of ESRD due to Type 1 diabetes at age 30-44 years correlated with published rates of childhood-onset insulin dependent diabetes mellitus (P = 0.0025). ESRD due to Type 2 diabetes was uncommon before 45 years of age; in older persons, the highest rates (in Canada and Austria) were five times the lowest rates (in Norway and the Basque region). Rates of ESRD due to Type 1 diabetes fell, per year, by 6.4%[95% confidence interval (CI): 2.1-10.6%) in persons aged 30-44 years, and by 7.7% (95% CI: 2.4-12.7%] in those aged 45-54 years. In contrast, rates of ESRD due to Type 2 diabetes increased annually by 16% (95% CI: 5-28%) in the 30-44-year age group, 11% (95% CI: 6-16%) at 45-54 years, and 9% (95% CI: 5-14%) at 55-64 years. CONCLUSIONS: Modern prevention has reduced progression of nephropathy to ESRD due to Type 1 diabetes, but the continuing rise of ESRD due to Type 2 diabetes represents a failure of current disease control measures that has serious public health implications.

Geographic, ethnic, age-related and temporal variation in the incidence of end-stage renal disease in Europe, Canada and the Asia-Pacific region, 1998-2002.

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.

Beauty product-related exposures and childhood brain tumors in seven countries: results from the SEARCH International Brain Tumor Study.

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.

Parental exposure to polycyclic aromatic hydrocarbons and the risk of childhood brain tumors: The SEARCH International Childhood Brain Tumor Study.

Experimental evidence suggests that parental exposure to polycyclic aromatic hydrocarbons (PAH), which occurs primarily through tobacco smoke, occupational exposure, and air pollution, could increase the risk of cancer during childhood. Population-based case-control studies carried out in seven countries as part of the SEARCH Program compared data for 1,218 cases of childhood brain tumors and 2,223 controls (1976-1994). Parental occupational exposure to PAH during the 5-year period before birth was estimated with a job exposure matrix. Risk estimates were adjusted for child's age, sex, and study center. Paternal preconceptional occupational exposure to PAH was associated with increased risks of all childhood brain tumors (odds ratio (OR) = 1.3, 95% confidence interval: 1.1, 1.6) and astroglial tumors (OR = 1.4, 95% confidence interval: 1.1, 1.7). However, there was no trend of increasing risk with predicted level of exposure. Paternal smoking alone (OR = 1.4) was also associated with the risk of astroglial tumors in comparison with nonsmoking, non-occupationally-exposed fathers. Risks for paternal occupational exposure were higher, with (OR = 1.6) or without (OR = 1.7) smoking. Maternal occupational exposure to PAH before conception or during pregnancy was rare, and this exposure was not associated with any type of childhood brain tumor. This large study supports the hypothesis that paternal preconceptional exposure to PAH increases the risk of brain tumors in humans.

Cytomegalovirus, Epstein-Barr virus and risk of breast cancer before age 40 years: a case-control study.

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.

Androgenetic alopecia in men aged 40-69 years: prevalence and risk factors.

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.

Risk factors for breast cancer in young women by oestrogen receptor and progesterone receptor status.

We used data from 765 cases and 564 controls in the population-based Australian Breast Cancer Family Study to investigate whether, in women under the age of 40, the profile of risk factors differed between breast cancer subtypes defined by joint oestrogen and progesterone receptor status. As hypothesised, no significant differences were found.

Sexual factors and prostate cancer.

OBJECTIVE: To assess whether prostate cancer might be related to hormone levels and, by inference, to differences in sexual activity. PATIENTS, SUBJECTS AND METHODS: In a case-control study of men with prostate cancer aged < 70 years at diagnosis and age-matched control subjects, information was collected on two aspects of sexual activity; the number of sexual partners and the frequency of total ejaculations during the third to fifth decades of life. RESULTS: There was no association of prostate cancer with the number of sexual partners or with the maximum number of ejaculations in 24 h. There was a negative trend (P < 0.01) for the association between risk and number of ejaculations in the third decade, independent of those in the fourth or fifth. Men who averaged five or more ejaculations weekly in their 20s had an odds ratio (95% confidence interval) of 0.66 (0.49-0.87) compared with those who ejaculated less often. CONCLUSIONS: The null association with the number of sexual partners argues against infection as a cause of prostate cancer in this population. Ejaculatory frequency, especially in early adult life, is negatively associated with the risk of prostate cancer, and thus the molecular biological consequences of suppressed or diminished ejaculation are worthy of further research.

Risk of prostate cancer associated with a family history in an era of rapid increase in prostate cancer diagnosis (Australia).

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 steroid 5alpha-reductase type II TA repeat polymorphism is not associated with risk of breast or ovarian cancer in Australian women.

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.

Parental occupations and childhood brain tumors: results of an international case-control study.

OBJECTIVE: To evaluate the role of parental occupations in the etiology of childhood brain tumors (CBT). METHODS: Population-based case-control studies were conducted concurrently in seven countries under the coordination of the International Agency for Research on Cancer, gathering 1,218 cases and 2,223 controls. We report here the findings related to parental occupations during the 5-year period before the child's birth. Risk estimates related to a number of paternal and maternal occupations were obtained by unconditional logistic regression adjusted for age, sex, year of birth, and center, for all types of CBT combined and for the subgroups of astroglial, primitive neuroectodermal tumors (PNET), and other glial tumors. RESULTS: An increased risk in relation with agricultural work was seen for all CBT combined and for other glial tumors. Increased risks for all tumors and PNET were seen for paternal occupation as an electrician; the same pattern held for maternal occupation when children under 5 were selected. Paternal occupation as a driver or mechanic, and maternal work in an environment related to motor-vehicles were associated with an increased risk for all CBT and astroglial tumors. More case mothers compared to control mothers were employed in the textile industry. CONCLUSION: Our study reinforces previous findings relative to the role of parental work in agriculture, electricity, or motor-vehicle related occupations and maternal work in the textile industry. It does not confirm previous associations with work environments including aerospace, the chemical industry, or the food industry, or with maternal occupation as a hairdresser, a nurse, or a sewing machinist, and paternal occupation as a welder.

Smoking and prostate cancer: findings from an Australian case-control study.

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.

Prevalence of urinary symptoms in urban Australian men aged 40-69.

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.

Morphologic typing of papillary renal cell carcinoma: comparison of growth kinetics and patient survival in 66 cases.

Whereas papillary renal cell carcinoma is now established as a subtype of renal cell neoplasia, division of these tumors into 2 distinctive morphotypes has been proposed. Type 1 tumors have cells with scanty pale cytoplasm arranged in a single layer on the basement membrane of papillary cores. In these tumors, psammoma bodies and foamy macrophages are frequently seen, and the tumors frequently express cytokeratin 7. Type 2 tumor cells have pseudostratified nuclei and usually have voluminous eosinophilic cytoplasm. Recent studies have supported this subclassification of papillary renal cell carcinoma by demonstrating differing genotypes for type 1 and 2 tumors. To further study the subclassification of papillary renal carcinoma, we compared clinical features, nuclear grade, stage, tumor growth kinetics, and survival in a series of 50 type 1 and 16 type 2 papillary renal cell carcinomas. Comparison of patient age at presentation, sex, and primary tumor size shows no significant difference between the 2 tumor types. Type 1 tumors were of significantly lower Fuhrman grade (P =.0001) and higher Robson stage (P =.009) than type 2 tumors. There was no significant difference when tumors were staged according to the TNM classification. Assessment of tumor growth kinetics showed significantly different mean silver-staining nucleolar organizer region (AgNOR) scores and Ki-67 indices (AgNOR type 1, 3.83, type 2, 7.24, P =.0001; Ki-67 type 1, 3.17%, type 2, 6.01%, P =.0002). Multivariate analysis showed tumor type (P =.03), presence of metastases (P =.04), AgNOR score (P =.001), and Ki-67 index (P =.03) to be independently associated with survival. These results provide evidence of the clinical utility of dividing papillary renal cell carcinomas into 2 types according to histologic characteristics.

Segregation analyses of 1,476 population-based Australian families affected by prostate cancer.

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.

After BRCA1 and BRCA2-what next? Multifactorial segregation analyses of three-generation, population-based Australian families affected by female breast cancer.

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.

Prevalence of self-reported arm morbidity following treatment for breast cancer in the Australian Breast Cancer Family Study.

Population-based women (n=1049) with breast cancer diagnosed mainly between 1996 and 1998, when aged 20-59 years, were mailed a questionnaire seeking information about self-reported shoulder stiffness and swelling, numbness and pain/ache in the arm following treatment (excluding 6 months from diagnosis). Of the 809 who completed the survey, approximately seven in eight experienced at least one symptom, one in six reported all four symptoms, and one in three considered that their arm morbidity interfered substantially with activities of daily living. Arm swelling occurred at some time in 39% of women, was present in 20% 1 year, and in 29% 4 years, after diagnosis. The prevalence of arm swelling was higher in women with axillary node dissection (OR=2.4; 95% Cl 1.0-5.6), and was increased in a women with a higher body mass index (P=0.02) and less education (P=0.01), but was not related to age, number of nodes excised or self-reports of radiation or type of surgery.

CYP17 promoter polymorphism and breast cancer in Australian women under age forty years.

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.