A candidate gene approach to searching for low-penetrance breast and prostate cancer genes.

Most cases of breast and prostate cancer are not associated with mutations in known high-penetrance genes, indicating the involvement of multiple low-penetrance risk alleles. Studies that have attempted to identify these genes have met with limited success. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium--a pooled analysis of multiple large cohort studies with a total of more than 5,000 cases of breast cancer and 8,000 cases of prostate cancer--was therefore initiated. The goal of this consortium is to characterize variations in approximately 50 genes that mediate two pathways that are associated with these cancers--the steroid-hormone metabolism pathway and the insulin-like growth factor signalling pathway--and to associate these variations with cancer risk.

That recognised risk factors can explain past and present international differences in breast cancer incidence: misconceptions 5.

Recent discussions on research priorities in the United States have revealed a widespread assumption that known risk factors entirely explain the historic international differences in rates of breast cancer. In fact, formal investigations of this question, both by modelling between-country differences and studies of migrants, indicate that an appreciable amount of the international differences in this disease remains unexplained. If this is not recognised, opportunities for research on breast cancer aetiology may be lost.

Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk.

BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

Birth defects in the sons and daughters of women who were exposed in utero to diethylstilbestrol (DES).

Prenatal exposure to diethylstilbestrol (DES) is associated with adverse health outcomes, including anatomic anomalies of the reproductive tract in women and of the genitourinary tract in men. The mouse model, which replicates many DES-related effects seen in humans, suggests that prenatal DES exposure causes alterations that may affect the next generation of offspring. We asked women participating in a large, multi-centre study of prenatal DES exposure to report birth defects occurring among 4029 sons and 3808 daughters (i.e., the third generation). A subcohort of 793 third generation daughters was also queried for birth defects. We used logistic regression models to generate odds ratio and 95% confidence intervals for the association between prenatal DES exposure in the mother and birth defects in the offspring. Based on the mothers' reports, overall birth defects were elevated in the sons (OR = 1.53; 95% CI = 1.04, 2.23) and in the daughters (OR = 2.35; 95% CI = 1.44, 3.82). Most estimates of association were imprecise, but daughters appeared to have an excess of heart conditions (OR = 4.56; 95% CI = 1.27, 16.34). Our data suggest a possible association between the mother's prenatal DES exposure and birth defects in their offspring, particularly in daughters. We cannot, however, rule-out the possible influence of reporting bias. In particular, the exposed daughters' elevated risk of cardiac defects may be as a result of the underreporting of these conditions by unexposed mothers.

A Case-Control Study of Fluoridation and Osteosarcoma.

Public health policy decisions in the United States have resulted in 62.4% of the population having access to fluoridated water. The purpose of this study was to examine the association between community water fluoridation and osteosarcoma. A secondary data analysis was performed with data collected from 2 separate but linked studies. Patients for phase 1 and phase 2 were selected from US hospitals via a matched case-control study design. For both phases, cases included patients diagnosed with osteosarcoma, and controls were patients diagnosed with other bone tumors or nonneoplastic conditions. In phase 1, cases (n = 209) and controls (n = 440) were patients of record in the participating orthopedic departments from 1989 to 1993. In phase 2, cases (n = 108) and controls (n = 296) were incident patients who were identified and treated by orthopedic physicians from 1994 to 2000. This analysis included all patients who met eligibility criteria on whom we had complete data on covariates, exposures, and outcome. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% CIs for the association of community water fluoridation with osteosarcoma. A modestly significant interaction existed between fluoridation living status and bottled water use (P = 0.047). The adjusted OR for osteosarcoma and ever having lived in a fluoridated area for nonbottled water drinkers was 0.51 (95% CI, 0.31 to 0.84; P = 0.008). In the same comparison, the adjusted OR for bottled water drinkers was 1.86 (95% CI, 0.54 to 6.41; P = 0.326). Findings from this study demonstrated that community water fluoridation is not associated with an increased risk for osteosarcoma.

Circulating maternal and umbilical cord steroid hormone and insulin-like growth factor concentrations in twin and singleton pregnancies.

In addition to being associated with a higher risk of complications during pregnancy, twinning may also be a proxy for altered hormonal exposure for mothers and twin offspring, with implications for their health later in life. We compared maternal and fetal steroid hormone and insulin-like growth factor concentrations between singleton (n=62) and twin (n=41) pregnancies. Maternal concentrations of androgens, estrogens, insulin-like growth factor (IGF)-1, IGF-binding protein (BP)-3 and prolactin were quantified during the third trimester and at delivery, as well as in the fetal circulation at birth. Geometric means accounting for gestational age were calculated for hormone concentrations and compared between matched twin and singleton pregnancies. Most maternal hormone concentrations were modestly higher in twin than in singleton pregnancies in the third trimester (ranging from 8.3% for IGF-1 to 17.1% for estradiol) and at delivery (ranging from 11.1% for IGFBP-3 to 15.2% for estriol). Cord serum hormones were generally similar in twin and singleton pregnancies, except for IGFBP-3, which was 200% lower in twins. The modest differences in maternal hormones in late gestation seem unlikely to explain alterations in hormonally related disease risk in mothers of twins compared with singletons. The large deficit of IGFBP-3 in the fetal circulation of twins at birth may allow for sufficient concentrations of IGF-2 for growth and development in an environment of shared nutritional resources.

Maternal, prenatal and perinatal characteristics and first trimester maternal serum hormone concentrations.

In uncomplicated pregnancies, first trimester androgen, oestrogen and prolactin concentrations were higher in nulliparous (n=160) than parous (n=260) mothers. Androgens and estrogens were higher in younger than older mothers. These data are consistent with elevated hormone concentrations mediating the breast cancer protection from a first pregnancy and pregnancies occurring at younger ages.

Past body mass index and risk of mortality among women.

BACKGROUND: Epidemiologic studies of body mass index (BMI) in relation to mortality commonly exclude persons with health conditions and/or a history of smoking to prevent bias resulting from illness-related weight loss ('reverse causation'). Analysis of BMI from an earlier time period may minimize reverse causation without requiring exclusion of participants based on disease or smoking history. METHODS: We prospectively examined BMI based on technician measurements of weight and height from 10 years prior to start of follow-up in relation to subsequent mortality in a cohort of 50 186 women who were 40-93 years old at baseline in 1987-1989. Deaths were ascertained through the US National Death Index. Proportional hazards regression was used to estimate hazard ratios (HRs) of mortality, adjusted for age, education, race/ethnicity, income, menopausal hormone use, smoking and physical activity. RESULTS: During 10 years of follow-up through 1997, 5201 women died. Overall, we observed a J-shaped association between BMI and mortality, with increased risk for women who were underweight, overweight or obese. The HRs and 95% confidence intervals of mortality for BMI categories of <18.5, 18.5-20.9, 21.0-23.4 (reference), 23.5-24.9, 25.0-27.4, 27.5-29.9, 30.0-34.9 and 35.0+ kg m(-2) were 1.43 (1.19, 1.72), 1.07 (0.98, 1.17), 1.00 (reference), 1.10 (1.00, 1.20), 1.20 (1.11, 1.31), 1.23 (1.11, 1.37), 1.60 (1.44, 1.77) and 1.92 (1.64, 2.24). There was little evidence that pre-existing conditions (heart disease, diabetes and/or cancer) or smoking history modified the past BMI and mortality relation (P=0.54 and 0.76). CONCLUSIONS: In this large cohort of women, BMI based on technician measurements of weight and height from 10 years prior to baseline showed increased risk for mortality across the range of overweight and obesity, regardless of disease and smoking history. Observed associations between overweight, obesity and mortality in healthy individuals may also apply to persons with a history of disease or smoking.

TET2 binds the androgen receptor and loss is associated with prostate cancer.

Genetic alterations associated with prostate cancer (PCa) may be identified by sequencing metastatic tumour genomes to identify molecular markers at this lethal stage of disease. Previously, we characterized somatic alterations in metastatic tumours in the methylcytosine dioxygenase ten-eleven translocation 2 (TET2), which is altered in 5-15% of myeloid, kidney, colon and PCas. Genome-wide association studies previously identified non-coding risk variants associated with PCa and melanoma. We perform fine-mapping of PCa risk across TET2 using genotypes from the PEGASUS case-control cohort and identify six new risk variants in introns 1 and 2. Oligonucleotides containing two risk variants are bound by the transcription factor octamer-binding protein 1 (Oct1/POU2F1) and TET2 and Oct1 expression are positively correlated in prostate tumours. TET2 is expressed in normal prostate tissue and reduced in a subset of tumours from the Cancer Genome Atlas (TCGA). Small interfering RNA-mediated TET2 knockdown (KD) increases LNCaP cell proliferation, migration and wound healing, verifying loss drives a cancer phenotype. Endogenous TET2 bound the androgen receptor (AR) and AR-coactivator proteins in LNCaP cell extracts, and TET2 KD increases prostate-specific antigen (KLK3/PSA) expression. Published data reveal TET2 binding sites and hydroxymethylcytosine proximal to KLK3. A gene co-expression network identified using TCGA prostate tumour RNA-sequencing identifies co-regulated cancer genes associated with 2-oxoglutarate (2-OG) and succinate metabolism, including TET2, lysine demethylase (KDM) KDM6A, BRCA1-associated BAP1, and citric acid cycle enzymes IDH1/2, SDHA/B, and FH. The co-expression signature is conserved across 31 TCGA cancers suggesting a putative role for TET2 as an energy sensor (of 2-OG) that modifies aspects of androgen-AR signalling. Decreased TET2 mRNA expression in TCGA PCa tumours is strongly associated with reduced patient survival, indicating reduced expression in tumours may be an informative biomarker of disease progression and perhaps metastatic disease.

Rising incidence of breast cancer: relationship to stage and receptor status.

We used the population-based tumor registry of Kaiser Permanente in the United States (Portland, OR) to analyze breast cancer incidence from 1960 to 1985. Overall, incidence rose 45% during this period. The largest increases occurred in women 60 years of age or older (74%) and in those 45-59 (36%). The rate in women aged 20-44 has remained essentially unchanged. Localized and regional disease showed similar increases. Review of medical records revealed that only a small portion of this increase was likely to result from increased screening activities. From the increased availability of receptor assays in a large proportion of cases since the mid-1970s, we observed that incidence of estrogen receptor-negative cancers rose 22%-27% between the mid-1970s and the mid-1980s. In contrast, incidence of estrogen receptor-positive tumors increased an average of 131% in the same period, perhaps implicating hormonal factors in the rising incidence of breast cancer.

Fluoridated drinking water and the occurrence of cancer.

A recent report by the National Health Federation, a private agency, related cancer mortality patterns in the United States to fluoridation of water supplies, triggering much public health concern and some political response. To clarify the issues raised, we studied cancer mortality and incidence statistics for U.S. counties, 1950-69. No trends could be ascribed to the consumption of water that is artificially or naturally fluoridated.

Subsequent cancer in patients with chronic lymphocytic leukemia--a possible immunologic mechanism.

Among 4,869 patients with chronic lymphocytic leukemia (CLL) from the series of the End Results Program of the National Cancer Institute, Bethesda, Maryland, second primary cancers developed in 234 patients, compared to 204.9 expected. The risk was significantly elevated for malignant melanoma, soft-tissue sarcomas, and lung cancer. The frequency of rectal cancer was also elevated, but not significantly. The excess risk for these specific sites persisted throughout the period of follow-up, suggesting a susceptibility state that complicated the leukemic process rather than suggesting methodologic, diagnostic, or therapeutic effects. Immunologic defects to CLL may be involved in the etiology of excess risk for these sites, because a similar array of nonlymphoid tumors was seen following therapeutic immunosuppression among renal transplant recipients.

Occupational risks of bladder cancer in the United States: II Nonwhite men.

Occupational risks of bladder cancer among nonwhite men were assessed based on interviews with 126 cases and 383 controls conducted during the National Bladder Cancer Study, a population-based, case-control study conducted in 10 areas of the United States. Our findings indicated that nonwhite men who were ever employed as auto workers have an elevated risk of bladder cancer [relative risk (RR) = 2.3; 95% confidence intervals (CI) = 0.8-6.4] with a significant positive trend in RR with increasing duration of employment (P = .017) and with the RR rising to 4.7 for those employed at least 10 years. Dry cleaners, ironers, and pressers also experienced increased bladder cancer risk (RR = 2.8, CI = 1.1-7.4). Nonsignificant excesses of similar magnitude to those seen among white men were found for nonwhite men employed in several other occupations. Overall, our findings suggest that the risk of occupational bladder cancer among white and nonwhite men is similar. When inconsistencies between whites and nonwhites did occur, they appeared either due to chance or possibly racial differences in exposure among men within the same industry and occupation. In all, we estimate that the population attribute risk for occupation among nonwhite U.S. men is 27% (CI = 9% to 56%), which is slightly higher than the estimate of 21% to 25% previously reported for white U.S. men, although this difference was not statistically significant.

Occupation and cancer of the lower urinary tract in Detroit.

The relationship between occupation and cancer of the lower urinary tract in Detroit was examined by means of a population-based case-control study conducted as part of the National Bladder Cancer Study. Three hundred three white male patients with transitional or squamous cell carcinoma of the lower urinary tract and 296 white male controls selected from the general population of the study area were interviewed to obtain lifetime occupational histories. Our findings suggested that truck drivers have a significant increased risk of lower urinary tract cancer [relative risk = 2.1; 95% confidence interval (Cl) = 1.4-4.4]. A significant trend in risk was apparent with increasing duration of employment as a truck driver (P = 0.004); the relative risk estimated for truck drivers employed at least 10 years was 5.5 (Cl = 1.8-17.3). Truck drivers with a history of operating vehicles with diesel engines experienced a significant elevated risk compared to non-truck drivers (relative risk = 11.9; Cl = 2.3-61.1), but whether the increased risk observed among truck drivers was attributable to diesel exposure could not be evaluated. Nonsignificant excess risks were also seen for tool and die makers as well as for workers in several other industries and occupations. Employment in the motor vehicle manufacturing industry was associated with no significant excess risk of lower urinary tract cancer (relative risk = 1.1; Cl = 0.8-1.5).

Occupational risks of bladder cancer in the United States: I. White men.

We examined the relationship between occupation and bladder cancer risk using data obtained from interviews conducted with 2,100 white males with bladder cancer and 3,874 population controls during the National Bladder Cancer Study, a population-based, case-control study conducted in 10 areas of the United States. The strongest evidence of increased risk among white men was observed for painters, truck drivers, and drill press operatives. For painters, the overall relative risk was 1.5 [95% confidence intervals (CI) = 1.2-2.0]. Among painters who started working prior to 1930, a significant trend in risk with increasing duration of employment as a painter was apparent; the relative risk for such painters employed 10 or more years was 3.0. For truck drivers and drill press operatives, overall risks were 1.3 (CI = 1.1-1.4) and 1.4 (CI = 0.9-2.1), respectively. We observed a significant, positive trend in risk with increasing duration of employment in each of these occupations, with relative risks peaking at approximately two for long-term workers. Excess risks were also observed for workers in several other occupations. In all, we estimate that 21%-25% of bladder cancer diagnosed among white men in the United States is attributable to occupational exposures.

Rauwolfia use and breast cancer: a case-control study.

Breast cancer risk among 1,362 cases and 1,250 controls participating in a large multicenter screening program was examined in relation to hypertension and the use of rauwolfia derivatives. A previous diagnosis of hypertension, reported by 22% of the cases and 23% of the controls, was not associated with an increased risk of breast cancer [odds ratio (OR) = 0.9]; nor was there any excess risk for long-term hypertensives. In addition, there was no significant increase in risk associated with use of either rauwolfia derivatives (OR = 1.2), thiazide preparations (OR = 1.2), or methyldopa (OR = 1.1). However, there were significant excess risks among long-term users and those with extended intervals since first use of rauwolfia. Rauwolfia users of 10 or more years' duration or those whose initial use occurred greater than or equal to 10 years before diagnosis had risk ratios of 4.5 (95% Cl, 1.2-19.8) and 3.8 (95% Cl, 2.3-11.6), respectively. These results suggest that women exposed to long-term rauwolfia use have an elevated risk of developing breast cancer, although the results fail to support previous observations of a generalized adverse effect.

Alcohol consumption and breast cancer.

The association between alcohol consumption and breast cancer was investigated in a case-control study involving 1,524 cases and 1,896 controls identified through a nationwide screening program. Ever drinking alcohol was not associated with any substantial increase in risk [odds ratio (OR) = 1.1; 95% confidence interval (Cl) = 1.0-1.3], but there was a significant trend in risk with increasing average weekly intake (P less than .04). Women who had one or fewer drinks daily (83% of all drinkers) did not experience any excess risk compared to nondrinkers, but significant excess risks were observed among those who drank from 1 to 2 (OR = 1.3; 95% Cl = 1.0-1.7) or more than 2 (OR = 1.7; 95% Cl = 1.2-2.4) drinks a day. An increased risk associated with alcohol consumption was evident only for those who drank at younger ages (less than 30 yr), regardless of current consumption. Alcohol effects were adjusted for a variety of factors, including reproductive history, were adjusted for a variety of factors, including reproductive history, socioeconomic indicators, and obesity, but none exerted any appreciable confounding influence. The results support an association between moderate alcohol consumption in early life and subsequent breast cancer risk, although interpretation should be cautious in the absence of dietary information.

Breast cancer risk factors among screening program participants.

PIP: Data were obtained by mailed questionnaire from 405 breast cancer patients identified during the first 2 years of operation of the Breast Cancer detection Demonstration Project in the U.S. and from a sample of 1156 normal screenees (response rate = 88%) in an attempt to examine whetHer the usual risk indicators for breast cancer apply to individuals participating in screening programs. No substantial differences were found between the respondents and the nonrespondents for the variables on which information had been obtained at the time of the initial screening. Nearly all of t(e recognized risk factors were seen in this population. The relative risk (FF) of breast cancer was 3.9 among women whose mothers were also affected; this finding was statistically significant. Relative risk was increased for women reporting early menarche, late menopause, nulliparity, late age when 1st child was born, and excessive weight. The relative risk was not elevated in women with a prior breast biopsy but was excessive for those with more than 1 biopsy. No association with thyroid medications or menopausal hormones was found. Among women having undergone a natural menopause, a nonstatistically significant elevation in the relative risk was noted for long term oral contraceptive users; this excess relative risk was restricted to those using OCs in the presence of breast cancer risk indicators. The results indicate the need for further study of women with extended periods of OC use, particularly when accompanied by other known risk indicators.^ieng

Geographic variation in mortality from breast cancer among white women in the United States.

BACKGROUND: For several decades, mortality from breast cancer has been higher in the northeastern part of the United States than in other regions, particularly the South. Rates have also been somewhat higher in the Midwest and West than in the South, especially among older women. The reasons for these geographic variations are not well understood. PURPOSE: The objective of this study was to evaluate geographic differences in U.S. breast cancer mortality rates in 1987, after taking into account regional differences in the distribution of recognized breast cancer risk factors (e.g., late age at first live birth) and certain prognostic factors (e.g., mammography use). METHODS: The 1987 breast cancer mortality rates for four regions of the country were obtained from the National Center for Health Statistics. Regional data on the distribution of breast cancer risk factors were obtained from 1987 National Health Interview Cancer Epidemiology Supplement interviews with 9778 white women aged 20-79 years. Regional data on the distribution of mammography use were obtained from 1987 National Health Interview Cancer Control Supplement interviews with 3795 white women aged 50-79 years. RESULTS: Age-adjusted mortality ratios (MRs) among women 50 years and older were 1.15, 1.18, and 1.30 in the West, Midwest, and Northeast, respectively, compared with the South. Corresponding MRs among women 20-49 years old were 1.01, 1.08, and 1.07 in the West, Midwest, and Northeast, respectively, compared with the South. After adjustment for recognized risk factors and certain prognostic factors, MRs among older women were 1.13 (95% confidence interval [CI] = 1.04-1.23), 1.08 (95% CI = 1.01-1.16), and 1.13 (95% CI = 1.04-1.23) in the West, Midwest, and Northeast, respectively, compared with the South. Corresponding MRs among younger women were 0.94 (95% CI = 0.76-1.16), 1.05 (95% CI = 0.92-1.18), and 0.99 (95% CI = 0.86-1.14), respectively. CONCLUSION: Before adjustment for regional differences in recognized risk factors and prognostic factors, mortality excesses among younger women in the Northeast, Midwest, and West were less than 10% compared with the South. After adjustment, MRs were near unity for all regions. Among older women, the excess mortality was more substantial before adjustment for relevant factors, ranging from 15% in the West to 30% in the Northeast. Approximately 50% of the excesses in the Northeast and Midwest and 10% of the excess in the West could be explained on the basis of regional differences in the prevalence of recognized breast cancer risk factors and prognostic factors. After adjustment for these factors, the magnitude of excess in breast cancer mortality in the Northeast (13%) was comparable to that in the West (13%) but still slightly higher than that in the Midwest (8%).

Proportion of breast cancer cases in the United States explained by well-established risk factors.

BACKGROUND: Few estimates of the fraction of cases of breast cancer attributable to recognized risk factors have been published. All estimates are based on selected groups, making their generalizability to the U.S. population uncertain. PURPOSE: Our goal was to estimate the fraction of breast cancer cases in the United States attributable to well-established risk factors (i.e., later age at first birth, nulliparity, higher family income, and first-degree family history of breast cancer), using data from the first National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study (NHEFS), the survey and follow-up of a probability sample of the U.S. population. METHODS: From a cohort of 7508 female participants surveyed in the early 1970s, and followed up between 1982 and 1984 and again in 1987, 193 breast cancer cases were accrued for study. We calculated incidence rates, relative risks (RRs), and population attributable risks (PARs) for breast cancer risk factors and extended our results to the U.S. female population by using sample weights from the NHANES I survey. RESULTS: Our PAR estimates suggest that later age at first birth and nulliparity accounted for a large fraction of U.S. breast cancer cases, 29.5% (95% confidence interval [CI] = 5.6%-53.3%); higher income contributed 18.9% (95% CI = -4.3% to 42.1%), and family history of breast cancer accounted for 9.1% (95% CI = 3.0%-15.2%). Taken together, these well-established risk factors accounted for approximately 47% (95% CI = 17%-77%) of breast cancer cases in the NHEFS cohort and about 41% (95% CI = 2%-80%) in the U.S. population. CONCLUSIONS: The RRs for most of these risk factors were modest, but their prevalence as a group was high, leading to estimates that suggest that a substantial proportion of breast cancer cases in the United States are explained by well-established risk factors. IMPLICATIONS: Elucidation of the determinants underlying recognized factors and study of other factors that may confer risk or protection are needed in efforts to advance understanding of breast cancer etiology and to aid in devising strategies for prevention.