Biomedical subjects

Yutaka Yasui

Publications and source records attributed to Yutaka Yasui.

At least 19 recordsLinked to original sources

PubMed2026

Integrating genetic predictors into subsequent breast cancer risk prediction in survivors of childhood cancer.

PURPOSE: Female survivors of childhood cancer are at high risk for developing breast cancer. The contributions of most general population primary breast cancer genetic predictors to this risk have not been explored. METHODS: Analyses included females who survived ≥5 years after their childhood cancer diagnosis with available array (N = 2096, subsequent breast cancer [SBC]=218) or whole-genome sequencing (WGS; N = 3292, SBC=101) data from the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. We computed 99 externally-validated primary breast cancer polygenic risk scores (PRS). Using deep-coverage WGS, ClinVar-annotated pathogenic/likely pathogenic (P/LP) variants in breast cancer susceptibility genes were identified. Cox proportional hazards models assessed associations with SBC risk, adjusting for treatments and genetic ancestry. RESULTS: Among 5388 female survivors (genetic ancestry, European: N = 4,752; African: N = 444; East Asian: N = 192), 319 developed SBC. Most (90.9%) PRSs were nominally associated with SBC risk (P < 0.05), but effect sizes varied substantially. PRSs with superior discriminatory ability had greater genome-wide coverage (e.g., 6.4 million-variant PRS, HR per SD = 1.71, 95% CI = 1.43 to 2.05; P = 4.2x10-9) and 7.7-fold higher odds (P = 7.0x10-4) of including variants in multiple DNA damage repair pathways compared with PRSs with weaker risk associations. Among survivors with WGS, 1.6% carried P/LP variants in clinical testing panel genes, which was associated with a 7.4-fold greater risk (95% CI = 3.16 to 17.19). Including genetic factors improved SBC risk prediction by age 40 (P < 0.001) compared to treatment exposures alone. CONCLUSIONS: Externally-validated primary breast cancer genetic susceptibility predictors are relevant for SBC risk prediction and should be prioritized for risk stratification in survivors.

Journal Article↗

PubMed2005

Long-term medical effects of childhood and adolescent rhabdomyosarcoma: a report from the childhood cancer survivor study.

BACKGROUND: This study was conducted to evaluate the incidence of adverse medical conditions and to assess the risk of developing these conditions in a cohort of long-term survivors of rhabdomyosarcoma (RMS) diagnosed before age 21. PROCEDURE: Using data from the Childhood Cancer Survivor Study (CCSS), we evaluated the incidence of self-reported adverse medical conditions for 606 RMS survivors and 3,701 siblings of cancer survivors. Cancer and treatment data abstracted from medical records were used to evaluate the effects of primary tumor site and combined modality therapy on the risk of developing sequelae in survivors. RESULTS: The relative risk (RR) for developing sequelae among survivors compared with siblings was greatest within 5 years after diagnosis. RR was elevated more than 5 years after diagnosis for several conditions (RR, 95% CI) as follows: eye impairment (cataract: 7.4, 2.9-18.9; visual disturbances: 3.2, 2.0-5.1; very dry eyes: 2.0, 1.2-3.3), endocrine impairment (growth hormone deficiency: 83.9, 33.0-213.6; hypothyroidism: 6.9, 4.1-11.3; need for medications to induce puberty: 90.4, 30.2-270.5), cardiopulmonary impairment (congestive heart failure: 43.0, 12.7-145.5; angina-like symptoms: 2.0, 1.3-2.9), neurosensory impairment (legal blindness: 9.8, 4.8-20.0; abnormal sensations: 1.5, 1.0-2.2), and neuromotor impairment (repeated seizures: 2.3, 1.2-4.4; motor problems: 3.7, 2.2-6.4; problems chewing or swallowing: 3.8, 1.9-7.5). CONCLUSIONS: Survivors are at risk for developing sequelae many years after their initial diagnosis and treatment. Continued medical surveillance is necessary to ensure the long-term health and well-being of RMS survivors.

Adolescent↗

PubMed2005

Reliability, effect size, and responsiveness of health status measures in the design of randomized and cluster-randomized trials.

BACKGROUND: New health status survey instruments are often described by their psychometric (measurement) properties, such as Validity, Reliability, Effect Size, and Responsiveness. For cluster-randomized trials, another important statistic is the Intraclass Correlation (ICC) for the instrument within clusters. Studies using better instruments can be performed with smaller sample sizes, but better instruments may be more expensive in terms of dollars, opportunity cost, or poorer data quality due to the response burden of longer instruments. METHODS: We defined the psychometric statistics in terms of a mathematical model, and examined the power of a two-sample test as a function of the test-retest Reliability, Effect Size, Responsiveness, and Intraclass Correlation of the instrument. We examined the "cost-effectiveness" of using a one-item versus a five-item measure of mental health status. FINDINGS: Under the standard model for measurement error, the psychometric statistics are all functions of the same error term. They are also functions of the setting in which they were estimated. In randomized trials, power is a function of Reliability and sample size, and a less reliable instrument can achieve the desired power if N is increased. In cluster-randomized trials, adequate power may be obtained by increasing the number of clusters per treatment group (and often the number of persons per cluster), as well as by choosing a more reliable instrument. The one-item measure of mental health status may be more cost-effective than the five-item measure in some situations. CONCLUSION: If the goal is to diagnose or refer individual patients, an instrument with high Validity and Reliability is needed. In settings where the sample sizes are large or can be increased easily, any valid instrument may be cost-effective. It is likely that many published values of psychometric statistics are accurate only in settings similar to that in which they were estimated.

Cost-Benefit Analysis↗

PubMed2005

Evaluation of matrix-assisted laser desorption/ionization-time of flight mass spectrometry proteomic profiling: identification of alpha 2-HS glycoprotein B-chain as a biomarker of diet.

Biomarkers have the potential to impact a wide range of public health concerns, including early detection of diseases, drug discovery, and improved accuracy of monitoring effects of interventions. Given new technological developments, broad-based screening approaches will likely advance biomarker discovery at an accelerated pace. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) allows for the elucidation of individual protein masses from a complex mixture with high throughput. We have developed a method for identifying serum biomarkers using MALDI-TOF and statistical analysis. However, before applying this approach to screening of complex diseases, we evaluated the approach in a controlled dietary intervention study. In this study, MALDI-TOF spectra were generated using samples from a randomized controlled trial. During separate feeding periods, 38 participants ate a basal diet devoid of fruits and vegetables and a basal diet supplemented with cruciferous (broccoli) family vegetables. Serum samples were obtained at the end of each 7-day feeding period and treated to remove large, abundant proteins. MALDI-TOF spectra were analyzed using peak picking algorithms and logistic regression models. Our bioinformatics methods identified two significant peaks at m/z values of 2740 and 1847 that could classify participants based on diet (basal vs. cruciferous) with 76% accuracy. The 2740 m/z peak was identified as the B-chain of alpha 2-HS glycoprotein, a serum protein previously found to vary with diet and be involved in insulin resistance and immune function.

Adult↗

PubMed2005

Cancer preventive screening: a cross-border comparison of United States and Canadian Chinese women.

OBJECTIVE: To compare screening mammography and Pap testing among Chinese women in Seattle, Washington to Vancouver, and British Columbia. METHODS: Using community-based sampling methods, trilingual female interviewers surveyed Chinese women in Seattle and Vancouver. Multiple preventive health behaviors and health care access variables were assessed. Mammography analysis included 409 women aged 50-74 years. Pap testing analysis included 973 women aged 20-69 years. Main outcome measures were ever use and use in the last 2 years of screening mammography and Pap testing. RESULTS: Chinese women in Vancouver were younger, more educated and fluent in English. Unadjusted rates of mammography and Pap testing were similar between the two cities. Provider type was consistently associated with screening in both cities; female providers had the highest rates and Chinese male providers the lowest. Adjusted logistic regression analysis demonstrated similar mammography use in the two cities. However, for Pap testing, women in Seattle had higher odds of screening compared to Vancouver. CONCLUSION: Despite universal health care coverage and baseline characteristics typically associated with greater utilization of preventive screening services, Chinese women in Vancouver did not have higher rates of screening mammography and Pap testing compared to Chinese women in Seattle.

Age Factors↗

PubMed2005

Effects of exercise on metabolic risk variables in overweight postmenopausal women: a randomized clinical trial.

OBJECTIVE: This study examined the effects of exercise on metabolic risk variables insulin, leptin, glucose, and triglycerides in overweight/obese postmenopausal women. RESEARCH METHODS AND PROCEDURES: Sedentary women (n = 173) who were overweight or obese (BMI > or = 25 kg/m(2) or > or =24 kg/m(2) with > or =33% body fat), 50 to 75 years of age, were randomized to 12 months of exercise (> or =45 minutes of moderate-intensity aerobic activity 5 d/wk) or to a stretching control group. Body composition (DXA) and visceral adiposity (computed tomography) were measured at baseline and 12 months. Insulin, glucose, triglycerides, and leptin were measured at baseline and 3 and 12 months. Insulin resistance was evaluated by the homeostasis model assessment formula. Differences from baseline to follow-up were calculated and compared across groups. RESULTS: Exercisers had a 4% decrease and controls had a 12% increase in insulin concentrations from baseline to 12 months (p = 0.0002). Over the same 12-month period, leptin concentrations decreased by 7% among exercisers compared with remaining constant among controls (p = 0.03). Homeostasis model assessment scores decreased by 2% among exercisers and increased 14% among controls from baseline to 12 months (p = 0.0005). The exercise effect on insulin was modified by changes in total fat mass (trend, p = 0.03), such that the exercise intervention abolished increases in insulin concentrations associated with gains in total fat mass. DISCUSSION: Regular moderate-intensity exercise can be used to improve metabolic risk variables such as insulin and leptin in overweight/obese postmenopausal women. These results are promising for health care providers providing advice to postmenopausal women for lifestyle changes to reduce risk of insulin resistance, coronary heart disease, and diabetes.

Adipose Tissue↗

PubMed2005

No effect of exercise on insulin-like growth factor 1 and insulin-like growth factor binding protein 3 in postmenopausal women: a 12-month randomized clinical trial.

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Aged↗

PubMed2005

Associations among circulating sex hormones, insulin-like growth factor, lipids, and mammographic density in postmenopausal women.

OBJECTIVE: Hormone therapy use has been positively associated with mammographic density in several studies. However, few studies have examined the association between endogenous hormone levels and mammographic density. Therefore, we evaluated the relationship of endogenous sex hormones, insulin-like growth factor (IGF), and lipids with mammographic density in 88 overweight, postmenopausal women not taking hormone therapy. METHODS: Percent density and dense area were evaluated as continuous measures using a computer-assisted program. We used multiple linear regression to evaluate the associations of sex hormones, IGF, and cholesterol with mammographic density, adjusting for confounders, including adiposity. We evaluated stratification by history of hormone therapy use (former versus never) and hormone therapy latency (<5 versus > or = 5 years). RESULTS: Among former hormone therapy users, mammographic density was inversely associated with circulating levels of estrone (P = 0.01), estradiol (P = 0.003), free estradiol (P = 0.004), testosterone (P = 0.04), free testosterone (P = 0.02), androstenedione (P < 0.001), dehydroepiandrosterone (P = 0.01), and the ratio of IGF-I to its binding protein (IGF-I/IGFBP-3; P = 0.04). We found similar associations when we limited the analyses to women who had used hormone therapy within the past 5 years. We also noted positive associations of mammographic density with total cholesterol (P = 0.03) and low-density lipoprotein (P = 0.03) among former hormone therapy users. No associations were noted among women who had never used hormone therapy. CONCLUSIONS: These results suggest that there is an inverse relationship between endogenous sex hormones and mammographic density in postmenopausal women among former users of hormone therapy. This is not consistent with the hormone therapy literature and should be confirmed in larger studies.

Aged↗

PubMed2005

Evaluation of serum protein profiling by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry for the detection of prostate cancer: I. Assessment of platform reproducibility.

BACKGROUND: Protein expression profiling for differences indicative of early cancer has promise for improving diagnostics. This report describes the first stage of a National Cancer Institute/Early Detection Research Network-sponsored multiinstitutional evaluation and validation of this approach for detection of prostate cancer. METHODS: Two sequential experimental phases were conducted to establish interlaboratory calibration and standardization of the surface-enhanced laser desorption (SELDI) instrumental and assay platform output. We first established whether the output from multiple calibrated Protein Biosystem II SELDI-ionization time-of-flight mass spectrometry (TOF-MS) instruments demonstrated acceptable interlaboratory reproducibility. This was determined by measuring mass accuracy, resolution, signal-to-noise ratio, and normalized intensity of three m/z "peaks" present in a standard pooled serum sample. We next evaluated the ability of the calibrated and standardized instrumentation to accurately differentiate between selected cases of prostate cancer and control by use of an algorithm developed from data derived from a single site 2 years earlier. RESULTS: When the described standard operating procedures were established at all laboratory sites, the across-laboratory measurements revealed a CV for mass accuracy of 0.1%, signal-to-noise ratio of approximately 40%, and normalized intensity of 15-36% for the three pooled serum peaks. This was comparable to the intralaboratory measurements of the same peaks. The instrument systems were then challenged with sera from a selected group of 14 cases and 14 controls. The classification agreement between each site and the established decision algorithm were examined by use of both raw peak intensity boosting and ranked peak intensity boosting. All six sites achieved perfect blinded classification for all samples when boosted alignment of raw intensities was used. Four of six sites achieved perfect blinded classification with ranked intensities, with one site passing the criteria of 26 of 28 correct and one site failing with 19 of 28 correct. CONCLUSIONS: These results demonstrate that "between-laboratory" reproducibility of SELDI-TOF-MS serum profiling approaches that of "within-laboratory" reproducibility as determined by measuring discrete m/z peaks over time and across laboratories.

Calibration↗

PubMed2004

Human plasma ghrelin levels increase during a one-year exercise program.

Weight loss resulting from decreased caloric intake raises levels of the orexigenic hormone, ghrelin. Because ingested nutrients suppress ghrelin, increased ghrelin levels in hypophagic weight loss may result from decreased inhibitory input by ingested food, rather than from lost weight. We assessed whether ghrelin levels increase in response to exercise-induced weight loss without decreased caloric intake. We randomized 173 sedentary, overweight, postmenopausal women to an aerobic exercise intervention or stretching control group. At baseline, 3 months, and 12 months, we measured body weight and composition, food intake, cardiopulmonary fitness (maximal oxygen consumption), leptin, insulin, and ghrelin. Complete data were available for 168 women (97%) at 12 months. Exercisers lost 1.4 +/- 0.4 kg (P < 0.05 compared with baseline; P = 0.01 compared with stretchers) and manifested a significant, progressive increase in ghrelin levels, whereas neither measure changed among stretchers. Ghrelin increased 18% in exercisers who lost more than 3 kg (P < 0.001). There was no change in caloric intake in either group and no effect on ghrelin of exercise per se independent of its impact on body weight. In summary, ghrelin levels increase with weight loss achieved without reduced food intake, consistent with a role for ghrelin in the adaptive response constraining weight loss and, thus, in long-term body weight regulation.

Body Mass Index↗

PubMed2004

Methylenetetrahydrofolate reductase genotype affects risk of relapse after hematopoietic cell transplantation for chronic myelogenous leukemia.

PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) directs intracellular folate toward homocysteine metabolism and away from nucleotide synthesis. Two common MTHFR polymorphisms, C677T and A1298C, are associated with reduced enzyme activity. We evaluated the association of these polymorphisms with risk of relapse and bcr-abl mRNA transcript detection among 336 Caucasian patients who underwent allogeneic hematopoietic cell transplantation for chronic myelogenous leukemia. EXPERIMENTAL DESIGN: Data on the transplant course and folate-related exposures were abstracted from medical records. MTHFR C677T and A1298C genotypes were determined using polymerase chain reaction/restriction fragment length polymorphism and TaqMan assays. Qualitative bcr-abl mRNA testing was conducted using a two-step reverse transcription-polymerase chain reaction assay. Cox regression analysis was used to assess the association between MTHFR genotypes and time to relapse and bcr-abl mRNA detection. RESULTS: A statistically significant decreased risk of relapse was observed in patients with the variant A1298C genotype [1298AC, hazard ratio (HR)=0.48 and 95% confidence interval (CI)=0.26-0.88; 1298CC, HR=0.28 and 95% CI=0.09-0.84; P-trend <0.01). For the joint C677T/A1298C genotype, variant genotypes were associated with a decreased risk of relapse when compared with the wild-type 677CC/1298AA genotype. This risk was lowest for the 677CC/1298CC genotype (HR, 0.23; 95% CI, 0.08-0.72). MTHFR genotypes were not associated with bcr-abl transcript detection. CONCLUSIONS: These findings suggest that individuals with the 677CC/1298AA genotype are at higher risk of relapse after hematopoietic cell transplantation and that the balance of intracellular folate metabolites available for nucleotide synthesis (regulated by the relative activity of the MTHFR enzyme) may affect the progression from bcr-abl positivity to clinical relapse.

Adolescent↗

PubMed2004

Breast cancer after childhood cancer: a report from the Childhood Cancer Survivor Study.

BACKGROUND: Survivors of childhood cancer are at risk for secondary breast cancer. Other than previous chest radiation therapy, risk factors for secondary breast cancer have not been established. OBJECTIVE: To identify risk factors for breast cancer among female survivors of childhood cancer. DESIGN: Retrospective cohort study. SETTING: The Childhood Cancer Survivor Study (CCSS), a multicenter study of persons who survived more than 5 years after childhood cancer diagnosed from 1970 to 1986. PARTICIPANTS: Among 6068 women in the CCSS, 95 women had 111 confirmed cases of breast cancer. MEASUREMENTS: Standardized incidence ratios for breast cancer were calculated by using age-specific incidence rates in the general population. Breast cancer incidence was evaluated with respect to primary cancer diagnosis and therapy, age at and time since primary diagnosis, menstrual and reproductive history, and family history of cancer. RESULTS: Breast cancer risk was increased in survivors who were treated with chest radiation therapy (standardized incidence ratio, 24.7 [95% CI, 19.3 to 31.0]) and survivors of bone and soft-tissue sarcoma who were not treated with chest radiation therapy (standardized incidence ratios, 6.7 and 7.6, respectively). Family history of breast cancer (relative rate, 2.7 [CI, 1.3 to 5.0]) and history of thyroid disease (relative rate, 1.7 [CI, 1.1 to 2.6]) were independently associated with increased risk, and exposure to pelvic radiation was protective (relative rate, 0.6 [CI, 0.4 to 0.9]). Age at primary cancer diagnosis and menstrual and reproductive histories did not statistically significantly modify risk. LIMITATIONS: This cohort has not yet attained an age at which breast cancer risk is greatest. CONCLUSION: Survivors of childhood sarcomas and those who received chest radiation therapy are at risk for secondary breast cancer. When assessing a survivor's risk, clinicians should consider primary diagnosis, previous radiation therapy, family cancer history, and history of thyroid disease.

Adult↗

PubMed2004

XRCC1 and glutathione-S-transferase gene polymorphisms and susceptibility to radiotherapy-related malignancies in survivors of Hodgkin disease.

BACKGROUND: One of the most serious late effects of treatment for childhood cancer is the occurrence of subsequent malignancy. Survivors of Hodgkin disease (HD), in particular, have been shown to be at high risk of subsequent malignancy, the occurrence of which has been associated strongly with exposure to radiotherapy. METHODS: In the current study, the authors investigated the association between polymorphisms in 3 genes--glutathione-S-transferase M1 (GSTM1), glutathione-S-transferase T1 (GSTT1), and XRCC1, with roles in protection from a variety of DNA-damaging agents-and the risk of subsequent malignancy in 650 survivors of HD enrolled in the Childhood Cancer Survivor Study who had received radiotherapy. RESULTS: Individuals lacking GSTM1 but not GSTT1 were at increased risk of any subsequent malignancy (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.0-2.3), and for subsequent cancer within the radiation field (OR, 1.4; 95% CI, 0.9-2.1). A nonsignificant increased risk of thyroid carcinoma was observed in individuals lacking either GSTM1 (OR, 2.9; 95% CI, 0.8-10.9) or GSTT1 (OR, 3.7; 95% CI, 0.6-23.5). Individuals having the genotype of the arginine/glutamine polymorphism at codon 399 in the XRCC1 gene (R399) showed a nonsignificant increased risk of breast carcinoma compared with those without (OR, 1.4; 95% CI, 0.7-2.7), and a nonsignificant decreased risk against a subsequent thyroid carcinoma (OR, 0.6; 95% CI, 0.2-1.6). No differences in genotype frequencies were observed between survivors with basal cell carcinoma when compared with survivors without a subsequent cancer. CONCLUSIONS: These data illustrated the potential value of incorporating the collection of genomic DNA in longitudinal cohort studies of populations with well defined, potentially carcinogenic exposures. Evaluation of additional genetic polymorphisms in this cohort may help define genes that influence individual sensitivity to radiotherapy.

Adolescent↗

PubMed2004

Genetic variation in the leptin receptor gene and obesity in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study.

PURPOSE: Overweight (body mass index [BMI] 25 to 29 kg/m2) and obesity (BMI > or = 30 kg/m2) frequently follow treatment for childhood acute lymphoblastic leukemia (ALL). Recent studies suggest that risk is most apparent in females treated with cranial radiation at a younger age. Because radiation at a young age may affect the hypothalamus causing leptin receptor insensitivity, we hypothesized that a polymorphism in the leptin receptor (LEPR) gene, Gln223Arg, might influence susceptibility to obesity in survivors of childhood ALL. PATIENTS AND METHODS: We genotyped 600 non-Hispanic white adult ALL survivors enrolled onto the Childhood Cancer Survivor Study. BMI was compared between those with two copies of the Arg allele to those who had at least one copy of the Gln allele. RESULTS: Female survivors with BMI > or = 25 kg/m2 were more likely Arg homozygous than those with BMI less than 25 kg/m2 (24% v 12%; P =.007). This difference was not observed in males. Moreover, among females treated with > or = 20 Gy cranial radiation, Arg/Arg individuals had six times higher odds of having BMI > or = 25 kg/m2 (95% CI, 2.1 to 22.0) than those with a Gln allele (P =.04 for interaction). CONCLUSION LEPR polymorphism may influence obesity in female survivors of childhood ALL, particularly those exposed to cranial radiation. Because obesity is associated with increased morbidity and mortality in later life, identification of children at high risk might allow for early targeted interventions.

Adolescent↗

PubMed2004

p19Arf suppresses growth, progression, and metastasis of Hras-driven carcinomas through p53-dependent and -independent pathways.

Ectopic expression of oncogenes such as Ras induces expression of p19(Arf), which, in turn, activates p53 and growth arrest. Here, we used a multistage model of squamous cell carcinoma development to investigate the functional interactions between Ras, p19(Arf), and p53 during tumor progression in the mouse. Skin tumors were induced in wild-type, p19(Arf)-deficient, and p53-deficient mice using the DMBA/TPA two-step protocol. Activating mutations in Hras were detected in all papillomas and carcinomas examined, regardless of genotype. Relative to wild-type mice, the growth rate of papillomas was greater in p19(Arf)-deficient mice, and reduced in p53-deficient mice. Malignant conversion of papillomas to squamous cell carcinomas, as well as metastasis to lymph nodes and lungs, was markedly accelerated in both p19 (Arf)- and p53-deficient mice. Thus, p19(Arf) inhibits the growth rate of tumors in a p53-independent manner. Through its regulation of p53, p19(Arf) also suppresses malignant conversion and metastasis. p53 expression was upregulated in papillomas from wild-type but not p19( Arf)-null mice, and p53 mutations were more frequently seen in wild-type than in p19( Arf)-null carcinomas. This indicates that selection for p53 mutations is a direct result of signaling from the initiating oncogenic lesion, Hras, acting through p19(Arf).

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2004

UDP-glucuronosyltransferase and sulfotransferase polymorphisms, sex hormone concentrations, and tumor receptor status in breast cancer patients.

INTRODUCTION: UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes are involved in removing sex hormones from circulation. Polymorphic variation in five UGT and SULT genes - UGT1A1 ((TA)6/(TA)7), UGT2B4 (Asp458Glu), UGT2B7 (His268Tyr), UGT2B15 (Asp85Tyr), and SULT1A1 (Arg213His)--may be associated with circulating sex hormone concentrations, or the risk of an estrogen receptor-negative (ER-) or progesterone receptor-negative (PR-) tumor. METHODS: Logistic regression analysis was used to estimate the odds ratios of an ER- or PR- tumor associated with polymorphisms in the genes listed above for 163 breast cancer patients from a population-based cohort study of women in western Washington. Adjusted geometric mean estradiol, estrone, and testosterone concentrations were calculated within each UGT and SULT genotype for a subpopulation of postmenopausal breast cancer patients not on hormone therapy 2-3 years after diagnosis (n = 89). RESULTS: The variant allele of UGT1A1 was associated with reduced risk of an ER- tumor (P for trend = 0.03), and variants of UGT2B15 and SULT1A1 were associated with non-statistically significant risk reductions. There was some indication that plasma estradiol and testosterone concentrations varied by UGT2B15 and SULT1A1 genotypes; women with the UGT2B15 Asp/Tyr and Tyr/Tyr genotypes had higher concentrations of estradiol than women with the Asp/Asp genotype (P = 0.004). Compared with women with the SULT1A1 Arg/Arg and Arg/His genotypes, women with the His/His genotype had elevated concentrations of testosterone (P = 0.003). CONCLUSIONS: The risk of ER- breast cancer tumors may vary by UGT or SULT genotype. Further, plasma estradiol and testosterone concentrations in breast cancer patients may differ depending on some UGT and SULT genotypes.

Adult↗

PubMed2004

Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomized clinical trial.

Elevated circulating estrogens and a sedentary lifestyle increase risk for breast cancer. The effect of exercise on circulating estrogens in sedentary postmenopausal women is unknown. The objective of this study was to examine the effects of a 12-month moderate-intensity exercise intervention on serum estrogens. We randomly assigned 173 sedentary, overweight (body mass index > 24.0 kg/m(2), body fat > 33%), postmenopausal women, ages 50-75 years, not using hormone therapy, living in the Seattle, Washington, area for the next year, and willing to be randomly assigned to an exercise intervention or stretching control group. The exercise intervention included facility and home-based exercise (45 min, 5 days/week moderate intensity sports/recreational exercise). A total of 170 (98.3%) women completed the study with exercisers averaging 171 min/week of exercise. After 3 months, exercisers experienced declines in estrone, estradiol, and free estradiol of 3.8, 7.7, and 8.2%, respectively, versus no change or increased concentrations in controls (P = 0.03, 0.07, and 0.02, respectively). At 12 months, the direction of effect remained the same, although the differences were no longer statistically significant. The effect was limited to women who lost body fat: women whose percentage of body fat [by dual energy x-ray absortiometry (DEXA)] decreased by >/==" BORDER="0">2% had statistically significant (comparing exercisers versus controls) decreases at 12 months of 11.9, 13.7, and 16.7% for serum estrone, estradiol, and free estradiol, respectively. We concluded that a 12-month moderate-intensity exercise intervention in postmenopausal women resulted in significant decreases in serum estrogens. The association between increased physical activity and reduced risk for postmenopausal breast cancer may be partly explained by effects on serum estrogens.

Aged↗

PubMed2004

TGFbeta1 polymorphism (L10P) and risk of colorectal adenomatous and hyperplastic polyps.

BACKGROUND: Transforming growth factor-beta1 (TGFbeta1) is a multifunctional signalling molecule with a wide array of roles. Animal experiments suggest that TGFbeta1 plays a biphasic role in carcinogenesis by protecting against the early formation of benign epithelial growths, but promoting malignant transformation of those growths that do develop. A polymorphism in the signal peptide sequence of the TGFbeta1 gene (L10P) has been associated with increased levels of plasma TGFbeta1 in individuals with the P allele. METHODS: We investigated whether this polymorphism was associated with the risk of colorectal adenomatous or hyperplastic polyps in a case-control study of individuals from Minnesota. Risk of colorectal polyps was evaluated separately for individuals with adenomatous polyps (n = 513) and hyperplastic polyps (n = 191) relative to polyp-free controls (n = 606) using logistic regression analysis. RESULTS: No overall association was seen between the L10P polymorphism and risk of colorectal adenomatous polyps. The age- and sex-adjusted odds ratios (OR) of developing colorectal hyperplastic polyps were 1.0 (95% CI: 0.7, 1.4) and 0.7 (95% CI: 0.4, 1.1) for individuals with the LP and PP genotypes, respectively, compared with individuals with the LL genotype. When stratified by smoking, evidence for a decreased risk of hyperplastic polyps associated with the P allele was seen only among ever smokers (P for trend = 0.05). CONCLUSIONS: Whereas adenoma risk did not vary by TGFbeta1 L10P genotype, these results suggest that the L10P variant allele may have a protective role in the development of colorectal hyperplastic polyps, possibly consistent with its role as an inhibitor of epithelial growths.

Adenomatous Polyps↗