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Background Relatively little is known about the differences in prognostic factors for early vs late recurrence among women with early stage estrogen receptor–positive breast cancer. Methods We analyzed factors related to early (<5 years) vs late (≥5 years) recurrence in 2992 women with stage I-IIB estrogen receptor–positive breast cancer in the Pathways Study, a prospective cohort of women with breast cancer enrolled between 2006 and 2013, with ascertainment of recurrence and death through December 2021. Results After a median follow-up of 13.3 years, 341 (13.8%) women had recurrences, including 181 (53.7%) with late recurrence. Higher stage and grade were associated with recurrence regardless of timing, whereas progesterone receptor negativity was associated with early but not late recurrence. Receipt of endocrine therapy was associated with reduced risk of overall recurrence, but the length of endocrine therapy was not statistically significant in multivariable models. Minoritized racial and ethnic groups, including Asian, Black, and Hispanic women, had higher risk of early but not late recurrence compared to non-Hispanic White women. The trend of higher risk of early recurrence among these groups remained after adjustment for clinical, demographic, and socioeconomic factors but was statistically significant only in Asian women. Conclusions Our study revealed potentially important distinctions for early vs late recurrence, including the associations with progesterone receptor negativity and self-identified race and ethnicity. Possible higher risk of early recurrence among Asian, Black, and Hispanic women provides novel evidence for the existence of disparities in cancer outcomes, even within the breast cancer subtype indicative of generally good prognosis. [ABSTRACT FROM AUTHOR]

Bladder cancer is primarily diagnosed as non–muscle-invasive bladder cancer (NMIBC), with high recurrence and progression rates. Environmental and occupational exposures to carcinogens are well-known risk factors for developing bladder cancer, yet their effects on prognosis remain unknown. In the Be-Well Study, a population-based prospective cohort study of 1472 Kaiser Permanente patients newly diagnosed with NMIBC in California from 2015 to 2019, we examined history of environmental and occupational exposures in relation to tumor stage and grade at initial diagnosis by multivariable logistic regression, and subsequent recurrence and progression by Cox proportional hazards regression. Exposure to environmental and occupational carcinogens was significantly associated with increased risk of progression (hazard ratio (HR) = 1.79; 95% CI, 1.04-3.09), specifically with increased progression to muscle-invasive disease (HR = 2.28; 95% CI, 1.16-4.50). Exposures to asbestos and arsenic were associated with increased odds of advanced stage at diagnosis (asbestos: odds ratio (OR) = 1.43 [95% CI, 1.11-1.84]; arsenic: OR = 1.27 [95% CI, 1.01-1.63]), and formaldehyde exposure was associated with increased risk of recurrence (HR = 1.38; 95% CI, 1.12-1.69). Our findings suggest that considering a patient's history of these exposures may benefit current risk stratification systems in better tailoring clinical care and improving prognosis among patients with NMIBC. [ABSTRACT FROM AUTHOR]

Although racial/ethnic disparities in health-care access, treatment, and cancer outcomes are well documented, the impact of racial/ethnic discrimination on cancer survivorship is unclear. We examined associations between quality of life (QoL) and self-reported discrimination among 3,991 women with breast cancer recruited during 2006–2013 from the Pathways Study in the Kaiser Permanente Northern California integrated health-care system, using linear regression models. Overall, 31% of women reported experiencing racial/ethnic discrimination, with differences by race/ethnicity (82% among non-Hispanic Black women vs. 19% among non-Hispanic White women) and nativity (40% among foreign-born Hispanic women vs. 76% among US-born Asian-American women). Experiencing racial/ethnic discrimination was associated with lower QoL in fully adjusted models. The mean QoL score was 119.6 (95% confidence interval (CI): 102.0, 137.1) for women who did not report discrimination, 115.5 (95% CI: 98.0, 133.0) for those who reported some discrimination/less than the median level, and 110.2 (95% CI: 92.7, 127.7) for those who reported more discrimination/greater than or equal to the median level. Discrimination was associated with lower QoL among women who used passive coping strategies or lived in neighborhoods with high neighborhood socioeconomic status, neighborhoods with high levels of segregation, or non–ethnic enclaves. Among breast cancer survivors, clinically meaningful differences in QoL scores were associated with racial/ethnic discrimination. Additional studies are needed to understand potential pathways through which these social factors affect survivorship outcomes. [ABSTRACT FROM AUTHOR]

The gamma-ray emission from Starburst and Star-forming Galaxies (SBGs and SFGs) strongly suggests a correlation between star-forming activity and gamma-ray luminosity. However, the very nature of cosmic ray (CR) transport and the degree of their confinement within SBG cores are still open questions. We aim at probing the imprints left by CR transport on gamma-ray and neutrino observations of point-like SFGs and SBGs, looking into quantitative ways to discriminate among different transport models. We analyse the 10-yr Fermi-LAT spectral energy distributions of 13 nearby galaxies with two different CR transport models, taking into account the corresponding IR and UV observations. We also generate mock gamma-ray data to simulate the CTA performance in detecting these sources. In this way, we propose a test to discriminate between the two CR models, quantifying the statistical confidence at which one model can be preferred over the other. We point out that the current data already give a slight preference to CR models that are dominated by advection. Moreover, we show that CTA will allow us to firmly disfavour models dominated by diffusion over self-induced turbulence, compared to advection-dominated models, with Bayes factors, which can be as large as 107 for some of the SBGs. Finally, we estimate the diffuse gamma-ray and neutrino fluxes of SFGs and SBGs, showing that they can explain |$25{{\,\rm per\ cent}}$| of the diffuse HESE data while remaining consistent with gamma-ray limits on non-blazar sources. [ABSTRACT FROM AUTHOR]

Background: Blacks tend to have a stronger inflammatory immune response than Whites. We hypothesized that racial differences in host immunity also manifest in the tumor microenvironment, constituting part of a distinct aggressive tumor biology underlying higher mortality in Black women.Methods: Pathological and gene expression profiling approaches were used for characterizing infiltrating immune cells in breast tumor microenvironment from 1315 patients from the Women's Circle of Health Study. Racial differences in tumor immune phenotypes were compared, with results validated in a publicly accessible dataset. Prognostic associations of immune phenotypes were assessed in 3 independent cohorts.Results: We found marked and consistent differences in tumor immune responses between Black and White patients. Not only did tumors from Blacks display a stronger overall immune presence but also the composition and quality of immune infiltrates differed, regardless of tumor subtypes. Black patients had a stronger CD4+ and B-cell response, and further, a more exhausted CD8+ T-cell profile. A signature indicating a higher ratio of exhausted CD8+ T cells to total CD8+ T cells (ExCD8-r) was consistently associated with poorer survival, particularly among hormone receptor-positive patients. Among hormone receptor-negative patients, combinations of the absolute fraction of CD8+ T cells and ExCD8-r signature identified the CD8lowExCD8-rhigh subgroup, the most prevalent among Blacks, with the worst survival.Conclusions: Our findings of a distinct exhausted CD8+ T-cell signature in Black breast cancer patients indicate an immunobiological basis for their more aggressive disease and a rationale for the use of immune checkpoint inhibitors targeting the exhaustion phenotype. [ABSTRACT FROM AUTHOR]

Starburst galaxies, which are known as 'reservoirs' of high-energy cosmic-rays, can represent an important high-energy neutrino 'factory' contributing to the diffuse neutrino flux observed by IceCube. In this paper, we revisit the constraints affecting the neutrino and gamma-ray hadronuclear emissions from this class of astrophysical objects. In particular, we go beyond the standard prototype-based approach leading to a simple power-law neutrino flux, and investigate a more realistic model based on a data-driven blending of spectral indexes, thereby capturing the observed changes in the properties of individual emitters. We then perform a multi-messenger analysis considering the extragalactic gamma-ray background (EGB) measured by Fermi-LAT and different IceCube data samples: the 7.5-yr high-energy starting events (HESE) and the 6-yr high-energy cascade data. Along with starburst galaxies, we take into account the contributions from blazars and radio galaxies as well as the secondary gamma-rays from electromagnetic cascades. Remarkably, we find that, differently from the highly-constrained prototype scenario, the spectral index blending allows starburst galaxies to account for up to |$40{{\ \rm per\ cent}}$| of the HESE events at |$95.4{{\ \rm per\ cent}}$| CL, while satisfying the limit on the non-blazar EGB component. Moreover, values of |$\mathcal {O}(100\, \mathrm{PeV})$| for the maximal energy of accelerated cosmic-rays by supernovae remnants inside the starburst are disfavoured in our scenario. In broad terms, our analysis points out that a better modelling of astrophysical sources could alleviate the tension between neutrino and gamma-ray data interpretation. [ABSTRACT FROM AUTHOR]

Background: The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies.Methods: Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer.Results: Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer.Conclusions: The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing. [ABSTRACT FROM AUTHOR]

Breast cancer is a heterogeneous disease, characterized by molecularly and phenotypically distinct tumor subtypes, linked to disparate clinical outcomes. American women of African ancestry (AA) are more likely than those of European ancestry (EA) to be diagnosed with aggressive, estrogen receptor negative (ER−) or triple negative breast cancer, and to die of this disease. However, the underlying causes of AA predisposition to ER−/triple negative breast cancer are still largely unknown. In this study, we performed high-throughput whole-genome miRNA expression profiling in breast tissue samples from both AA and EA women. A number of differentially expressed miRNAs, i.e. DEmiRs defined as >2-fold change in expression and false discovery rate <0.05, were identified as up- or downregulated by tumor ER status or by ancestry. We found that among 102 ER-subtype-related DEmiRs identified in breast tumors, the majority of these DEmiRs were race specific, with only 23 DEmiRs shared in tumors from both AAs and EAs; this finding indicates that there are unique subsets of miRNAs differentially expressed between ER− and ER positive tumors within AAs versus EAs. Our overall results support the notion that miRNA expression patterns may differ not only by tumor subtype but by ancestry, indicating differences in tumor biology and heterogeneity of breast cancer between AAs and EAs. These results will provide the basis for further functional analysis to elucidate biological differences between AAs and EAs and to help develop targeted treatment strategies to reduce disparities in breast cancer. [ABSTRACT FROM AUTHOR]

Substantial preclinical data suggest estrogen's carcinogenic role in prostate cancer development; however, epidemiological evidence based on circulating estrogen levels is largely null. Compared with circulating estrogen, the intraprostatic estrogen milieu may play a more important role in prostate carcinogenesis. Using a nested case-control design in the Prostate Cancer Prevention Trial (PCPT), we examined associations of genetic variants of genes that are involved in estrogen synthesis, metabolism and function with prostate cancer risk. A total of 25 potentially functional single nucleotide polymorphisms (SNPs) in 13 genes (PGR, ESR1, ESR2, CYP17A1, HSD17B1, CYP19A1, CYP1A1, CYP1B1, COMT, UGT1A6, UGT1A10, UGT2B7, UGT2B15) were examined in whites only. Controls (n = 1380) were frequency matched to cases on age, PCPT treatment arm, and family history (n = 1506). Logistic regression models adjusted for age and family history were used to estimate odds ratios (OR) and 95% confidence intervals (CI) separately in the placebo and finasteride arms. SNPs associated with prostate cancer risk differed by treatment arm. The associations appeared to be modified by circulating estrogen and androgen levels. CYP19A1 was the only gene harboring SNPs that were significantly associated with risk in both the placebo and finasteride arms. Haplotype analysis with all three CYP19A1 SNPs genotyped (rs700518, rs2445765, rs700519) showed that risk-allele haplotypes are associated with the increased prostate cancer risk in both arms when comparing with the non-risk allele haplotype. In conclusion, associations between SNPs in estrogen-related genes and prostate cancer risk are complex and may be modified by circulating hormone levels and finasteride treatment. [ABSTRACT FROM AUTHOR]

Exposures to carcinogens in hair products have been explored as breast cancer risk factors, yielding equivocal findings. We examined hair product use (hair dyes, chemical relaxers and cholesterol or placenta-containing conditioners) among African American (AA) and White women, and explored associations with breast cancer. Multivariable-adjusted models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to describe the associations of interest among 2280 cases (1508 AA and 772 White) and 2005 controls (1290 AA and 715 White). Among controls, hair dye use was more common among Whites than AAs (58 versus 30%), while relaxer (88 versus 5%) and deep conditioner use (59 versus 6%) was more common among AAs. Among AAs, use of dark hair dye shades was associated with increased breast cancer risk (OR = 1.51, 95% CI: 1.20-1.90) and use of dark shades (OR = 1.72, 95% CI: 1.30-2.26) and higher frequency of use (OR = 1.36, 95% CI: 1.01-1.84) were associated with ER+ disease. Among Whites, relaxer use (OR = 1.74, 95% CI: 1.11-2.74) and dual use of relaxers and hair dyes (OR = 2.40, 95% CI: 1.35-4.27) was associated with breast cancer; use of dark hair dyes was associated with increased ER+ disease (OR = 1.54, 95% CI: 1.01-2.33), and relaxer use was associated with increased ER- disease (OR = 2.56, 95% CI: 1.06-6.16). These novel findings provide support a relationship between the use of some hair products and breast cancer. Further examinations of hair products as important exposures contributing to breast cancer carcinogenesis are necessary. [ABSTRACT FROM AUTHOR]

Objectives: Ki-67 has been proposed to be used as a surrogate marker to differentiate luminal breast carcinomas (BCs). The purpose of this study was to determine the utility of and best approaches for using tissue microarrays (TMAs) and Ki-67 staining to distinguish luminal subtypes in large epidemiology studies of luminal/human epidermal growth factor receptor 2 (HER2)-negative BC.Methods: Full-section and TMA (three 0.6-mm cores and two 1.0-mm cores) slides of 109 cases were stained with Ki-67 antibody. We assessed two ways of collapsing TMA cores: a weighted approach and mitotically active approach.Results: For cases with at least a single 0.6-mm TMA core (n = 107), 16% were misclassified using a mitotically active approach and 11% using a weighted approach. For cases with at least a single 1.0-mm TMA core (n = 101), 5% were misclassified using either approach. For the 0.6-mm core group, there were 33.3% discordant cases. The number of discordant cases increased from 18% in the group of two cores to 40% in the group of three cores (P = .039).Conclusions: Ki-67 tumor heterogeneity was common in luminal/HER2- BC. Using a weighted approach was better than using a mitotically active approach for core to case collapsing. At least a single 1.0-mm core or three 0.6-mm cores are required when designing a study using TMA. [ABSTRACT FROM AUTHOR]

The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. Dysfunction of the Hippo pathway components has been linked with breast cancer stem cell regulation, as well as breast tumor progression and metastasis. TAZ, a key component of the Hippo pathway, is highly expressed in triple negative breast cancer; however, the associations of genetic variations in this important pathway with breast cancer risk remain largely unexplored. Here, we analyzed 8309 germline variants in 15 genes from the Hippo pathway with a total of 3663 cases and 4687 controls from the African American Breast Cancer Epidemiology and Risk Consortium. Odds ratios (ORs) were estimated using logistic regression for overall breast cancer, by estrogen receptor (ER) status (1983 ER positive and 1098 ER negative), and for case-only analyses by ER status. The Hippo signaling pathway was significantly associated with ER-negative breast cancer (pathway level P = 0.02). Gene-based analyses revealed that CDH1 was responsible for the pathway association (P < 0.01), with rs4783673 in CDH1 statistically significant after genelevel adjustment for multiple comparisons (P = 9.2 × 10-5, corrected P = 0.02). rs142697907 in PTPN14 was associated with ER-positive breast cancer and rs2456773 in CDK1 with ER-negativity in case-only analysis after gene-level correction for multiple comparisons (corrected P < 0.05). In conclusion, common genetic variations in the Hippo signaling pathway may contribute to both ER-negative and ER+ breast cancer risk in AA women. [ABSTRACT FROM AUTHOR]

A large percentage of breast cancer heritability remains unaccounted for, and most of the known susceptibility loci have been established in European and Asian populations. Rare variants may contribute to the unexplained heritability of this disease, including in women of African ancestry (AA). We conducted an exome-wide analysis of rare variants in relation to risk of overall and subtype-specific breast cancer in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, which includes data from four large studies of AA women. Genotyping on the Illumina Human Exome Beadchip yielded data for 170 812 SNPs and 8287 subjects: 3629 cases (1093 estrogen receptor negative (ER-), 1968 ER+, 568 ER unknown) and 4658 controls, the largest exome chip study to date for AA breast cancer. Pooled gene-based association analyses were performed using the unified optimal sequence kernel association test (SKAT-O) for variants with minor allele frequency (MAF) ≤ 5%. In addition, each variant with MAF >0.5% was tested for association using logistic regression. There were no significant associations with overall breast cancer. However, a novel gene, FBXL22 (P = 8.2 × 10-6), and a gene previously identified in GWAS of European ancestry populations, PDE4D (P = 1.2 × 10-6), were significantly associated with ER- breast cancer after correction for multiple testing. Cases with the associated rare variants were also negative for progesterone and human epidermal growth factor receptors--thus, triple-negative cancer. Replication is required to confirm these gene-level associations, which are based on very small counts at extremely rare SNPs. [ABSTRACT FROM AUTHOR]

Recent population studies suggest a role of smoking in the etiology of breast cancer, but few have been conducted among African American women. In a collaborative project of four large studies, we examined associations between smoking measures and breast cancer risk by menopause and hormone receptor status [estrogen receptor-positive (ER+), ER-negative (ER-) and triple-negative (ER-, PR-, HER2-)]. The study included 5791 African American women with breast cancer and 17 376 African American controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in multivariable logistic regression analysis with adjustment for study and risk factors. Results differed by menopausal status. Among postmenopausal women, positive associations were observed for long duration and greater pack-years of smoking: relative to never smoking, fully adjusted ORs were 1.14 (95% CI: 1.03-1.26) for duration ≥20 years and 1.16 (95% CI: 1.01-1.33) for ≥20 pack-years. By contrast, inverse associations were observed among premenopausal women, with ORs of 0.80 (95% CI: 0.68-95) for current smoking and 0.81 (95% CI: 0.69-0.96) for former smoking, without trends by duration. Associations among postmenopausal women were somewhat stronger for ER+ breast cancer. The findings suggest that the relation of cigarette smoking to breast cancer risk in African American women may vary by menopausal status and breast cancer subtype. [ABSTRACT FROM AUTHOR]

Background: Use of estrogen with progestin (combination therapy) is associated with increased incidence of estrogen receptor-positive (ER+) breast cancer in observational studies and randomized trials among postmenopausal white women. Whether this is also the case among African American women is not established.Methods: Using data from the AMBER consortium collected from 1993 to 2013, we assessed use of estrogen alone and of combination therapy in relation to ER+ and ER-negative (ER-) breast cancer risk in postmenopausal African American women, based on 1132 ER+ case patients, 512 ER- case patients, and 6693 control patients. Odds ratios (ORs) and confidence intervals (CIs) were estimated using multinomial logistic regression with control for breast cancer risk factors.Results: Forty-seven percent of control patients had used estrogen alone, combination therapy, or both. The odds ratio for ER+ breast cancer associated with combination use, relative to never use of either estrogen alone or combination therapy, was 1.50 (95% CI = 1.25 to 1.79). The increase was greater for recent (OR = 1.55, 95% CI = 1.21 to 1.99) and long-term use (OR = 1.75, 95% CI = 1.13 to 2.73) and among nonobese women (OR = 1.91, 95% CI = 1.29 to 2.83). Breast cancer risk was increased regardless of the interval between onset of menopause and initiation of combination use (OR = 1.43, 95% CI = 1.11 to 1.85, for <5 year interval; OR = 1.78, 95% CI = 1.34 to 2.37, for ≥5 year interval). Combination use was not associated with risk of ER- breast cancer, and use of estrogen alone was not associated with risk of either ER+ or ER- breast cancer.Conclusion: Use of estrogen with progestin increases risk of ER+ breast cancer in African American women. A decrease in use would be expected to reduce the number of ER+ cancers. [ABSTRACT FROM AUTHOR]

The phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin (mTOR) pathway has been implicated in breast carcinogenesis. However, there has been no large-scale investigation of genetic variants in the mTOR pathway and breast cancer risk. We examined 28 847 single-nucleotide polymorphisms (SNPs) in 61 mTOR pathway genes in the African American Breast Cancer Epidemiology and Risk consortium of 3663 cases [1983 estrogen receptor-positive (ER+) and 1098 ER-negative (ER-)] and 4687 controls. Gene-level analyses were conducted using the adaptive rank truncated product (ARTP) test for 10 773 SNPs that were not highly correlated (r2 < 0.8), and SNP-level analyses were conducted with logistic regression. Among genes that were prioritized (nominal P < 0.05, ARTP tests), associations were observed for intronic SNPs TSC2 rs181088346 [odds ratio (OR) of each copy of variant allele = 0.77, 95% confidence interval (CI) = 0.65-0.88 for all breast cancer] and BRAF rs114729114 (OR = 1.53, 95% CI = 1.24-1.91 for all breast cancer and OR = 2.03, 95% CI = 1.50-2.76 for ER- tumors). For ER- tumors, intronic SNPs PGF rs11542848 (OR = 1.38, 95% CI = 1.15-1.66) and rs61759375 (OR = 1.34, 95% CI = 1.14-1.57) and MAPK3 rs78564187 (OR = 1.26, 95% CI = 1.11-1.43) were associated with increased risk. These SNPs were significant at a gene-wide level (Bonferronicorrected P < 0.05). The variant allele of RPS6KB2 rs35363135, a synonymous coding SNP, was more likely to be observed in ER- than ER+ tumors (OR = 1.18, 95% CI = 1.05-1.31, gene-wide Bonferroni-corrected P = 0.06). In conclusion, specific mTOR pathway genes are potentially important to breast cancer risk and to the ER negativity in African American women. [ABSTRACT FROM AUTHOR]

Background: Menarche is a critical time point for diverging fates of mammary cells of origin. African American women have young age at menarche, which could be associated with their high rates of estrogen receptor-negative (ER-) breast cancer.Methods: In the AMBER Consortium, using harmonized data from 4426 African American women with breast cancer and 17 474 controls, we used polytomous logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for ages at menarche and first live birth (FLB), and the interval between, in relation to ER+ and ER- breast cancer. All statistical tests were two-sided.Results: Risk of ER- breast cancer was reduced with later age at menarche among both parous and nulliparous women (≥15 vs <11 years OR = 0.62, 95% CI = 0.48 to 0.81 and OR = 0.56, 95% CI = 0.29 to 1.10, respectively), with no effect of age at FLB. For ER+ breast cancer, the inverse association was weaker among nulliparous women. While longer intervals between menarche and FLB were associated with increased risk of ER+ breast cancer in a dose-response fashion (OR for 20 year interval = 1.39, 95% CI = 1.08 to 1.79, P trend = .003), ER- risk was only increased for intervals up to 14 years and not beyond (P trend = .33).Conclusions: While ER- breast cancer risk was markedly reduced in women with a late age at menarche, there was not a clear pattern of increased risk with longer interval between menarche and FLB, as was observed for ER+ breast cancer. These findings indicate that etiologic pathways involving adolescence and pregnancy may differ for ER- and ER+ breast cancer. [ABSTRACT FROM AUTHOR]

Introduction: Research across the past 4 decades has supported a cross-sectional association between adult cigarette smoking and lower fruit and vegetable consumption (FVC), and emerging research suggests higher FVC may predict cessation. Among youth, findings are limited to a few cross-sectional studies with somewhat mixed results. Here we evaluated the FVC-smoking association among youth both cross-sectionally and longitudinally. Methods: We analyzed data from a subsample of the National Longitudinal Survey of Youth 1979: Child and Young Adult. The subsample included adolescents aged 14-18 years at baseline in the year 2004. Multivariable cross-sectional analyses assessed whether baseline FVC was associated with smoking frequency among ever-smokers (n = 578). Longitudinally, the study assessed whether baseline FVC predicted smoking progression among baseline never-smokers who tried a cigarette by 4-year follow-up (n = 388). Multivariable regression models adjusted for age, gender, race/ethnicity, parental education, and health behavior orientation. Results: Cross-sectionally, youth who consumed fruit ≥2 times per day were 53% less likely (RR = 0.47; p < .05) than those who typically did not consume fruit to be in a higher smoking frequency category. Longitudinally, the fruit consumption and smoking association was not significant (RR = 0.61; p = .282). There were no significant associations observed between vegetable consumption and smoking. Conclusions: Fruit consumption, but not vegetable consumption, was inversely associated with smoking frequency cross-sectionally but not longitudinally. Further research is needed to provide information on the consistency of the FVC-smoking relationship among youth and may help to elucidate possible explanatory mechanisms. [ABSTRACT FROM AUTHOR]

Salt and drought stress severely reduce plant growth and crop productivity worldwide. The identification of genes underlying stress response and tolerance is the subject of intense research in plant biology. Through microarray analyses, we previously identified in potato (Solanum tuberosum) StRGGA, coding for an Arginine Glycine Glycine (RGG) box-containing RNA-binding protein, whose expression was specifically induced in potato cell cultures gradually exposed to osmotic stress. Here, we show that the Arabidopsis (Arabidopsis thaliana) ortholog, AtRGGA, is a functional RNA-binding protein required for a proper response to osmotic stress. AtRGGA gene expression was up-regulated in seedlings after long-term exposure to abscisic acid (ABA) and polyethylene glycol, while treatments with NaCl resulted in AtRGGA down-regulation. AtRGGA promoter analysis showed activity in several tissues, including stomata, the organs controlling transpiration. Fusion of AtRGGA with yellow fluorescent protein indicated that AtRGGA is localized in the cytoplasm and the cytoplasmic perinuclear region. In addition, the rgga knockout mutant was hypersensitive to ABA in root growth and survival tests and to salt stress during germination and at the vegetative stage. AtRGGA-overexpressing plants showed higher tolerance to ABA and salt stress on plates and in soil, accumulating lower levels of proline when exposed to drought stress. Finally, a global analysis of gene expression revealed extensive alterations in the transcriptome under salt stress, including several genes such as ASCORBATE PEROXIDASE2, GLUTATHIONE S-TRANSFERASE TAU9, and several SMALL AUXIN UPREGULATED RNA-like genes showing opposite expression behavior in transgenic and knockout plants. Taken together, our results reveal an important role of AtRGGA in the mechanisms of plant response and adaptation to stress. [ABSTRACT FROM AUTHOR]

Background African American (AA) women have a disproportionately high incidence of estrogen receptor-negative (ER-) breast cancer, a subtype with a largely unexplained etiology. Because childbearing patterns also differ by race/ ethnicity, with higher parity and a lower prevalence of lactation in AA women, we investigated the relation of parity and lactation to risk of specific breast cancer subtypes. Methods Questionnaire data from two cohort and two case-control studies of breast cancer in AA women were combined and harmonized. Case patients were classified as ER+ (n = 2446), ER- (n = 1252), or triple negative (ER-, PR-, HER2-; n = 567) based on pathology data; there were 14 180 control patients. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated in polytomous logistic regression analysis with adjustment for study, age, reproductive and other risk factors. Results ORs for parity relative to nulliparity was 0.92 (95% CI = 0.81 to 1.03) for ER+, 1.33 (95% CI = 1.11 to 1.59) for ER-, and 1.37 (95% CI = 1.06 to 1.70) for triple-negative breast cancer. Lactation was associated with a reduced risk of ER- (OR = 0.81, 95% CI = 0.69 to 0.95) but not ER+ cancer. ER- cancer risk increased with each additional birth in women who had not breastfed, with an OR of 1.68 (95% CI = 1.15 to 2.44) for 4 or more births relative to one birth with lactation. Conclusions The findings suggest that parous women who have not breastfed are at increased risk of ER- and triple-negative breast cancer. Promotion of lactation may be an effective tool for reducing occurrence of the subtypes that contribute disproportionately to breast cancer mortality. [ABSTRACT FROM AUTHOR]

Background: Little is known about the development of posttraumatic stress disorder (PTSD) over time among women diagnosed with breast cancer. This study examines changes in PTSD symptoms in the first 6 months after diagnosis and assesses racial/ethnic differences in PTSD symptomatology over time.Methods: We recruited women with newly diagnosed breast cancer, stages I to III, from three sites in the United States. Three telephone interviews were conducted: baseline at about 2 to 3 months after diagnosis, first follow-up at 4 months after diagnosis, and second follow-up at 6 months after diagnosis. We measured traumatic stress in each interview using the Impact of Events Scale; recorded sociodemographic, tumor, and treatment factors; and used generalized estimating equations and polytomous logistic regression modeling to examine the associations between variables of interest and PTSD.Results: Of 1139 participants, 23% reported symptoms consistent with a diagnosis of PTSD at baseline, 16.5% at first follow-up, and 12.6% at the second follow-up. Persistent PTSD was observed among 12.1% participants, as defined by having PTSD at two consecutive interviews. Among participants without PTSD at baseline, 6.6% developed PTSD at the first follow-up interview. Younger age at diagnosis, being black (odds ratio [OR] = 1.48 vs white, 95% confidence interval [CI] =1.04 to 2.10), and being Asian (OR = 1.69 vs white, 95% CI = 1.10 to 2.59) were associated with PTSD.Conclusions: Nearly one-quarter of women newly diagnosed with breast cancer reported symptoms consistent with PTSD shortly after diagnosis, with increased risk among black and Asian women. Early identification of PTSD may present an opportunity to provide interventions to manage symptoms. [ABSTRACT FROM AUTHOR]

Background Little is known about the development of posttraumatic stress disorder (PTSD) over time among women diagnosed with breast cancer. This study examines changes in PTSD symptoms in the first 6 months after diagnosis and assesses racial/ethnic differences in PTSD symptomatology over time. Methods We recruited women with newly diagnosed breast cancer, stages I to III, from three sites in the United States. Three telephone interviews were conducted: baseline at about 2 to 3 months after diagnosis, first follow-up at 4 months after diagnosis, and second follow-up at 6 months after diagnosis. We measured traumatic stress in each interview using the Impact of Events Scale; recorded sociodemographic, tumor, and treatment factors; and used generalized estimating equations and polytomous logistic regression modeling to examine the associations between variables of interest and PTSD. Results Of 1139 participants, 23% reported symptoms consistent with a diagnosis of PTSD at baseline, 16.5% at first follow-up, and 12.6% at the second follow-up. Persistent PTSD was observed among 12.1% participants, as defined by having PTSD at two consecutive interviews. Among participants without PTSD at baseline, 6.6% developed PTSD at the first follow-up interview. Younger age at diagnosis, being black (odds ratio [OR] = 1.48 vs white, 95% confidence interval [CI] =1.04 to 2.10), and being Asian (OR = 1.69 vs white, 95% CI = 1.10 to 2.59) were associated with PTSD. Conclusions Nearly one-quarter of women newly diagnosed with breast cancer reported symptoms consistent with PTSD shortly after diagnosis, with increased risk among black and Asian women. Early identification of PTSD may present an opportunity to provide interventions to manage symptoms. [ABSTRACT FROM AUTHOR]

The rs2046210 single nucleotide polymorphism (SNP) in the 6q25.1 region was identified in a breast cancer genome-wide association study of Chinese women. The SNP has been replicated in European ancestry populations, but replication efforts have failed in African ancestry populations. We evaluated a total of 13 tagging SNPs in the linkage disequilibrium block around rs2046210 in a case-control study of breast cancer nested within the Black Women’s Health Study, which included 1191 cases and 1941 controls. Replication of initial significant findings was carried out in 665 cases and 821 controls of African ancestry from the Women’s Circle of Health Study (WCHS). No significant association was found for rs2046210 in univariate analysis. A new SNP, rs2046211, was significantly associated with reduced risk of breast cancer and was replicated in data from WCHS. In joint analyses that included both SNPs, the rs2046210-A allele was associated with increased risk of breast cancer [odds ratio (OR) = 1.14; 95% confidence interval (CI) = 1.02–1.28], and the rs2046211-G allele was associated with reduced risk (OR = 0.80; 95% CI = 0.67–0.95). Haplotype analysis confirmed these results and showed that the rs2046210-A allele is present in high-risk (rs2046211-C/rs2046210-A) and low-risk (rs2046211-G/rs2046210-A) haplotypes. Our results confirm the importance of 6q25.1 as a breast cancer susceptibility region. We replicated the rs2046210 association, after accounting for the haplotype background that included rs2046211 in African–American women, and we report the presence of a novel signal that is tagged by rs2046211. [ABSTRACT FROM PUBLISHER]

As the number of cancer survivors continues to grow, research investigating the factors that affect cancer outcomes, such as disease recurrence, risk of second malignant neoplasms, and the late effects of cancer treatments, becomes ever more important. Numerous epidemiologic studies have investigated factors that affect cancer risk, but far fewer have addressed the extent to which demographic, lifestyle, genomic, clinical, and psychosocial factors influence cancer outcomes. To identify research priorities as well as resources and infrastructure needed to advance the field of cancer outcomes and survivorship research, the National Cancer Institute sponsored a workshop titled “Utilizing Data from Cancer Survivor Cohorts: Understanding the Current State of Knowledge and Developing Future Research Priorities” on November 3, 2011, in Washington, DC. This commentary highlights recent findings presented at the workshop, opportunities to leverage existing data, and recommendations for future research, data, and infrastructure needed to address high priority clinical and research questions. Multidisciplinary teams that include epidemiologists, clinicians, biostatisticians, and bioinformaticists will be essential to facilitate future cancer outcome studies focused on improving clinical care of cancer patients, identifying those at high risk of poor outcomes, and implementing effective interventions to ultimately improve the quality and duration of survival. [ABSTRACT FROM PUBLISHER]

Interindividual variations of microRNA expression are likely to influence the expression of microRNA target genes and, therefore, contribute to phenotypic differences in humans, including cancer susceptibility. Whether microRNA expression variation has any role in ovarian cancer development is still unknown. Here, we evaluated microRNA expression profiles in lymphoblastoid cell lines from 74 women with familial ovarian cancer and 47 unrelated controls matched on gender and race. We found that the cases and unrelated controls can be clustered using 95 differentially expressed microRNAs with 91% accuracy. To assess the potential implications of microRNAs in ovarian cancer, we investigated the associations between microRNA expression and seven ovarian cancer risk variants discovered from genome-wide association studies (GWAS), namely, rs3814113 on 9p22.2, rs2072590 on 2q31, rs2665390 on 3q25, rs10088218, rs1516982, rs10098821 on 8q24.21 and rs2363956 on 19p13. We observed 130 significant associations at a permutation level of 0.01. Compared with other risk variants, rs3814113 and rs2072590 had the greatest number of significant associations (68 and 37, respectively). Interestingly, 14 microRNAs that were associated with ovarian cancer risk alleles belong to five microRNA clusters. The most notable cluster is the tumorigenic miR-17-92 cluster with five microRNAs, all of which are significantly associated with rs3814113. Using pathway analysis, several key biological pathways were significantly overrepresented, such as cellular response to stress (P = 2.87 × 10−06), etc. Further characterization of significant associations between microRNAs and risk alleles could facilitate the understanding of the functions of these GWAS discovered risk alleles in the genetic etiology of ovarian cancer. [ABSTRACT FROM AUTHOR]

The etiology of prostate cancer remains elusive, although steroid hormones probably play a role. Considering the carcinogenic potential of estrogen metabolites as well as altered intraprostatic estrogen biosynthesis during the development of prostate cancer, we investigated associations between repeat polymorphisms of three key estrogen-related genes (CYP11A1, CYP19A1, UGT1A1) and risk of prostate cancer in the Prostate Cancer Prevention Trial (PCPT), designed to test finasteride versus placebo as a chemoprevention agent. Using data and specimens from 1154 cases and 1351 controls who were frequency matched on age, family history of prostate cancer and PCPT treatment arm, we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) separately in the placebo and finasteride arms. Among men in the placebo arm, CYP19A1 7/8 genotype carriers had a significantly higher risk of prostate cancer compared with those with the 7/7 genotype (OR = 1.70, 95% CI = 1.16–2.5), regardless of Gleason grade. This genotype was also associated with elevated serum estrogen levels. For the (TA)n repeat polymorphism in UGT1A1, the heterozygous short (<7 repeats)/long (≥7 repeats) genotype was significantly associated with the risk of low-grade prostate cancer (OR = 1.34, 95% CI = 1.05–1.70) compared with the short/short genotype. No significant association was found with CYP11A1. These associations were not observed among men in the finasteride arm. The results indicate that repeat polymorphisms in genes involved in estrogen biosynthesis and metabolism may influence risk of prostate cancer but that their effects may be modified by factors altering hormone metabolism, such as finasteride treatment. [ABSTRACT FROM AUTHOR]

Base excision repair (BER) and nucleotide excision repair (NER) pathways repair damaged DNA, and polymorphisms in these genes might affect breast cancer susceptibility. We evaluated associations between seven single-nucleotide polymorphisms in four DNA repair genes (ERCC4 rs1799801, XPC rs2227998, rs2228001, rs2228000, OGG1 rs1052133 and XRCC1 rs25487 and rs25486) and breast cancer risk, examining modification by smoking and alcohol consumption, using data from the Western New York Exposures and Breast Cancer Study. Women aged 35–79 years with incident breast cancer (n = 1170) and age- and race-matched controls (n = 2115) were enrolled. Genotyping was performed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). No significant associations were observed in premenopausal women. Among postmenopausal women, rs25487 and rs25486 (OR = 1.24; 95% CI 1.01–1.51 and OR = 1.23; 95% CI 1.01–1.49, respectively, for combined heterozygous and homozygous variant compared with reference) were associated with increased risk of breast cancer. Postmenopausal women carrying the variant allele of the synonymous XPC polymorphism (rs2227998) were also at borderline significantly increased risk (OR = 1.24; 95% CI 1.01–1.52, heterozygous variant compared with reference; OR = 1.22; 95% CI 1.01–1.48, for combined heterozygous and homozygous variant compared with reference). There was no evidence of genotype–smoking and genotype–alcohol consumption interactions for pre- and postmenopausal women. These results indicate that some of the variants in BER and NER genes may influence risk of postmenopausal breast cancer. [ABSTRACT FROM AUTHOR]

Background: Global DNA hypomethylation may result in chromosomal instability and oncogene activation, and as a surrogate of systemic methylation activity, may be associated with breast cancer risk. Methods: Samples and data were obtained from women with incident early-stage breast cancer (I–IIIa) and women who were cancer free, frequency matched on age and race. In preliminary analyses, genomic methylation of leukocyte DNA was determined by measuring 5-methyldeoxycytosine (5-mdC), as well as methylation analysis of the LINE-1-repetitive DNA element. Further analyses used only 5-mdC levels. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of breast cancer in relation to amounts of methylation. Results: In a subset of samples tested (n = 37), 5-mdC level was not correlated with LINE-1 methylation. 5-mdC level in leukocyte DNA was significantly lower in breast cancer cases than healthy controls (P = 0.001), but no significant case–control differences were observed with LINE-1 methylation (P = 0.176). In the entire data set, we noted significant differences in 5-mdC levels in leukocytes between cases (n = 176) and controls (n = 173); P value < 0.001. Compared with women in the highest 5-mdC tertile (T3), women in the second (T2; OR = 1.49, 95% CI = 0.84–2.65) and lowest tertile (T1; OR = 2.86, 95% CI = 1.65–4.94) had higher risk of breast cancer (P for trend ≤0.001). Among controls only and cases and controls combined, only alcohol intake was found to be inversely associated with methylation levels. Conclusion: These findings suggest that leukocyte DNA hypomethylation is independently associated with development of breast cancer. [ABSTRACT FROM PUBLISHER]

Myeloperoxidase, an antimicrobial enzyme, produces oxidative free radicals. Rarely found in normal brain tissue, myeloperoxidase has been detected in microglia associated with Alzheimer's disease plaques. The authors examined a G-463A polymorphism in the promoter region of the myeloperoxidase gene (MPO) to determine the relation of MPO variants to cognitive decline over 4 years in a cohort of adults, aged 70–79 years at baseline (1997–1998), recruited from Memphis, Tennessee, and Pittsburgh, Pennsylvania, into the Health, Aging, and Body Composition Study. In this sample, 8% of the participants had the AA, 36.9% the AG, and 55.2% the GG genotype of MPO. The frequency of AA and AG genotypes was higher in Blacks than Whites (11.2% vs. 5.9%, and 44.1% vs. 32.9%, respectively). Multivariate logistic regression analyses showed that, for participants with the MPO AA genotype, cognitive decline was 1.58 (95% confidence interval: 1.07, 2.35) times more likely than for participants with the AG genotype and 1.96 (95% confidence interval: 1.33, 2.88) times more likely than for those with the GG genotype. Interactions between MPO and race, sex, or the apolipoprotein gene were not significant. In this sample, MPO AA, associated with decreased production of myeloperoxidase, was found to be a risk factor for cognitive decline. [ABSTRACT FROM AUTHOR]

Observed weak or null associations between fruit and vegetable intake and breast cancer risk could be due to heterogeneity in endogenous antioxidant capabilities. The authors evaluated potential relations between a functional polymorphism in catalase, an antioxidant enzyme, and breast cancer risk, particularly in relation to fruit and vegetable intake and supplement use. Women (1,008 cases and 1,056 controls) in the Long Island Breast Cancer Study Project (1996–1997) were interviewed, completed a food frequency questionnaire, and provided blood for genotyping. The high-activity catalase CC genotype was associated with an overall 17% reduction in risk of breast cancer compared with having at least one variant T allele (odds ratio = 0.83, 95% confidence interval: 0.69, 1.00). Vegetable and, particularly, fruit consumption contributed to the decreased risk associated with the catalase CC genotype. Associations were more pronounced among women who did not use vitamin supplements, with a significant multiplicative interaction (pinteraction = 0.02) for the CC genotype and high fruit intake (odds ratio = 0.59, 95% confidence interval: 0.38, 0.89), and there was no association among supplement users. These results indicate the importance of diet, rather than supplement use, in concert with endogenous antioxidant capabilities, in the reduction of breast cancer risk. CC genotypes were prevalent in approximately 64% of controls; thus, the preventive potential for fruit consumption has widespread implications. [ABSTRACT FROM AUTHOR]

Relationships between dietary components and cancer risk are often unclear, and the results from epidemiologic studies are inconsistent. While some inconsistencies could be due to study design issues, we propose that genetic heterogeneity of study populations could mask associations. In this report, we review the literature regarding meat consumption and risk of colon, breast, and prostate cancers, particularly in relation to phenotypes and genotypes for enzymes that metabolize food-borne promutagens. The role of consumption of fruits and vegetables, as well as the role of genetic variants in oxidative stress genes, in the risk of breast cancer are also discussed. [ABSTRACT FROM AUTHOR]

STK15 is considered a potential cancer susceptibility gene owing to its functions in normal cell mitosis. Two common coding region polymorphisms in the gene (F31I and V57I) may affect ubiquitin-dependent degradation and thus the half-life of the encoded protein. There are limited data on the relevance of these polymorphisms to population cancer rates. To examine whether functional variation in STK15 may affect breast cancer risk, we genotyped a large series of incident breast cancer cases (n = 941) and age-matched population controls (n = 830) for the F31I and V57I polymorphisms. Individually, neither the F31I polymorphism [odds ratio (OR) 1.54; 95% confidence interval (CI) 0.962.47, comparing 31I with 31F homozygotes] nor the V57I polymorphism (OR 0.92; 95% CI 0.501.71, comparing 57I with 57V homozygotes) was significantly associated with breast cancer risk. A relatively common genotype, combining the two polymorphisms (31I-57V/31I-57V, 3% of controls) was related to a significant 2-fold increase in the risk of post-menopausal breast cancer (OR 1.96; 95% CI 1.013.79). No interaction was detected between STK15 variants and estrogenic risk factors, although the power of these analyses was limited. These results suggest that STK15 may represent a low penetrance type breast cancer susceptibility gene. [ABSTRACT FROM AUTHOR]

There is evidence linking alcohol consumption to p53 mutations in tumors, considerable evidence linking alcohol consumption with risk of breast cancer and some evidence that alcohol and folate consumption interact to affect risk. Further, while there is some indication that oxidation may play a role in breast cancer etiology, there has been little examination of an association of oxidative stress with p53 mutations. We examined several dietary components related to one-carbon metabolism and antioxidants to determine if these factors were related to the prevalence of p53 mutations in breast tumors. We conducted a case-control study of primary, histologically confirmed breast cancer in western New York. Controls <65 were selected from drivers license lists; those ≥65 were selected from Health Care Finance Administration lists. p53 mutations in archived tumor blocks were identified in exons 2–11 and flanking intron sequences. Usual dietary intake was assessed by interview regarding intake in the previous 2 years; alcohol consumption was queried for 2, 10 and 20 years in the past. Our data were consistent with increased likelihood of tumors with p53 mutations for premenopausal breast cancer with increased alcohol intake 10 or 20 years previous; for intake of 16 or more drinks per month in the period 20 years before the interview compared with non-drinkers, the OR was 5.25, 95% CI 1.48–18.58. For postmenopausal women, there was increased likelihood of tumors with p53 mutations among women with higher folate. Antioxidant nutrients were not differentially related to p53 mutations. These results indicate that there may be heterogeneity in breast tumors, as indicated by differences in associations for those with or without p53 mutations, and that causal pathways for these nutrients may vary for pre- and postmenopausal women. For premenopausal women, alcohol consumption in the past was associated with p53 mutations. [ABSTRACT FROM AUTHOR]

Background: Human sulfotransferase 1A1 (SULT1A1) catalyzes the sulfation of a variety of phenolic and estrogenic compounds, including 4-hydroxytamoxifen (4-OH TAM), the active metabolite of tamoxifen. A functional polymorphism in exon 7 of the SULT1A1 gene (SULT1A1*2) has been described that generates an enzyme that has approximately twofold lower activity and is less thermostable than that of the common allele SULT1A1*1. We investigated the hypothesis that that high sulfation activity would increase the elimination of 4-OH TAM by examining whether the presence of this polymorphism affects the efficacy of tamoxifen therapy.Methods: We examined the relationship between the SULT1A1*2 allele and survival in a cohort of 337 women with breast cancer who received tamoxifen (n = 160) or who did not (n = 177). SULT1A1 genotype was determined by restriction fragment polymorphism analysis. Patient survival was evaluated according to SULT1A1 genotype using Kaplan-Meier survival functions. Hazard ratios (HRs) were calculated from adjusted Cox proportional hazards modeling. All statistical tests were two-sided.Results: Among tamoxifen-treated patients, those who were homozygous for the SULT1A1*2 low-activity allele had approximately three times the risk of death (HR = 2.9, 95% confidence interval [CI] = 1.1 to 7.6) as those who were homozygous for the common allele or those who were heterozygous (SULT1A1*1/*2). Among patients who did not receive tamoxifen, there was no association between survival and SULT1A1 genotype (HR = 0.7, 95% CI = 0.3 to 1.5).Conclusions: Sulfation of 4-OH TAM provides a previously unanticipated benefit, possibly due to alterations in the bioavailability of the active metabolite or to undefined estrogen receptor-mediated events. These data alternatively suggest that variability in the metabolism of tamoxifen may affect its efficacy. [ABSTRACT FROM AUTHOR]

Evaluates molecular epidemiology of genetic polymorphisms in estrogen metabolizing enzymes in human breast cancer. Genetic polymorphism in estrogen bioformation; Molecular epidemiology of hormonal carcinogenesis; Associations between breast cancer and CYP1A1.

Carcinogen–DNA adducts may represent an intermediate end-point in the carcinogenic cascade and may reflect exposure to chemical carcinogens, as well as susceptibility and, ultimately, cancer risk. Interindividual variability in activity of enzymes involved in the metabolism of polycyclic aromatic hydrocarbons to mutagenic diol epoxides may predict adduct levels and, indirectly, lung cancer risk. Using 32P-postlabeling methods, the levels of bulky DNA adducts were determined in macroscopically normal bronchial tissues obtained from resected lobes of 143 Hungarian patients with lung malignancy and other pulmonary conditions. DNA from normal tissue was also evaluated for polymorphisms in cytochrome P450 2C9 (CYP2C9) at two sites, codons 144 (Arg/Cys) and 359 (Ile/Leu), for glutathione S-transferase P1 (GSTP1) at codon 105 and for NAD(P)H:quinone oxidoreductase (NQO1) at codon 187 (Pro/Ser). Using the Mann–Whitney U-test and analysis of variance, levels of adducts were evaluated in relation to variant genotypes, separately for smokers and non-smokers. As previously reported, bulky DNA adduct levels in smokers (n = 104) were estimated to be 54% higher than in non-smokers (n = 39) (8.6 ± 4.2 versus 5.6 ± 3.3 per 108 nucleotides, respectively, P < 0.01). Adduct levels were 16–29% higher in individuals with the homozygous Ile359/Ile359 CYP2C9 allele than in those heterozygous for the variant allele (Ile359/Leu359) [8.8 ± 4.3 (n = 84) versus 7.6 ± 3.5 (n = 20) for smokers and 5.8 ± 3.5 (n = 32) versus 4.5 ± 1.3 (n = 7) for non-smokers], although differences were not statistically significant. There were no clear differences in adduct levels in relation to genotypes of NQO1 or GSTP1. Although numbers of patients in this study are large in relation to many studies of carcinogen–DNA adducts, it is still possible that significant differences were not noted for polymorphisms in xenobiotic metabolizing enzymes due to relatively small numbers in stratified data. [ABSTRACT FROM PUBLISHER]

The emergence of “molecular epidemiology” as a scientific approach within the fields of epidemiology and toxicology has led to spirited discussion within the biomedical community, particularly in the area of cancer research. At scientific meetings and in peer-reviewed journals, numerous issues have been raised not only with regard to the practice of molecular epidemiology, but also with regard to its role in traditional epidemiology, toxicology, and risk assessment. Furthermore, the utility of information gleaned from such studies and the implications for public heafth have been the subject of considerable debate. Conceptual differences in how one views the function of epidemiologic and laboratory research may be reflected in discussions on the merits of molecular epidemiology. This commentary reviews some of the prevailing attitudes toward molecular epidemiology, with the goal of identifying areas of concern and suggesting means of achieving harmonization. The need for cross-training of epidemiologists and laboratory scientists is discussed, and suggestions are made for building successful collaborative relations across disciplines. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy-induced peripheral neuropathy (CIPN) can interfere with daily function and quality of life, and there are no known preventive approaches. In a cohort of breast cancer patients receiving paclitaxel as part of a clinical trial (SWOG 0221), we examined the use of dietary supplements both before diagnosis and during treatment in relation to CIPN.Methods: At registration to S0221, 1225 breast cancer patients completed questionnaires regarding the use of multivitamins and supplements before and at diagnosis. A second questionnaire at six months queried use during treatment. Supplement use was evaluated in relation to CIPN, assessed via the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v. 3.0) and the self-reported Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) subscale. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed with logistic regression for the CTCAE analyses and ordinal regression for the FACT/GOG-Ntx analyses.Results: Multivitamin use before diagnosis was associated with reduced symptoms of CIPN (CTCAE-adjusted OR = 0.60, 95% CI = 0.42 to 0.87; FACT/GOG-Ntx-adjusted OR = 0.78, 95% CI = 0.61 to 1.00). Use during treatment was marginally inversely associated with CIPN (CTCAE-adjusted OR = 0.73, 95% CI = 0.49 to 1.08; FACT/GOG-Ntx-adjusted OR = 0.77, 95% CI = 0.60 to 0.99). Other supplement use, either before diagnosis or during treatment, was not statistically significantly associated with CIPN.Conclusions: Multivitamin use may be associated with reduced risk of CIPN, although individual dietary supplement use did not appreciably affect risk. Multivitamin use could be a surrogate for other related behaviors that are the actual drivers of the association with reduced CIPN. Without prospective randomized trials of vitamin supplementation, recommendations for use or changes to clinical practice are clearly not warranted. [ABSTRACT FROM AUTHOR]

Summary: The Illumina Infinium HumanMethylation450 BeadChip is a newly designed high-density microarray for quantifying the methylation level of over 450 000 CpG sites within human genome. Illumina Methylation Analyzer (IMA) is a computational package designed to automate the pipeline for exploratory analysis and summarization of site-level and region-level methylation changes in epigenetic studies utilizing the 450K DNA methylation microarray. The pipeline loads the data from Illumina platform and provides user-customized functions commonly required to perform exploratory methylation analysis for individual sites as well as annotated regions.Availability: IMA is implemented in the R language and is freely available from http://www.rforge.net/IMA.Contact: song.liu@roswellpark.org [ABSTRACT FROM AUTHOR]