Search

BackgroundInterstitial lung abnormalities (ILA) share many features with idiopathic pulmonary fibrosis; however, it is not known if ILA are associated with decreased mean telomere length (MTL).MethodsTelomere length was measured with quantitative PCR in the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) and Age Gene/Environment Susceptibility Reykjavik (AGES-Reykjavik) cohorts and Southern blot analysis was used in the Framingham Heart Study (FHS). Logistic and linear regression were used to assess the association between ILA and MTL; Cox proportional hazards models were used to assess the association between MTL and mortality.ResultsIn all three cohorts, ILA were associated with decreased MTL. In the COPDGene and AGES-Reykjavik cohorts, after adjustment there was greater than twofold increase in the odds of ILA when comparing the shortest quartile of telomere length to the longest quartile (OR 2.2, 95% CI 1.5–3.4, p=0.0001, and OR 2.6, 95% CI 1.4–4.9, p=0.003, respectively). In the FHS, those with ILA had shorter telomeres than those without ILA (−767 bp, 95% CI 76–1584 bp, p=0.03). Although decreased MTL was associated with chronic obstructive pulmonary disease (OR 1.3, 95% CI 1.1–1.6, p=0.01) in COPDGene, the effect estimate was less than that noted with ILA. There was no consistent association between MTL and risk of death when comparing the shortest quartile of telomere length in COPDGene and AGES-Reykjavik (HR 0.82, 95% CI 0.4–1.7, p=0.6, and HR 1.2, 95% CI 0.6–2.2, p=0.5, respectively).ConclusionILA are associated with decreased MTL.

Background Biomass fuels are still in use for cooking by many households in resource poor countries such as Nepal and is a major source of household air pollution (HAP). Chronic exposure to HAP has been shown to be associated with shorter telomere length in adults. Objectives To measure the association between exposure related to household biomass fuel in infancy and leukocyte telomere length (LTL) at 18–23 months of age among 497 children from Bhaktapur, Nepal. Methods In a prospective cohort study design, we have collected information on household cooking fuel use and several clinical, anthropometric, demographic, and socioeconomic variables. We estimated the association between biomass fuel use and the relative LTL in multiple linear regression models. Results Most of the families (78%) reported liquified petroleum gas (LPG) as the primary cooking fuel, and 18.7% used biomass. The mean relative (SD) LTL was 1.03 (0.19). Children living in households using biomass fuel had on average 0.09 (95% CI: 0.05 to 0.13) units shorter LTL than children in households with no biomass fuel use. The observed association was unaltered after adjusting for relevant confounders. The association between LTL and biomass use was strongest among children from households with ≤2 rooms and without separate kitchen. Significance Exposure to biomass fuel use in early life might have consequences for longevity, and risk of chronic illnesses reflected in shortening of the telomeres. Our findings support the ongoing effort to reduce exposure to biomass fuel in low-resource settings. Impact statements Biomass for cooking is a leading source of household air pollution in low and middle-income countries, contributing to many chronic diseases and premature deaths. Chronic exposure to biomass fuel through oxidative stress and inflammation has been associated with a shortening of the telomeres, a “biological marker” of longevity. This prospective cohort study describes the association between household biomass fuel use and leukocyte telomere length among 497 toddlers. Leukocyte telomere length was significantly shorter among children living in households with biomass fuel than in children from homes where mainly LPG was used for cooking. Clinical Trial registration Clinicaltrials.gov: NCT02272842, registered October 21, 2014, Universal Trial Number: U1111-1161-5187 (September 8, 2014)

Background Telomeres cap and protect DNA but shorten with each somatic cell division. Aging and environmental and lifestyle factors contribute to the speed of telomere attrition. Current evidence suggests a link between relative telomere length (RTL) and depression but the directionality of the relationship remains unclear. We prospectively examined associations between RTL and subsequent depressive symptom trajectories. Methods Among 8,801 women of the Nurses' Health Study, depressive symptoms were measured every 4 years from 1992 to 2012; group-based trajectories of symptoms were identified using latent class growth-curve analysis. Multinomial logistic models were used to relate midlife RTLs to the probabilities of assignment to subsequent depressive symptom trajectory groups. Results We identified four depressive symptom trajectory groups: minimal depressive symptoms (62%), worsening depressive symptoms (14%), improving depressive symptoms (19%), and persistent-severe depressive symptoms (5%). Longer midlife RTLs were related to significantly lower odds of being in the worsening symptoms trajectory versus minimal trajectory but not to other trajectories. In comparison with being in the minimal symptoms group, the multivariable-adjusted odds ratio of being in the worsening depressive symptoms group was 0.78 (95% confidence interval, 0.62-0.97; p = 0.02), for every standard deviation increase in baseline RTL. Conclusions In this large prospective study of generally healthy women, longer telomeres at midlife were associated with significantly lower risk of a subsequent trajectory of worsening mood symptoms over 20 years. The results raise the possibility of telomere shortening as a novel contributing factor to late-life depression.

Introduction Accelerated biological aging is related to worse brain aging. However, the interface of Alzheimer's Disease (AD) and the biology of aging is little understood. The study of epigenetics and epigenetic aging may yield advances in prevention and treatment of AD by identifying new therapeutic targets or approaches. Further, signals from epigenetic measures may provide novel mechanistic links between neuropsychiatric symptoms (NPS) and cognitive outcomes in aging; NPS are highly prevalent in Alzheimer's Disease and related dementia (ADRD) and even appear in pre-clinical and early stages. Methods We included 45 adults aged 60+ years who are participants in a depression prevention ancillary study (VITAL-DEP) to the VITamin D and OmegA-3 TriaL, a randomized trial of fish oil and vitamin D supplements. We identified the presence of NPS using established behavioral measures. Neuropsychiatric Inventory (NPI) severity scores were mapped from dozens of item-level NPS variables extracted from mood and anxiety questionnaires and structured psychiatric diagnostic interviews in the VITAL-DEP protocol. We defined 3 groups based on cognitive status: normal cognition with or without NPS (n=20), and mild cognitive impairment (MCI) with or without NPS (n=25). Genomic DNA was extracted from leukocytes, and DNA methylation was assayed using Illumina Infinium MethylationEPIC BeadArray technology (Methyl850K chip) at baseline and year-2 follow-up. Epigenetic aging metrics [DNA methylation age (DNAmAge), AgeAccel, DNAmGrimAge, DNAmPhenoAge] were computed using the DNA epigenetic clock - Horvath method. Results The mean age of participants was 69.8 (range=60.3-83.4) years; percentages of who were females=48.9% and with post-graduate education=62.2%. In preliminary analysis , epigenetic measures were significantly correlated with chronological age (Spearman correlation (rho): for DNAmAge=0.51, p Conclusions Our preliminary results suggest that accelerated biological aging may be related to cognitive and neuropsychiatric phenotypes.

Study Design: Cross-sectional study Objectives: To determine clinical factors associated with telomere length in persons with chronic spinal cord injury (SCI). Setting: Veterans Affairs Medical Center, Boston, MA. Methods: 278 participants with chronic SCI provided blood samples for measurement of C-reactive protein (CRP), interleukin-6 (IL-6), and telomere length, completed respiratory health questionnaires, underwent dual x-ray absorptiometry (DXA) to assess body fat, and completed spirometry. High-throughput real-time PCR assays were used to assess telomere length in leukocyte genomic DNA. Linear regression models were used to assess cross-sectional associations with telomere length. Results: Telomere length was inversely related to age (p

Purpose Telomere length is considered a biomarker of human aging and premature morbidity and mortality which has been associated with chronic stress. Methods We assessed the relation between perceived racism and telomere length in the Black Women's Health Study, a follow-up study of U.S. black women begun in 1995. Participants were asked about frequency of “everyday racism” (e.g., “people act as if they think you are not intelligent”) and “institutional racism” (e.g., “ever treated unfairly due to race by police”). Using quantitative real-time polymerase chain reaction assay, relative telomere lengths (RTL) were measured as the copy number ratio of telomere repeat to a single control gene in 997 participants. Associations of racism variables with log-RTL were estimated by multivariable linear regression, with adjustment for age at blood draw and potential confounders. Results Participants were aged 40–70 years (mean = 55.6 years), and mean telomere length was 0.77 (range 0.21–1.38). In stratified analyses, there was an inverse association between everyday racism and log-RTL among women who did not discuss their experiences of racism with others (β = −0.1104; 95% CI = −0.2140 to −0.0067; P = .045). Conclusions Everyday racism was associated with shorter telomere length among women who reported not discussing those experiences with others.

RationaleShorter leukocyte telomere length (LTL) is associated with reduced health-related quality of life and increased risk for acute exacerbations (AEs) and mortality in chronic obstructive pulmonary disease (COPD). Increased physical activity and exercise capacity are associated with reduced risk for AEs and death. However, the relationships between LTL and physical activity, exercise capacity, and AEs in COPD are unknown.MethodsData from 3 COPD cohorts were examined: Cohort 1 (n = 112, physical activity intervention trial), Cohorts 2 and 3 (n = 182 and 294, respectively, separate observational studies). Subjects completed a 6-minute walk test (6MWT) and provided blood for LTL assessment using real-time PCR. Physical activity was measured as average daily step count using an accelerometer or pedometer. Number of self-reported AEs was available for 1) the year prior to enrollment (Cohorts 1 and 3) and 2) prospectively after enrollment (all cohorts). Multivariate models examined associations between LTL and average daily step count, 6MWT distance, and AEs.ResultsA significant association between longer LTL and increased 6MWT distance was observed in the three combined cohorts (β = 3x10-5, p = 0.045). No association between LTL and average daily step count was observed. Shorter LTL was associated with an increased number of AEs in the year prior to enrollment (Cohorts 1 and 3 combined, β = -1.93, p = 0.04) and with prospective AEs (Cohort 3, β = -1.3388, p = 0.0003).ConclusionsAmong COPD patients, increased LTL is associated with higher exercise capacity, but not physical activity. Shorter LTL was associated with AEs in a subgroup of cohorts.

IntroductionWe examined whether abuse in childhood and/or adolescence was associated with shorter telomere length in a pooled analysis of 3,232 participants from five diverse cohorts. We also assessed whether religion or spirituality (R/S) could buffer deleterious effects of abuse.MethodsPhysical and sexual abuse in childhood (age ResultsCompared to no abuse, severe sexual abuse was associated with lower RTL z-scores, in childhood: -15.6%, 95% CI: -25.9, -4.9; p-trend = 0.04; p-heterogeneity = 0.58 and in adolescence: -16.5%, 95% CI: -28.1, -3.0; p-trend = 0.08; p-heterogeneity = 0.68. Sexual abuse experienced in both childhood and adolescence was associated with 11.3% lower RTL z-scores after adjustment for childhood and demographic covariates (95% CI: -20.5%, -2.0%; p-trend = 0.03; p-heterogeneity = 0.62). There was no evidence of effect modification by R/S. Physical abuse was not associated with telomere length.ConclusionsSexual abuse in childhood or adolescence was associated with a marker of accelerated biological aging, decreased telomere length. The lack of moderation by R/S may be due to inability to capture the appropriate time period for those beliefs and practices.

International audience; Observational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry. Five BMI SNPs were associated with VTE at P < 0.05, with the strongest association seen for the FTO SNP rs1558902 (OR 1.07, 95% CI 1.02–1.12, P = 0.005). In addition, we observed a significant association between genetically predicted BMI and VTE (OR = 1.59, 95% CI 1.30–1.93 per standard deviation increase in BMI, P = 5.8 × 10−6). Our study provides evidence for a causal relationship between high BMI and risk of VTE. Reducing obesity levels will likely result in lower incidence in VTE.

In 2018, approximately 55,440 individuals were diagnosed with pancreatic cancer in the US, and only 8% of these individuals will survive the next five years. Given the high fatality rate of pancreatic ductal adenocarcinoma, and the silent progression of this cancer, identifying early detection biomarkers for risk stratification for screening and surveillance is critical to improve prognosis. While the immune response plays a critical role in tumor growth and survival, understanding its role in the development of cancer has been hampered by the lack of data on immune status prior to cancer diagnosis. The identification of DNA methylation markers to estimate immune cell proportions in archived bloods provides a method to examine the long-term impact of immune cell types on pancreatic cancer risk. For this study, we included pre-diagnostic bloods from 322 pancreatic cancer cases and 343 controls (matched on age, race, sex, date of blood draw) from three independent prospective cohort studies to examine associations with immune cell proportions based on validated differentially methylated regions (DMRs) of cell lineage. DNA methylation from archived buffy coat samples for the cases and controls was measured using Illumina’s Infinium MethylationEPIC array; the range of time of blood draw to cancer diagnosis in cancer patients was 6 months to 26 years. We examined associations with pancreatic cancer for the methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) and the ratio of CD4/CD8 cell types. The NLR has been linked to pancreatic cancer prognosis in several studies but has never been examined as a risk factor for incidence of pancreatic cancer (i.e., using blood drawn prior to cancer diagnosis). The CD4/CD8 ratio reflects the overall balance of T helper cells to cytotoxic T cells which is known to play a role in cancer immune surveillance in the tumor environment, and it may be associated with risk prior to diagnosis. In this nested case-control study, mdNLR was not associated the risk of pancreatic cancer (conditional OR = 1.19, 95% CI = 0.81 to 1.75, comparing top to bottom tertiles of mdNLR, additionally adjusting for smoking status). Furthermore, the association did not vary by sex or by time between blood draw and cancer diagnosis (< 5 years, OR = 1.18; 5-10 years, OR = 1.22; >10 years, OR =1.21). Similarly, we observed no association for the CD4/CD8 ratio and pancreatic cancer risk (OR = 0.94, 95% CI = 0.63 to 1.41) overall, or by time between blood draw and cancer diagnosis (< 5 years, OR = 0.97; 5-10 years, OR = 0.62; >10 years, OR =1.17). Our findings suggest that while the mdNLR may provide valuable information on prognosis after diagnosis of pancreatic cancer, a higher mdNLR in healthy individuals did not increase the risk of developing pancreatic cancer. In addition, prediagnostic CD4/CD8 ratio was not associated with pancreatic cancer risk. Further work examining additional immune cell type subfractions is currently underway. Citation Format: Dominique S. Michaud, Mengyuan Ruan, Devin Koestler, Dong Pei, Carmen Marsit, Immaculata DeVivo, Karl Kelsey. Immune cell proportions and risk of pancreatic cancer using prediagnostic bloods [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-195.

Background: Coffee has been reported to lower levels of estrogen and insulin, two hormones implicated in endometrial carcinogenesis, but prospective data on the relation between coffee consumption and risk of endometrial cancer are limited. Methods: We prospectively assessed coffee consumption in relation to endometrial cancer risk in the Nurses' Health Study (NHS) with 67,470 female participants aged 34 to 59 in 1980. Cumulative average coffee intake was calculated with all available questionnaires to assess long-term effects. Cox regression models were used to calculate incidence rate ratios (RR), controlling for other risk factors. Results: Fewer than 4 cups of coffee per day were not associated with endometrial cancer risk. However, women who consumed 4 or more cups of coffee had 25% lower risk of endometrial cancer than those who consumed less than 1 cup per day (multivariable RR = 0.75; 95% CI = 0.57–0.97; Ptrend = 0.02). We found the similar association with caffeinated coffee consumption (RR for ≥4 vs. Conclusions: These prospective data suggest that four or more cups of coffee per day are associated with a lower risk of endometrial cancer. Impact: Drinking of coffee, given its widespread consumption, might be an additional strategy to reduce endometrial cancer risk. However, addition of substantial sugar and cream to coffee could offset any potential benefits. Cancer Epidemiol Biomarkers Prev; 20(12); 2487–95. ©2011 AACR.

Apoptosis is important for targeting cancer cells for destruction. Various single-nucleotide polymorphisms (SNPs) in apoptotic genes have been associated with increased risks in lung cancer, particularly FAS −1377 G>A (rs2234767), FASLG −844 C>T (rs763110), IL1B +3954 C>T Phe105Phe (rs1143634) and BAT3 Ser625Pro (rs1052486). We studied the association of these SNPs with non-small cell lung cancer (NSCLC) in a large case–control study (N = 4263: 2644 cases and 1619 controls). No associations with NSCLC were observed in the main effects analysis for all four SNPs, adjusting for age, gender, smoking status, pack-years and years since smoking cessation. In subjects under age 60, for FASLG −844 C>T polymorphism, CT compared with the CC genotype, was significantly associated with increased risk of NSCLC, adjusted odds ratio (aOR) = 1.58 (1.22, 2.05), P = 0.0006 and TT aOR = 1.45 (1.01, 2.04), P = 0.04. In contrast, for those over age 60, the CT aOR = 0.91 (0.73, 1.13), P = 0.37 and TT aOR = 0.86 (0.64, 1.16), P = 0.32. The P-value for the age–genotype interaction was 0.004. For the IL1B +3954 C>T polymorphism, compared with the CC genotype, TT showed significant associations in former smokers and in men but tests of interaction were not significant (Psmoking = 0.24, Pgender = 0.17). No interactions were observed for FAS −1377 G>A and BAT3 Ser625Pro polymorphisms. Our findings indicate that age and smoking may modify the association of the FASLG −844 and IL1B + 3954 SNPs with the risk of NSCLC.

Leukocyte telomere length (LTL) is a marker of cellular turnover and oxidative stress. Studies suggest major depressive disorder (MDD) is associated with oxidative stress, but examinations of MDD and LTL have yielded mixed results, likely because of differences in measurement methods and unmeasured confounding. This study examined LTL and telomerase activity in 166 individuals with MDD compared to 166 age- and gender-matched matched controls free of any psychiatric disorder, using well-validated assays and clinical assessment methods, and controlling for a range of potential confounders.Subjects aged 18 to 70 were evaluated by trained raters and provided blood for LTL and telomerase activity measurement. LTL was assayed using Southern blot and replicated with qPCR, and telomerase activity was assayed with a repeat amplification protocol using a commercial kit.There was no significant difference in telomere length for individuals with MDD [mean (SD)=9.1 (3.0)kbp] compared to controls [mean(SD)=8.9(2.5)kbp] measured by Southern blot (p=0.65) or by confirmatory qPCR (p=0.91) assays. Controlling for potential confounders did not alter the results. Telomerase activity did not differ by MDD diagnosis overall (p=0.40), but the effect of MDD was significantly modified by gender (t(299)=2.67, p=0.0079) even after controlling for potential confounders, with telomerase activity significantly greater only in males with MDD versus controls.Our well-characterized, well-powered examination of concurrently assessed telomere length and telomerase activity in individuals with clinically significant, chronic MDD and matched controls failed to provide strong evidence of an association of MDD with shorter LTL, while telomerase activity was higher in men with MDD [corrected].

Objective Shortened telomeres have been linked to poorer health outcomes. Exposure to psychological stress is associated with accelerated telomere shortening, and a well-established body of evidence indicates that families with a child with autism spectrum disorder (ASD) experience heightened levels of psychological stress. Also, alterations in a number of biological processes implicated in telomere length dynamics (i.e., oxidative stress, DNA methylation) have been linked to ASD susceptibility. We examined whether families of children with ASD who have an infant show shortened telomeres. Method Saliva samples were collected from infants, their older sibling (proband), and parents in families with or without a child with ASD. Infants and their families were designated as high-risk for ASD (HRA; n = 86) or low-risk for ASD (LRA; n = 118) according to the older siblings' diagnostic status. We used the real-time polymerase chain reaction (PCR) telomere assay to determine relative average telomere length for each participant. Results HRA families demonstrated significantly shorter telomere length relative to LRA families. This effect was observed at the individual family member level, with infants, probands, and mothers in HRA families showing reduced relative telomere length compared to individuals in LRA families; although not significant, fathers of high-risk infants showed a similar pattern of decreased telomere length. Conclusion Families of children with ASD who have an infant show shortened telomeres relative to families with no history of ASD. These results suggest that such "high-risk" families should be monitored for the physical and mental health consequences that are often associated with accelerated telomere shortening.

Background: Previous epidemiologic studies have shown inconsistent results for the association between alcohol intake and endometrial cancer risk. Most of the studies, however, assessed alcohol intake after cancer diagnosis, or measured alcohol intake at baseline only. Methods: We prospectively examined the association between alcohol intake and endometrial cancer risk in the Nurses' Health Study with 68 067 female participants aged 34–59 years in 1980. Alcohol intake was measured several times with validated dietary questionnaires. We calculated cumulative average alcohol intake to represent long-term intakes of individual subjects. Using Cox proportional hazards models, we estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) for endometrial cancer risk after controlling for several risk factors simultaneously. Results: We identified a total of 794 invasive endometrial adenocarcinoma from 1980 to 2010. We found an inverse association among alcohol drinkers (multivariable RR=0.81; 95% CI: 0.68–0.96) compared with nondrinkers. Women with light alcohol intake of

Cellular proteins involved in growth signal transduction pathways represent potential molecular epidemiologic biomarkers for various disease processes of toxicologic interest, particularly cancer. In many instances, the proteins gain access to the extracellular environment and thus can be detected in easily accessible biological fluids such as serum or plasma. This paper reviews the experience with selected examples of such proteins, including growth factors, growth factor receptors, G proteins, and nuclear DNA-binding proteins, as serum or plasma biomarkers of disease.

Relatively short telomere length may serve as a marker of accelerated aging, and shorter telomeres have been linked to chronic stress. Specific lifestyle behaviors that can mitigate the effects of stress might be associated with longer telomere lengths. Previous research suggests a link between behaviors that focus on the well-being of others, such as volunteering and caregiving, and overall health and longevity. We examined relative telomere length in a group of individuals experienced in Loving-Kindness Meditation (LKM), a practice derived from the Buddhist tradition which utilizes a focus on unselfish kindness and warmth towards all people, and control participants who had done no meditation. Blood was collected by venipuncture, and Genomic DNA was extracted from peripheral blood leukocytes. Quantitative real time PCR was used to measure relative telomere length (RTL) (Cawthon, 2002) in fifteen LKM practitioners and 22 control participants. There were no significant differences in age, gender, race, education, or exposure to trauma, but the control group had a higher mean body mass index (BMI) and lower rates of past depression. The LKM practitioners had longer RTL than controls at the trend level (p=.083); among women, the LKM practitioners had significantly longer RTL than controls, (p=.007), which remained significant even after controlling for BMI and past depression. Although limited by small sample size, these results offer the intriguing possibility that LKM practice, especially in women, might alter RTL, a biomarker associated with longevity.

Mutations in ras oncogenes and expression of their encoded p21 protein products are believed to play an important role in carcinogenesis in humans. Detection of mutant p21 proteins in serum may be a useful molecular epidemiologic biomarker with which to study this process, and workers with heavy exposure to vinyl chloride (VC) represent a model population for such study. We studied the occurrence of a specific ras mutation (Asp 13 c-Ki-ras) by oligonucleotide hybridization and the expression of the corresponding p21 protein in tumor tissue and serum by immunohistochemistry and immunoblotting with monoclonal antibodies in five individuals with heavy exposure to VC and resultant angiosarcomas of the liver (ASL). Four of five (80 percent) of the cases of ASL were found to contain the mutation and to express the corresponding mutant protein in their tumor tissue and serum. Serum expression of the mutant protein also was examined in nine VC-exposed workers with liver angiomas and 45 VC-exposed workers with no evidence of liver neoplasia; eight of nine (89 percent) of the former and 22 of 45 (49 percent) of the latter were also positive for the mutant p21 in their serum. However, serum immunoblotting results for 28 age-gender-race matched, unexposed controls were all negative. Stratification by years of VC exposure showed a significant linear trend (P < 10(-5)) for the occurrence of the serum mutant p21 protein with increasing duration of exposure. These results suggest that detection of serum mutant p21 protein can be a valid surrogate for ras gene expression at the tissue level.(ABSTRACT TRUNCATED AT 250 WORDS)

Over-expression of the c-erbB-2 oncogene-encoded p185 protein product has been implicated in the pathogenesis of a wide variety of human malignancies, including lung cancer. Over-expression of p185 can be detected immunologically by quantification of the extracellular domain of p185 (c-erbB-2 oncopeptide) in extracellular fluid in vitro and in serum in vivo. An enzyme-linked immunosorbent assay (ELISA) for the c-erbB-2 oncopeptide was used to examine banked serum samples of 11 pneumoconiosis patients who subsequently developed lung cancer and serum samples from 11 hospital controls matched for age, sex, ethnic group and smoking as well as 55 unmatched general population controls. The mean serum level for the c-erbB-2 oncopeptide in human neu units/ml in the lung cancer cases (1,756 +/- 549 HNU/ml) was statistically significantly elevated (p < 0.001) in comparison to the mean level in the matched controls (976 +/- 488 HNU/ml) or the general population controls (888 +/- 655 HNU/ml). Defining a positive elevation of the serum c-erbB-2 oncopeptide as any value more than 2 standard deviations above the mean of the matched controls, 64% (7 of 11) of the lung cancer cases were positive compared to 0% (0 of 11) matched controls and 5% (3 of 55) of the unmatched controls. In addition, 4 of the 7 c-erbB-2 oncopeptide-positive cancer cases had positive serum samples prior to the time of disease diagnosis (average = 35 months). These results suggest that serum c-erbB-2 oncopeptide may be elevated at an early stage of pulmonary carcinogenesis and that further prospective study of the utility of this biomarker is warranted.

The tumor suppressor gene p53 has been identified as the most frequent target of genetic alterations in human cancers. Cancer-related mutations in the human p53 protein tend to cluster in four of the five highly conserved domains of the protein, and, in particular, in the central region of domain IV from residues 241 to 253. Using conformational energy analysis based on ECEPP (Empirical Conformational Energies for Polypeptides Program), we have determined the preferred three dimensional structures for this tridecapeptide sequence for the human wild-type p53 protein and four cancer-related mutant p53 proteins (Ala 245, Ile 246, Trp 248, Ser 249). The results show that the mutant peptides adopt conformations that are distinctly different from that of the wild-type peptide. These results are consistent with experimental conformational studies demonstrating altered detectability of antigenic epitopes in murine wild-type and mutant p53 proteins. These results suggest that the oncogenic effects of human mutant p53 proteins may be mediated by distinct local conformational changes in the protein.

A functional promoter polymorphism in the progesterone receptor (PR) gene previously has been associated with an increased risk of postmenopausal breast cancer. Whether the relationship between genetic variation in PR and risk of breast cancer is modified by postmenopausal hormone (PMH) use is unknown. Thus, we conducted a case-control study nested within the prospective Nurses’ Health Study to evaluate if the risk of breast cancer associated with having the +331 A risk allele was modified by PMH use. Genotyping of this SNP was available for 1664 postmenopausal breast cancer cases and 2391 controls. Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for breast cancer. Women who were carriers of one or both variant A alleles had a 31% increased risk of developing breast cancer (95%CI 1.04-1.65). PMH use significantly modified the association between the +331G/A polymorphism and risk (P-interaction

Nonsteroidal antiinflammatory drugs (NSAIDs) use, particularly aspirin, may lower the risk of several cancers, including bladder. NSAIDs may reduce development of bladder tumors by decreasing inflammation, inhibiting cycloxygenase-2, inhibiting proliferation and inducing apoptosis of cancer cells. However, acetaminophen, a major metabolite of phenacetin, may be positively associated with bladder cancer risk. Results from case-control studies on NSAIDs and acetaminophen use and bladder cancer risk are inconsistent. We investigated the association between NSAID and acetaminophen use and bladder cancer risk in a large cohort of US males. Among 49,448 men in the Health Professionals Follow-Up Study, 607 bladder cancer cases were confirmed during 18 years of follow-up. Relative risks (RR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards models. Multivariate RR were adjusted for age, current smoking status, pack years, geographic region and fluid intake. No significant associations were observed for regular aspirin (> or =2 tablets per week), (RR = 0.99, 95% CI 0.83-1.18), ibuprofen (RR = 1.11, 95% CI 0.81-1.54), acetaminophen (RR = 0.96, 95% CI 0.67-1.39) or total NSAID use (not including acetaminophen; RR = 1.01, 95% CI 0.85-1.20) and bladder cancer risk compared with nonuse. Consistent use (over 6 years) of aspirin, ibuprofen, acetaminophen and total NSAIDs, compared to nonuse, was not associated with bladder cancer risk. No association was observed between aspirin frequency and dose and bladder cancer risk. We observed no effect-modification by smoking, age or fluid intake. Our results suggest that regular NSAID or acetaminophen use has no substantial impact on bladder cancer risk among men.

Background Thyroid hormones may be involved in tumorigenesis and metastasis in hormone sensitive cancers. Thyroid hormones strongly influence the menstrual cycle, implantation and fertility, suggesting that thyroid hormones also could play a role in the development of endometrial cancer (EC), which is hormone-sensitive. No prospective studies have examined this association. Methods We prospectively evaluated the association between self-reported physician-diagnosed hypothyroidism and hyperthyroidism in the Nurses’ Health Study (NHS) from 1976 - 2010. Reports of thyroid dysfunction were based on self-report on biennial follow-up questionnaires, and have shown high validity when compared to medical records. Incident EC cases were confirmed with medical, pathology and death records. Multivariate rate ratios (RRs) for endometrial cancer were calculated, adjusting for major EC risk factors (i.e., body mass index, smoking, parity, age at last birth, oral contraceptive use, family history, age at menarche, age at menopause, postmenopausal hormone use, type 2 diabetes, and height). Results During 34 years of follow-up in NHS, we documented 917 cases of incident EC. Compared to those without any reported thyroid dysfunction, the multivariable RR for hypothyroidism was 0.99 (95% CI, 0.75-1.30) and the null associations were consistent across categories of time since hypothyroidism diagnosis. The multivariable RR for hyperthyroidism was 1.38 (95% CI 0.79 - 2.41). An association was observed with longer time since hyperthyroidism diagnosis (median time since hyperthyroidism diagnosis was 6 years in NHS); the RR for EC associated with 6+ years since hyperthyroidism diagnosis was 2.08 (95% CI, 1.02, 4.23). Conclusions Overall self-reported hypothyroidism and hyperthyroidism were not associated with risk of EC; however, longer time since hyperthyroidism diagnosis may be associated with an increased risk of EC. Due to the overall small number of cases with hyperthyroidism, on-going analyses will incorporate results from the Nurses’ Health Study II to increase power for these analyses. Citation Format: Angela Kueck, Jae Hee Kang, Richard Stevens, Gary Curhan, Erik Alexander, Bernard Rosner, Immaculata DeVivo, Shelley Tworoger. Hypothyroidism and hyperthyroidism in relation to endometrial cancer: A prospective study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 153. doi:10.1158/1538-7445.AM2013-153

Recent evidence indicates human mosaic abnormalities may be more common than previously expected. We performed an analysis on blood and buccal DNA of 30,918 individuals from a collection of 54 cancer-related studies using a modified mosaic alteration detection algorithm on renormalized B-allele frequencies and log2 relative probe intensity ratios from commercially available Illumina SNP microarray chips. 391 autosomal abnormalities >2Mb in size were detected in 232 (0.75%) individuals. The distribution includes copy-neutral loss of heterozygosity constituting 192 (49%) events, copy gains 85 (22%) events, and copy losses 102 (26%) events. There was no difference between blood and buccal sources of DNA. An overall analysis by age confirmed our earlier finding (p=8.93e-07), which was also observed in controls (p=0.0086). Similarly, an overall analysis by sex confirmed mosaic abnormalities are more frequent in males than females (p=0.0016); and this association was also observed in a control-only analysis (p=0.0019). Two or more distinct autosomal events were observed in 43 individuals. Comparable to earlier studies, the most common events were 4q copy neutral loss of heterozygosity, 9q copy neutral loss of heterozygosity, 13q14 deletion and 20q deletion. 13q14 deletion was observed in cancer-free controls and individuals with epithelial cancers. Cancer specific analyses for bladder, endometrium, stomach, lung (in nonsmoking women from Asia), osteosarcoma, and prostate cancer revealed no significant association with risk for cancer. These results replicate the prevalence and age/sex relationships from our previous findings in an analysis of 57,853 individuals and further suggest the importance of studying mosaic abnormalities in the general human population. The findings underscore the importance of thorough characterization of germline DNA in parallel with somatic characterization. Our results provide further support for age-related genomic senescence and could represent the tip of the iceberg for smaller somatic events. Citation Format: Mitchell J. Machiela, Weiyin Zhou, Meredith Yeager, Kevin Jacobs, Sonja Berndt, Qing Lan, Nathaniel Rothman, Sharon Savage, Phil R. Taylor, Immaculata deVivo, National Cancer Institute Detectable Clonal Mosaicism Consortium, Robert N. Hoover, Margaret A. Tucker, Stephen J. Chanock. Evidence for large somatic structural events detected as autosomal genetic mosaicism in GWAS data. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2542. doi:10.1158/1538-7445.AM2013-2542

EXTREME environmental pollution such as that found in the highly industrialized Silesian region of Poland has been associated with increased risk of cancer and adverse reproductive outcomes1,2. Among the most prevalent carcinogenic and mutagenic air pollutants in Silesia are the polycyclic aromatic hydrocarbons (PAH) which are largely produced by industrial and residential combustion of coal1. Molecular epidemiology aims to prevent disease by using biological markers to identify risks well before clinical onset to allow effective intervention3–7. Here, we use a battery of biological markers to measure molecular and genetic damage in peripheral blood samples from residents of Silesia and from persons living in a rural, less polluted area of Poland. The results show that their exposure to environmental pollution is associated with significant increases in carcinogen–DNA adducts (PAH–DNA and aromatic adducts), in sister chromatid exchange including high-frequency cells, and in chromosomal aberrations as well as a doubling in the frequency of ras oncogene overexpression. We found that aromatic adducts on DNA were significantly correlated with chromosomal mutation, providing us with a molecular link between environmental exposure and a genetic alteration relevant to cancer and reproductive risk.