Jason Y.Y. Wong

The association between leukocyte telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancer

Telomeres consist of nucleotide repeats and a protein complex at chromosome ends that are essential to maintaining chromosomal integrity. Several studies have suggested that subjects with shorter telomeres are at increased risk of bladder and lung cancer. In comparison to normal tissues, telomeres are shorter in high‐grade intraepithelial neoplasia and prostate cancer. We examined prostate cancer risk associated with relative telomere length as determined by quantitative PCR on prediagnostic buffy coat DNA isolated from 612 advanced prostate cancer cases and 1049 age‐matched, cancer‐free controls from the PLCO Cancer Screening Trial. Telomere length was analyzed as both a continuous and a categorical variable with adjustment for potential confounders. Statistically significant inverse correlations between telomere length, age and smoking status were observed in cases and controls. Telomere length was not associated with prostate cancer risk (at the median, OR = 0.85, 95% CI: 0.67, 1.08); associations were similar when telomere length was evaluated as a continuous variable or by quartiles. The relationships between telomere length and inflammation‐related factors, diet, exercise, body mass index, and other lifestyle variables were explored since many of these have previously been associated with shorter telomeres. Healthy lifestyle factors (i.e., lower BMI, more exercise, tobacco abstinence, diets high in fruit and vegetables) tended to be associated with greater telomere length. This study found no statistically significant association between leukocyte telomere length and advanced prostate cancer risk. However, correlations of telomere length with healthy lifestyles were noted, suggesting the role of these factors in telomere biology maintenance and potentially impacting overall health status.

Dichloroacetate induces apoptosis in endometrial cancer cells

PURPOSE A recent landmark study demonstrated that Dichloroacetate (DCA) treatment promoted apoptosis in lung, breast, and glioblastoma cancer cell lines by shifting metabolism from aerobic glycolysis to glucose oxidation coupled with NFAT-Kv1.5 axis remodeling. The objective of this study was to determine whether DCA induces apoptosis in endometrial cancer cells and to assess apoptotic mechanism. METHODS A panel of endometrial cancer cell lines with varying degrees of differentiation was treated with DCA and analyzed for apoptosis via flow cytometry. Biological correlates such as gene expression, intracellular Ca(2+), and mitochondrial membrane potential were examined to assess apoptotic mechanism. RESULTS Initiation of apoptosis was observed in five low to moderately invasive cancer cell lines including Ishikawa, RL95-2, KLE, AN3CA, and SKUT1B while treatment had no effect on non-cancerous 293T cells. Two highly invasive endometrial adenocarcinoma cell lines, HEC1A and HEC1B, were found to be resistant to DCA-induced apoptosis. Apoptotic responding cell lines had a significant increase in early and late apoptotis, a decrease in mitochondrial membrane potential, and decreased Survivin transcript abundance, which are consistent with a mitochondrial-regulated mechanism. DCA treatment decreased intracellular calcium levels in most apoptotic responding cell lines which suggests a contribution from the NFAT-Kv1.5-mediated pathway. DCA treatment increased p53 upregulated modulator of apoptosis (PUMA) transcripts in cell lines with an apoptotic response, suggesting involvement of a p53-PUMA-mediated mechanism. CONCLUSIONS Dichloroacetate effectively sensitizes most endometrial cancer cell lines to apoptosis via mitochondrial, NFAT-Kv1.5, and PUMA-mediated mechanisms. Further investigation of the cancer therapeutic potential of DCA is warranted.

The limitations of qPCR telomere length measurement in diagnosing dyskeratosis congenita.

Telomere length <1st percentile‐for‐age in leukocyte subsets by flow cytometry with fluorescence in situ hybridization (flow FISH) is highly sensitive and specific in diagnosing patients with dyskeratosis congenita (DC), a telomere biology disorder.

Circulating Sex Hormones and Risk of Uterine Fibroids: Study of Women's Health Across the Nation (SWAN)

CONTEXT Estrogen has been implicated in the development of uterine fibroids. However, the contribution of androgen in women is unknown. OBJECTIVE Our objective was to assess the longitudinal relations of circulating androgens and estradiol (E2) and their joint effects to the risk of developing fibroids. DESIGN This is a 13-year longitudinal study in the Study of Womens Health Across the Nation. SETTING This study was conducted in seven sites across the United States (1997-2013). PARTICIPANTS At baseline, 3240 pre- or early peri-menopausal women with an intact uterus, ages 45-52 years were included; 43.6% completed the follow-up. There were 512 incident and 478 recurrent fibroid cases. EXPOSURES We measured near-annual time-varying serum levels of bioavailable E2 and bioavailable T, dichotomized at the median (high vs low). MAIN OUTCOMES AND MEASURES We estimated the conditional odds ratio (OR) of fibroids in the ensuing year using discrete-time proportional odds models adjusted for race/ethnicity/site, age, body mass index, menopausal stage, reproductive factors, smoking, timing of blood draw, and FSH. RESULTS Women with high T had a statistically significant increased risk of incident fibroids (OR, 1.33; 95% confidence interval [CI], 1.01-1.76; P = .04), but not recurrent fibroids. This risk was further elevated in those with high T and E2 (OR, 1.52; 95% CI, 1.07-2.17; P = .02). High E2 and T was associated with lower risk of recurrent fibroids (OR, 0.50; 95% CI, 0.26-0.96; P = .04). CONCLUSIONS High T with high E2 was associated with an elevated risk of incident fibroids in midlife women who never reported fibroids before baseline. Conversely, the risk of recurrent fibroids was mitigated in women with high E2 and high T.

Occupational exposure to diesel engine exhaust and alterations in immune/inflammatory markers: a cross-sectional molecular epidemiology study in China.

The relationship between diesel engine exhaust (DEE), a known lung carcinogen, and immune/inflammatory markers that have been prospectively associated with lung cancer risk is not well understood. To provide insight into these associations, we conducted a cross-sectional molecular epidemiology study of 54 males highly occupationally exposed to DEE and 55 unexposed male controls from representative workplaces in China. We measured plasma levels of 64 immune/inflammatory markers in all subjects using Luminex bead-based assays, and compared our findings to those from a nested case-control study of these markers and lung cancer risk, which had been conducted among never-smoking women in Shanghai using the same multiplex panels. Levels of nine markers that were associated with lung cancer risk in the Shanghai study were altered in DEE-exposed workers in the same direction as the lung cancer associations. Among these, associations with the levels of CRP (β= -0.53; P = 0.01) and CCL15/MIP-1D (β = 0.20; P = 0.02) were observed in workers exposed to DEE and with increasing elemental carbon exposure levels (Ptrends <0.05) in multivariable linear regression models. Levels of a third marker positively associated with an increased lung cancer risk, CCL2/MCP-1, were higher among DEE-exposed workers compared with controls in never and former smokers, but not in current smokers (Pinteraction = 0.01). The immunological differences in these markers in DEE-exposed workers are consistent with associations observed for lung cancer risk in a prospective study of Chinese women and may provide some insight into the mechanistic processes by which DEE causes lung cancer.

Serologic markers of viral infection and risk of non-Hodgkin lymphoma: A pooled study of three prospective cohorts in China and Singapore: Serologic markers of viral infection and risk of non-Hodgkin lymphoma

Incidence rates of non‐Hodgkin lymphoma (NHL) and distributions of certain viruses differ between East Asian and Western populations. There are limited data on associations between serologic markers of multiple viral infections in pre‐diagnostic blood and NHL risk in East Asians. We conducted a nested case‐control study of 214 NHL cases and 214 matched controls from three population‐based prospective cohorts in Shanghai and Singapore. Antibodies against antigens from herpesviruses, Hepatitis B (HBV) and C (HCV) virus and polyomaviruses were measured in plasma or serum using fluorescent bead‐based multiplex assays. Conditional logistic regression was used to evaluate associations between antibody levels and NHL risk. An increased risk of NHL was observed for higher compared to lower EA‐D (Odds Ratio (OR) = 2.04, 95% Confidence Interval (CI) = 1.10‐3.81; ptrend = 0.005) and ZEBRA (OR = 2.17, 95% CI = 0.96‐4.89; ptrend = 0.008) Epstein‐Barr Virus (EBV) antibodies, as well as for antibody seropositivity against the IE1A human herpesvirus‐6 (HHV‐6) antigen (OR = 1.85, 95% CI = 1.04‐3.29). An increased NHL risk was also observed for higher compared to lower antibodies against the HBV‐HBc and HBe antigens. An increased risk of NHL in relation to EBV and HBV infection in East Asians is consistent with findings in several studies of Western populations, suggesting similar viral risk factors for NHL in these diverse populations with distinct patterns of NHL. The association between HHV‐6 antibodies and NHL has not previously been reported in a prospective study in this population and will require replication.

Personal exposure to fine particulate matter and benzo[a]pyrene from indoor air pollution and leukocyte mitochondrial DNA copy number in rural China

Households in Xuanwei and Fuyuan, China, possess hazardous levels of fine particulate matter with an aerodynamic diameter <2.5 microns (PM2.5) and polycyclic aromatic hydrocarbons (PAHs) from coal combustion. Previous studies found that increased exposure to PM2.5 and benzo[a]pyrene (BaP; a PAH) were associated with decreased mitochondrial DNA copy number (mtDNAcn), a marker of oxidative stress. We further evaluated these associations in a cross-sectional study of 148 healthy non-smoking women from Xuanwei and Fuyuan. Personal exposure to PM2.5 and BaP was measured using portable devices. MtDNAcn was measured using qPCR amplification of leukocyte DNA that was collected after air measurements. Linear regression models were used to estimate the associations between personal exposure to PM2.5 and BaP, and mtDNAcn adjusted for age, body mass index (BMI) and fuel type. We found inverse associations between exposure to PM2.5 and BaP, and mtDNAcn. Each incremental log-μg/m3 increase in PM2.5 was associated with a significant decrease in mtDNAcn of -10.3 copies per cell [95% confidence interval (95% CI): -18.6, -2.0; P = 0.02]. Additionally, each log-ng/m3 increase in BaP was associated with a significant decrease in mtDNAcn of -5.4 copies per cell (95% CI: -9.9, -0.8, P = 0.02). Age, BMI, fuel type and coal mine type were not significantly associated with mtDNAcn. Exposure to PM2.5 and BaP may alter mitochondrial dynamics in non-smoking Chinese women. MtDNAcn may be a potential mediator of indoor air pollution on chronic disease development.

Lung cancer risk in welders and foundry workers with a history of heavy smoking in the USA: The National Lung Screening Trial

Objectives Foundry work is a risk factor for lung cancer; however, the association with welding is unclear, as smoking is common among metalworkers and may mask the relationship. We evaluated whether history of welding and foundry work, independently and jointly, and employment duration were associated with lung cancer risk in heavy smokers. Methods We analysed data from the National Lung Screening Trial, a prospective randomised trial of 53 454 heavy smokers (>30 pack-years) in the USA. Cox regression models were used to estimate the HRs and 95% CIs of medically/histologically confirmed incident lung cancer during the follow-up period (2002–2009) in relation to history and duration of welding and foundry work assessed via questionnaires, adjusted for screening arm, component study, sex, age, race/ethnicity, education, smoking status and pack-years, body mass index and personal/family medical history. Results There were 2034 incident lung cancer cases throughout the follow-up. Increasing years of employment in welding (p-trend =0.039) and foundry work (p-trend =0.005) were related to increased lung cancer risk among heavy smokers. Having ever been employed (≥1 yr) as either a welder or foundry worker alone was associated with non-significant increased risks of lung cancer (HR=1.12 (95% CI 0.91 to 1.37) and HR=1.09 (95% CI 0.85 to 1.39), respectively). Further, there was a joint-effect in that those who were ever employed in both occupations had significantly increased risks (HR=1.48 (95% CI 1.08 to 2.04)). Conclusions Our findings provide further evidence that exposure to welding/metal fumes may be associated with elevated lung cancer risk. Trial registration number NCT00047385.

Religiosity and faith in relation to time to metabolic syndrome for Hispanic women in a multiethnic cohort of women—Findings from the Study of Women's Health Across the Nation (SWAN)

OBJECTIVES We investigated whether faith was associated with a difference in time to incident metabolic syndrome (MetS) among midlife Hispanic women vs women of other ethnicities. STUDY DESIGN The Study of Womens Health Across the Nation (SWAN) is a community-based, longitudinal study of a cohort of midlife women. Social, demographic, psychosocial, anthropometric, medical, and physiological measures, and incident MetS were assessed in near-annual intervals using questionnaires and assays. Each participant answered key questions related to religion and meaning in her life. Differences in time to MetS were modeled by Hispanic ethnicity (vs. otherwise) among women reporting low and high levels of faith. MAIN OUTCOME MEASURE Incident MetS in the 7 years after the SWAN baseline assessment. RESULTS Among 2371 women, average baseline age 46, Hispanic women (n = 168) were more likely to have higher perceived stress and financial strain than non-Hispanic women (n = 2203). Nevertheless, Hispanic women were far more likely than non-Hispanic women to report that faith brought them strength and comfort in times of adversity, that they prayed often, and that their faith was sustaining for them. Hispanic women had the highest incidence rate of MetS of any racial/ethnic group. However, among women with high levels of faith, the incidence rate of MetS was similar in the Hispanic and non-Hispanic groups. Conversely, among women with low levels of faith, Hispanic women had a faster progression to MetS than did non-Hispanic women. CONCLUSIONS Faith might be associated with a different risk of MetS among women of Hispanic vs other ethnicities. Among women who are not part of a faith community, Hispanic ethnicity might be a risk factor for MetS.

Abstract 5315: Dietary intake and risk of lung cancer in non-smoking women: a hospital-based case-control study in Xuanwei and Fuyuan, China

Xuanwei and Fuyuan are rural counties in China that have the highest lung cancer rates in the country among non-smoking women. This alarming public health burden has been attributed to the combustion of smoky (bituminous) coal for heating and cooking, which can produce carcinogenic emissions such as polycyclic aromatic hydrocarbons (PAHs). Previous studies found that green leafy vegetables could absorb PAHs through air and direct soil contamination. Further, oral ingestion of PAHs was found be to associated with pulmonary adenoma development in animal feeding studies. Therefore, we investigated the associations between lung cancer risk and dietary intake of specific green leafy vegetables and other foods in non-smoking women of this farming region. We conducted a hospital-based case-control study of 1,074 female lung cancer patients and 977 frequency-matched controls from Xuanwei and Fuyuan, China in 2006-2013. Dietary intake was self-reported on questionnaires and categorized as never, several times/year, several times/month, several times/week, and every day. Unconditional logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (CI) of lung cancer in relation to intake of specific green leafy vegetables (i.e. lettuce, cabbage, fennel, spinach, hollow vegetables), corn, buckwheat, carrots, tomatoes, dried and fresh chili, pickled vegetables, bean curd, mushrooms, and preserved meats. Models were adjusted for age, county, first-degree relative with lung cancer, passive smoke exposure, education, lifetime smoky coal tonnage, respiratory disease history, time spent indoors, and menopausal status. Separate models were fitted for each dietary factor. We found that increased consumption of several green leafy vegetables was associated with increased risk of lung cancer. Eating hollow vegetables every day was associated with 2.50 (95% CI: 1.18, 5.27) times the odds of lung cancer compared to never. Similarly, eating lettuce (OR=2.13, 95% CI: 1.41, 3.21) and cabbage (OR=1.82, 95% CI: 1.21, 2.69) every day was associated with increased risks compared to several times a year or less. Conversely, eating bean curd (OR=0.54, 95% CI: 0.40, 0.72) several times a week was associated with decreased risk compared to several times a year or less; while eating buckwheat (OR=0.59, 95% CI: 0.40, 0.89) several times a week was associated with decreased risk compared to never. No significant associations were found for fennel, spinach, and other foods. Our findings suggest that increased consumption of a variety of green leafy vegetables may be related to elevated lung cancer risk in non-smoking women from Xuanwei and Fuyuan, China, independent of other risk factors. The increased risk may be due to environmental contamination of crops from coal combustion. Conversely, frequent consumption of bean curd and buckwheat was found to be protective. Citation Format: Jason Y. Wong, Bryan A. Bassig, Wei Hu, Jinming Zhang, Wei Jie Seow, Neil E. Caporaso, Bu-tian Ji, Robert S. Chapman, George S. Downward, Jihua Li, Jun He, Kaiyun Yang, Yunchao Huang, Roel Vermeulen, Nathaniel Rothman, Qing Lan. Dietary intake and risk of lung cancer in non-smoking women: a hospital-based case-control study in Xuanwei and Fuyuan, China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5315. doi:10.1158/1538-7445.AM2017-5315