Search

Household air pollution (HAP) from indoor combustion of solid fuel is a global health burden that has been linked to lung cancer. A striking example occurs in Xuanwei, China where the lung cancer rate for never smoking women is among the highest in the world and largely attributed to high levels of various toxic constituents, including polycyclic aromatic hydrocarbons (PAHs), a combustion product of smoky (bituminous) coal used for cooking and heating. Several air pollution constituents have been associated with epigenetic accelerated aging (EAA) derived from DNA methylation (DNAm)-based biomarkers that are highly correlated with biological processes underlying aging-related diseases. We aim to assess the association between HAP exposure and EAA in Xuanwei, China. We analyzed 106 never smoking women in an exposure assessment study in Xuanwei, China with a repeat DNA sample from 23 subjects. Household fuel type used for cooking and heating (smoky vs. smokeless coal) was collected using a questionnaire, and exposure models were used to predict levels of 43 individual HAP constituents for current and childhood exposure. Leukocyte DNAm was measured using Illumina EPIC array. EAA was derived for five clocks using the Horvath calculator and defined as the residuals resulting from regressing each clock on chronological age. We used generalized estimating equations to assess the associations between fuel type, clusters derived from predicted levels of HAP exposure, and ambient 5-methylchrysene (5-MC), a carcinogenic PAH previously associated with lung cancer in Xuanwei and selected a priori for analyses, as independent variables and EAA clocks as dependent variables, while accounting for repeated-measurements. We observed a significant increase in GrimAge EAA among smoky coal users compared to smokeless coal users for current (β=1.84 years (y), 95% confidence interval (CI): 0.59, 3.09, P-value=0.004) and childhood (β=4.14 y, 95% CI: 1.63, 6.64, P-value=0.001) exposures. We also observed a monotonic increase in GrimAge EAA for a cluster of 31 PAHs reflecting current exposure (β=0.77 y, 95% CI: 0.36, 1.19, P-value=3 × 10−4) and for a cluster of 33 PAHs reflecting childhood exposure (β=0.92 y, 95% CI: 0.40, 1.45, P-value=0.001). Ambient 5-MC, one of the constituents within the PAH clusters, was found to have an increasing monotonic relationship with GrimAge EAA for current (β=0.15 y, 95% CI: 0.05, 0.25, P-value=0.003) and childhood (β=0.30 y, 95% CI: 0.13, 0.47, P-value=4.7 × 10−4) exposures. Our findings suggest that exposure to PAH from indoor smoky coal combustion is associated with EAA, particularly for the GrimAge clock, a strong biomarker of mortality. This finding is consistent with our recent observation linking accelerated GrimAge to increased risk of lung cancer in a prospective study of never smoking women in China. Additionally, our study provides further support for 5-MC as a prominent carcinogenic component of smoky coal emissions. Citation Format: Batel Blechter, Andres Cardenas, Seraphina (Junming) Shi, Mohammad L. Rahman, Jason Y.Y. Wong, Wei Hu, George S. Downward, Lutzen Portengen, Richard Cawthon, H. Dean Hosgood, Jihua Li, Debra T. Silverman, Yunchao Huang, Roel Vermeulen, Nathaniel Rothman, Qing Lan. Smoky coal exposure is associated with epigenetic accelerated aging. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4219.

Background: The etiology of lung cancer among never-smokers has not been adequately elucidated despite that globally15% of lung cancer cases in men and 53% in women are not smoking-related. Epigenetic modifications, including changes in DNA methylation (DNAm), have been suggested as possible underlying mechanisms. However, only a few prospective epigenome-wide association studies (EWAS) of lung cancer incidence have been conducted, all exclusively focused on DNAm in peripheral blood cells and included a minimal number of never-smokers. We aimed to investigate genome-wide DNAm associations and epigenetic age acceleration with future risk of lung cancer among never-smokers using pre-diagnostic oral rinse samples. Methods: We conducted a case-control study of 80 never-smoking incident lung cancer cases and 83 comparable never-smoking controls nested in two large prospective cohorts: the Shanghai Women’s Health Study and Shanghai Men’s Health Study. DNAm was measured using the Illumina EPIC array. The top 50 differentially methylated positions (DMPs) were identified from a discovery sample and tested for replication in a validation sample using robust linear regression models. We also conducted an EWAS in the pooled sample. We examined functional overlap enrichment across chromatin states and histone mark broadPeaks for the top 1000 DMPs using eFORGE and constructed enrichment biological pathways analyses. Results: Across discovery and pooled EWAS, we identified four DMPs associated with lung cancer at the epigenome-wide significance level of P Conclusions: To our knowledge, this is the first prospective EWAS of lung cancer among never-smokers using oral rinse samples. Our results show that DNAm in pre-diagnostic oral rinse samples can provide new insights into lung cancer etiology and risk factors. Citation Format: Mohammad L. Rahman, Charles E. Breeze, Xiao-Ou Shu, Jason YY Wong, Andres Cardenas, Xuting Wang, Bu-Tian Ji, Wei Hu, Batel Blechter, Qiuyin Cai, H Dean Hosgood, Gong Yang, Jianxin Shi, Jirong Long, Yu-Tang Gao, Douglas Bell, Wei Zheng, Qing Lan, Nathaniel Rothman. Epigenome-wide association study of lung cancer among never-smokers in two prospective cohorts in Shanghai [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3483.

Background: Peripheral blood levels of soluble CD27 (sCD27), sCD30 and chemokine ligand-13 (CXCL13) are proposed markers of immune activation, the effects of which may influence the development of non-Hodgkin lymphoma (NHL). Pre-diagnostic circulating levels of sCD27, sCD30 and CXCL13 have been associated with NHL, although individual studies have typically been underpowered to assess associations for individual NHL subtypes. We pooled data from eight case-control studies nested within general-population cohorts to investigate subtype-specific relationships with these immune markers. Methods: After pooling, immune marker data for 2,455 cases diagnosed >2 years after blood collection and 3,310 controls were available for analysis. Using polytomous regression models, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) relating study-specific tertiles of each immune marker to the following subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n=623), diffuse large B-cell lymphoma (DLBCL; n=621), follicular lymphoma (FL; n=398), marginal zone lymphoma (MZL; n=138), mantle cell lymphoma (MCL; n=82) and T-cell lymphoma (TCL; n=92). Results: We observed associations with DLBCL for elevated levels of sCD27 [OR for 3rd vs. 1st tertile (ORT3) = 2.2, 95% CI = 1.6-3.1; Ptrend = 9.3x10-6), sCD30 (ORT3 = 2.0, 95% CI 1.6-2.5; Ptrend = 6.5 x10-10) and CXCL-13 (ORT3 = 2.3, 95% CI 1.8-3.0; Ptrend = 3.9 x10-12). These associations remained in a model simultaneously adjusting for all three markers. We also observed associations with sCD27 for CLL/SLL (ORT3 = 3.3, 95% CI = 2.4-4.6; Ptrend = 1.6x10-13), MZL (ORT3 =7.7, 95% CI 3.0-20.1; Ptrend = 2.3x10-6) and TCL (ORT3 = 3.4, 95% CI 1.5-7.7; Ptrend = 0.003), and between sCD30 and FL (ORT3 = 2.7, 95% CI 2.0-3.5; Ptrend = 1.7x10-12), all of which remained after adjustment for the other immune markers. In analyses stratified by follow-up time from blood collection to case diagnosis, the sCD27-TCL association and all three DLBCL associations were equivalent across both follow-up periods (>2- Citation Format: Jongeun Rhee, Brenda M. Birmann, Anneclaire J. De Roos, Mara M. Epstein, Otoniel Martinez-Maza, Elizabeth C. Breen, Lynn I. Levin, Kala Visvanathan, H Dean Hosgood, Thomas Rohan, Lihong Qi, Qing Lan, Nathaniel Rothman, Mark P. Purdue. Circulating immune markers and risks of non-Hodgkin lymphoma subtypes: A pooled analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 685.

Prospective cohort and genome-wide association studies have found consistent associations between longer leukocyte telomere length (LTL) and increased lung cancer risk. These findings present a paradox in the traditional expectations of telomere dynamics in cancer development, as longer telomeres are generally considered to be reflective of less advanced age and greater genomic stability. We posited that longer LTL may reflect or lead to delayed cellular senescence allowing cells to accumulate genomic abnormalities that drive lung carcinogenesis. Furthermore, increased copy number of Alu retroelements, repetitive mobile DNA sequences that are approximately 300 base pairs in length, could also reflect genomic instability. We previously found that exposure to diesel exhaust, a known lung carcinogen, was associated with increased Alu copy number and suspect that increased Alu retrotransposition could influence lung carcinogenesis. However, the interrelationship between Alu retroelements, LTL, and lung cancer is unknown. Therefore, we investigated associations between Alu copy number, LTL, and lung cancer risk in the prospective Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We conducted a nested case-control study of 410 confirmed incident lung cancer cases and 416 controls individually matched on age, sex, race/ethnicity, study center, and blood draw date. Quantitative PCR was used to measure Alu copy number and telomere length relative to albumin (Alb) copy number (Alu/Alb and T/S ratio, respectively) in pre-diagnostic leukocytes. Conditional logistic regression was used to estimate associations between quartiles (Q) of Alu/Alb ratio (reference=Q1) and lung cancer risk, adjusted for matching factors, smoking status and packyears, and LTL. Additionally, we dichotomized Alu/Alb ratio and LTL at their medians and created a cross-combination variable to assess combined effects. We found a positive dose-response relationship between Alu/Alb ratio and lung cancer risk (odds ratio (OR), 95% confidence intervals (CI): Q2: 1.34 (0.73, 2.48); Q3:1.89 (0.94, 3.84); Q4: 2.66 (1.03, 5.63); p-trendordinal=0.02). The association was apparent for lung adenocarcinoma (LUAD) (Q2: 1.32 (0.46, 3.77); Q3: 2.88 (0.90, 9.25); Q4: 5.07 (1.29, 19.87); p-trendordinal=0.02). We have previously reported that longer measured LTL was also associated with an increased risk of LUAD (Q4: 2.82 (1.16-6.85); p-trend=0.011). The combined effect of both a higher Alu/Alb ratio and longer LTL was 6.07 (1.75, 21.04; p=4.5x10-3) for LUAD compared with lower/shorter levels of both. Higher Alu copy number and longer LTL were associated with increased risk of lung cancer, especially LUAD. Our findings require replication. If confirmed, evaluation of Alu copy number and LTL in risk stratification and prediction analyses is warranted. Citation Format: Jason Yat-Yang Wong, Richard Cawthon, Wei Hu, Somayina Ezennia, Shahinaz Gadalla, Charles Breeze, Batel Blechter, Neal Freedman, Wen-Yi Huang, H. Dean Hosgood, Wei Jie Seow, Bryan Bassig, Mohammad Rahman, Richard Hayes, Nathaniel Rothman, Qing Lan. Alu retroelement copy number, leukocyte telomere length, and lung cancer risk in the prospective Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2251.

The association between obesity and multiple myeloma risk may be partly attributed to reduced circulating levels of adiponectin in obese individuals. To prospectively evaluate multiple myeloma risk in relation to adiponectin levels overall and stratified by body mass index and other characteristics, we conducted a pooled investigation of pre-diagnosed peripheral blood samples from 624 multiple myeloma cases and 1,246 individually matched controls from seven cohorts participating in the Multiple Myeloma Cohort Consortium. Analysis of circulating analyte levels measured by ELISA revealed that higher total adiponectin levels were associated with reduced multiple myeloma risk overall [highest quartile vs. lowest: OR, 0.64; 95% confidence interval (CI) 0.47–0.85; Ptrend = 0.001]. This association was apparent among cases diagnosed six or more years after blood collection (OR, 0.60; 95% CI, 0.40–0.90; Ptrend = 0.004) and was similar in magnitude for men and women (OR, 0.59 and 0.66, respectively). Interestingly, we observed strong associations among subjects who were overweight (OR, 0.41; 95% CI, 0.26–0.65) or obese (OR, 0.41; 95% CI, 0.17–0.98) but not among those with normal weight (OR, 1.20; 95% CI, 0.73–2.00; overweight/obese vs. normal weight, Pinteraction = 0.04). Our findings provide the strongest epidemiologic evidence to date that adiponectin protects against multiple myeloma development, particularly among overweight and obese individuals, and offer a method for risk assessment in this susceptible population of heavier patients. Cancer Res; 76(7); 1935–41. ©2016 AACR.

We investigated the relationship between telomere length and lung cancer in a pooled analysis from three prospective cohort studies: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, conducted among men and women in the United States, and previously published data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Trial conducted among male smokers in Finland, and the Shanghai Women's Health Study (SWHS), which is comprised primarily of never-smokers. The pooled population included 847 cases and 847 controls matched by study, age, and sex. Leukocyte telomere length was measured by a monochrome multiplex qPCR assay. We used conditional logistic regression models to calculate ORs and their 95% confidence intervals (CI) for the association between telomere length and lung cancer risk, adjusted for age and pack-years of smoking. Longer telomere length was associated with increased lung cancer risk in the pooled analysis [OR (95% CI) by quartile: 1.00; 1.24 (0.90–1.71); 1.27 (0.91–1.78); and 1.86 (1.33–2.62); P trend = 0.000022]. Findings were consistent across the three cohorts and strongest for subjects with very long telomere length, i.e., lung cancer risks for telomere length [OR (95% CI)] in the upper half of the fourth quartile were 2.41 (1.28–4.52), 2.16 (1.11–4.23), and 3.02(1.39–6.58) for the PLCO trial, the ATBC trial, and the SWHS, respectively. In addition, the association persisted among cases diagnosed more than 6 years after blood collection and was particularly evident for female adenocarcinoma cases. Telomere length in white blood cell DNA may be a biomarker of future increased risk of lung cancer in diverse populations. Cancer Res; 74(15); 4090–8. ©2014 AACR.

Background: Accounting for approximately 1.76 million annual deaths worldwide, lung cancer is a significant global health burden. While smoking is the most common cause of lung cancer, up to 25% of all lung cancer patients worldwide are never smokers. Lung cancer is the leading cause of cancer mortality in China, where most women do not smoke, making women in Asia an ideal population to study. Previously conducted genome-wide association studies (GWAS) of lung cancer risk among never-smoking women in Asia identified 10 lung cancer susceptibility loci. Indoor air pollution from coal burned for home cooking and heating is known to contain lung carcinogens and has been found to be causally associated with lung cancer. In the current analysis, we evaluated gene-environment interaction between a polygenic risk score (PRS) and coal use in relation to lung adenocarcinoma. Methods: Three studies (Taiwan, Shanghai, Shenyang) from the Female Lung Cancer Consortium in Asia (FLCCA) were used for the primary analysis (1,419 cases; 1,446 controls). A replication study was conducted using samples from Xuanwei, China (159 cases; 572 controls), where lung cancer rates for never-smokers are among the highest in the world and attributed to widespread coal use. We calculated a PRS as the weighted sum of the risk allele counts across the 10 loci, and modeled PRS as a continuous variable scaled by the standard deviation in controls. Logistic regression was used to estimate the main effects of the PRS and coal use, and a likelihood ratio test was used to evaluate the interaction. Models were adjusted for age ( Results: Coal use was associated with an increased risk of lung adenocarcinoma (OR=1.31, 95% CI: 1.01-1.68). We observed an exposure-response relationship between PRS and lung adenocarcinoma (p-trend= 2x10-16) and found a significant multiplicative interaction between PRS and coal use (p-interaction= 0.005). The association between PRS and lung adenocarcinoma was significantly higher among the never coal users (OR=1.68, 95% CI: 1.52-1.86) compared to ever coal users in the three studies (OR=1.24, 95% CI: 1.03-1.50) (p-interaction=0.005), as well as between never coal users in the three studies and ever coal users in Xuanwei (OR=1.25, 95% CI: 1.04-1.49) (p-interaction=0.004). Conclusion: We observed an antagonistic interaction between PRS and coal use with lung adenocarcinoma, where the genetic effect was attenuated among those exposed to coal combustion in the home. We replicated the finding in Xuanwei. These results suggest that the pathogenesis of lung cancer among never-smoking women in Asia differs by exposure to coal combustion emissions and provides one of the few examples of sub-multiplicative gene-environment interactions in the cancer literature. Citation Format: Batel Blechter, Chao Agnes Hsiung, Zhihua Yin, Xiao-Ou Shu, H. Dean Hosgood, Jason Y.Y Wong, Jianxin Shi, Wei Hu, Bryan Bassig, Wei Jie Seow, Yu -ang Gao, Qiuyin Cai, Yong-Bing Xiang, I-Shou Chang, Baosen Zhou, Wei Zheng, Kyoung-Mu Lee, Stephen Chanock, Nilanjan Chatterjee, Nathaniel Rothman, Qing Lan. Analysis of polygenic risk score interaction with coal use and risk of lung adenocarcinoma among never-smoking women in Asia [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 2682.

The Hispanic paradox refers to findings in the United States (US) showing similar or better health outcomes in Hispanics than in non-Hispanic whites (NHWs) despite lower average socioeconomic status (SES). This paradox has been reported for non-small cell lung cancer (NSCLC) using data from national cancer registries, with Hispanics experiencing lower mortality rates than Non-Hispanics (NHs). However, these registries often lack critical covariate data such as smoking. To this end, we developed the Lung Cancer Clinical Cohort at Montefiore Medical Center (LC3MMC) in the Bronx, NY, to describe the growing but understudied US Hispanic population and to further elucidate factors in lung cancer survival. Subjects in LC3MMC were ≥18 years old with no prior cancer history who were diagnosed with incident primary lung carcinoma of any histology and of stage 1-4, between 2004-2017. Demographic and clinical data were obtained from MMC’s clinical systems, and tumor-related information was obtained from MMC/Einstein’s Cancer Registry. Of the 5102 subjects in LC3MMC, the mean age at diagnosis was 68 (±12) years, 50% were male, 80% were ever-smokers, 72% had known ethnicity [NHW: n=1278, Non-Hispanic Black (NHB): n=1222, Hispanic: n=855], and 80% had known histology (NSCLC: n=3554, SCLC: n=505). Based on log-rank tests, overall survival was greater in Hispanics compared to NHs (all subjects: p=0.01, NSCLC only: p=0.01) and did not differ between NHWs and NHBs (all: p=0.26, NSCLC: p=0.21). Cancer subtype (χ2: NSCLC vs. SCLC: p=0.18) and treatment rates (yes vs. no) [χ2: surgery (all: p=.08, NSCLC: p=0.12), radiation (all: p=.85, NSCLC: p=0.55), chemotherapy (all: p=0.26, NSCLC: p=0.23)] did not vary by ethnicity. Multivariate Cox proportional hazards modeling compared survival between Hispanics and NHs while adjusting for age; gender; stage; adenocarcinoma histology; smoking status; receipt of surgery, chemotherapy, radiation, and palliative care; marital status; and SES. In NSCLC patients, Hispanic ethnicity was associated with decreased risk of death (HR=0.86, 95% CI=0.74-0.99). When limiting the model to Hispanics, stage (regional: HR=2.81, 95% CI=1.72-4.57; distant: HR=6.78, 95% CI=4.24-10.85; unknown: HR=4.17, 95% CI=2.42-7.18), receipt of surgery (HR=0.53, 95% CI=0.39-0.72) and receipt of chemotherapy (HR=0.74, 95% CI=0.57-0.97) were associated with survival. Hispanic ethnicity was not associated with better survival in SCLC subjects (adjusted HR=0.97, 95% CI: 0.68-1.39). We have observed the Hispanic paradox in NSCLC in one of the largest US academic medical centers. Clinical and social factors do not fully explain the improved survival in this group. Our results provide the basis for detailed exploration of the demographic, cultural, and molecular drivers of lung cancer survival disparities among different racial/ethnic groups in the Bronx. Citation Format: Madelyn Klugman, Xiaonan Xu, Mindy Ginsberg, Thomas Rohan, H. Dean Hosgood. Elucidating drivers of the Hispanic paradox in non-small cell lung cancer [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 4207.

Background: Organochlorines (OCs) are environmentally persistent compounds that have been extensively used as pesticides and for other industrial applications. Residues of OCs have been detected at hazardous waste sites and in various environmental media worldwide and serum levels of OCs continue to be detectable in the general population. Specific OCs have been associated with non-Hodgkin lymphoma (NHL) risk with varying degrees of evidence. These associations have not been evaluated in Asia, where the exposure patterns of substantially high levels of certain OC pesticides and lower levels of polychlorinated biphenyls (PCBs) are different from Western populations. China accounted for nearly 20% of the worldwide production of dichlorodiphenyltrichloroethane (DDT) through 1983 when it was restricted, and historical usage of hexachlorocyclohexane (HCH) in China has been among the highest in the world. Methods: We evaluated the risk of NHL in relation to pre-diagnostic blood levels of five OC pesticides/metabolites (hexachlorobenzene, β-HCH, oxychlordane, trans-nonachlor, and p,p’-DDE, the primary metabolite of DDT) and four PCB congeners (118, 138-158, 153, 180) in a case-control study of 167 NHL cases and 167 controls matched on age, sex, and blood collection date. The study was nested within three population-based cohorts of Chinese men and women in Shanghai and Singapore. Associations between lipid-adjusted OC concentrations and NHL risk were analyzed using conditional logistic regression. Results: Median levels of p,p’-DDE and β-HCH were up to 12 and 65 times higher, respectively, in Shanghai (blood collected between 1986-2000) compared to reported levels in population-based cohorts in the United States (CLUE; Nurse’s Health Study) and Norway (Janus) with blood collected between 1972-1990. Median levels of p,p’-DDE and β-HCH were more comparable in Singapore (blood collected between 2000-2004) relative to the Western cohorts (1-2 fold concentration differences). Levels of β-HCH were associated with increased risk of overall NHL (3rd vs. 1st tertile OR=1.78, 95%CI=0.98-3.23; ptrend =0.049) in the pooled analysis of three cohorts. No significant associations were observed for other OCs and NHL risk, including for p,p’-DDE. Results for β-HCH and p,p’-DDE were consistent across cohorts. Discussion: Associations between β-HCH and NHL risk have not been consistent in studies of Western populations. Our findings provide the first evidence suggesting associations between blood levels of β-HCH and NHL risk in a population in Asia that experienced far higher exposures. Although there is limited evidence that DDT (IARC Group 2A) is associated with NHL based on studies in Western populations, our findings among Asians, who had higher p,p’-DDE levels than reported in the general population in the West, do not support an association with environmental exposure. Citation Format: Bryan A. Bassig, Xiao-Ou Shu, Andreas Sjodin, Woon-Puay Koh, Yu-Tang Gao, Jennifer Adams-Haduch, Mark Davis, Renwei Wang, Yong-Bing Xiang, Mark Purdue, Bu-Tian Ji, Gong Yang, Richard Jones, H. Dean Hosgood, Wei Jie Seow, Wei Hu, Wei Zheng, Jian-Min Yuan, Qing Lan, Nathaniel Rothman. Pre-diagnostic blood levels of organochlorines and risk of non-Hodgkin lymphoma in three population-based cohorts in China and Singapore [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 5043.

Background: Infections with some viruses, including HIV and Epstein-Barr Virus (EBV) in immunocompromised individuals, are known risk factors for specific subtypes of non-Hodgkin lymphoma (NHL). Epidemiological studies have also provided evidence that hepatitis viruses, and EBV in immunocompetent individuals, may also be associated with NHL. There are limited population-based prospective studies with pre-diagnostic blood samples that have comprehensively evaluated viral biomarkers and NHL risk in East Asians, in whom the descriptive characteristics of NHL and the prevalence of certain viral infections differ compared to Western populations. Methods: We conducted a nested case-control study of 214 NHL cases and 214 controls from three population-based prospective cohorts in Shanghai and Singapore. Cases and controls were individually matched by age, sex, date of blood draw, and cohort. Antibodies to 21 antigens associated with the evaluated viruses (herpesviruses, Hepatitis B (HBV) and C (HCV), and polyomaviruses) were measured in plasma/serum using fluorescent bead-based multiplex serology. Conditional logistic regression was used to evaluate associations between viral antibody levels measured as median fluorescence intensity and NHL. Results: For herpesviruses, an increased risk of NHL was observed for higher compared to lower early antigen diffuse (EA-D) (OR = 2.2, 95% CI = 1.2-4.1) and BZLF1-encoded replication activator (ZEBRA) (OR = 2.2, 95% CI = 1.0-4.9) antibodies (rsp = +0.5) associated with EBV. An increased risk of NHL was also observed among those seropositive for the intermediate-early 1A antigen (OR = 1.9, 95% CI = 1.0-3.3; rsp with EBV antibodies = +0.2) associated with human herpesvirus-6 (HHV-6). For hepatitis viruses, a significant NHL risk was observed for higher compared to lower antibodies to the HBV-associated core (HBc) antigen (OR = 1.8, 95% CI = 1.1-3.1), and this risk was particularly apparent in those with the highest HBc and EBV EA-D antibody levels (OR = 4.2, 95% CI = 1.4-12.7) compared to the lowest. Seropositivity to HCV was low (1.4% cases; 0.9% controls). No associations with NHL risk were observed for individual polyomaviruses (BK, JC, TSV, MCV). Discussion: Our study of serologic markers of infection and NHL risk in three prospective population-based studies of Chinese individuals suggests a role of specific viral agents in lymphomagenesis. The findings for EBV are consistent with some data from Western cohorts and indicate that EBV reactivation may be associated with NHL risk in the Chinese general population. HHV-6 is a lymphotropic virus that has been observed in some retrospective studies to be associated with lymphoma, but to our knowledge has not previously been associated with NHL prospectively in the general population. HBV is endemic to regions of East Asia, including China, and our data suggest that high levels of antibodies to the HBc antigen may be a marker for NHL risk. Citation Format: Bryan A. Bassig, Angelika Michel, Xiao-Ou Shu, Woon-Puay Koh, Yu-Tang Gao, Lesley M. Butler, Mark Purdue, Yong-Bing Xiang, Jennifer Adams-Haduch, Renwei Wang, Nicole Brenner, Tim Waterboer, Martina Willhauck-Fleckenstein, Bu-Tian Ji, H. Dean Hosgood, Charles S. Rabkin, Jason Y.Y. Wong, Jinming Zhang, Wei Hu, Gong Yang, Wong-Ho Chow, Michael Pawlita, Wei Zheng, Jian-Min Yuan, Qing Lan, Nathaniel Rothman. Serologic markers of infection and risk of non-Hodgkin lymphoma in a pooled prospective study of three Chinese cohorts [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 4245. doi:10.1158/1538-7445.AM2017-4245

Recent prospective studies conducted in Western populations among mostly Caucasians have suggested that higher levels of soluble CD27 (sCD27) and soluble CD30 (sCD30), two markers indicative of B-cell activation, are associated with risk of non-Hodgkin lymphoma (NHL), with significant associations persisting in individuals who were diagnosed with NHL >10 years after blood collection. However, there are currently no molecular epidemiologic data evaluating whether these biomarkers are associated with NHL risk in East Asian populations, in whom the descriptive characteristics of NHL in terms of subtype distributions and incidence rates are quite different from those in Western countries. To explore potential mechanistic commonalities for NHL in these populations, we conducted a pooled nested case-control study from three prospective studies of Chinese men and women including 218 NHL cases and 218 individually matched controls. Levels of sCD27 and sCD30 were measured in all study subjects at the same time using ELISA. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) according to quartile levels of sCD27 or sCD30 in all study controls. An increased risk of NHL in the pooled population was observed for elevated levels of both sCD27 and sCD30. Compared to the lowest quartile, ORs (95% CIs) for the 2nd, 3rd, and 4th quartiles of sCD27 were 1.60 (0.83-3.09), 1.94 (0.98-3.83), and 4.45 (2.25-8.81), respectively (ptrend = 0.000005). The corresponding ORs (95% CIs) for sCD30 were 1.74 (0.85-3.58), 1.86 (0.94-3.67), and 5.15 (2.62-10.12) (ptrend = 0.0000002). These associations remained statistically significant in individuals diagnosed with NHL 10 or more years after blood draw. Notably, the magnitude of the associations with risk of NHL was very similar to those in Western populations in previous studies. These findings of the similar association between sCD27 or sCD30 and NHL risk across different populations support an important underlying mechanism of B-cell activation in lymphomagenesis. Citation Format: Bryan A. Bassig, Xiao-Ou Shu, Woon-Puay Koh, Yu-Tang Gao, Mark P. Purdue, Lesley M. Butler, Jennifer Adams-Haduch, Yong-Bing Xiang, Troy J. Kemp, Renwei Wang, Ligia A. Pinto, Tongzhang Zheng, Bu-Tian Ji, H. Dean Hosgood, Wei Hu, Gong Yang, Heping Zhang, Wong-Ho Chow, Christopher Kim, Wei Jie Seow, Wei Zheng, Jian-Min Yuan, Qing Lan, Nathaniel Rothman. Soluble levels of CD27 and CD30 are associated with risk of non-Hodgkin lymphoma in a pooled analysis of three prospective cohorts of Chinese men and women in Shanghai and Singapore. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 846. doi:10.1158/1538-7445.AM2015-846

Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of 7 telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of 7 telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, P-value = 4.54×10−14) even after removing rs2736100 (P-value = 4.81×10−3), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk. Citation Format: Mitchell J. Machiela, Chao A. Hsiung, Xiao-Ou Shu, Wei J. Seow, Zhaoming Wang, Keitaro Matsuo, Yun-Chul Hong, Adeline Seow, Chen Wu, H Dean Hosgood, Kexin Chen, Jiu-Cun Wang, Wanqing Wen, Tangchun Wu, Maria P. Wong, Yi-Long Wu, Pan-Chyr Yang, Baosen Zhou, Min-Ho Shin, Joseph F. Fraumeni, Wei Zheng, Dongxin Lin, Stephen J. Chanock, Nathaniel Rothman, Qing Lan. Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: A report from the Female Lung Cancer Consortium in Asia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4596. doi:10.1158/1538-7445.AM2015-4596

Background: There is growing evidence that longer telomere length is associated with higher risk of lung cancer. We investigated this association in the prospective Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, which was conducted in the United States. We also combined these data with two previously published prospective cohorts: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial conducted among ever smoking males in Finland and the Shanghai Women's Health Study (SWHS) which comprised primarily of never-smoking women, resulting in a pooled analysis on a total of 847 cases and 847 controls matched by age, sex and study. Methods: Blood samples were collected prior to diagnosis of lung cancer and telomere length was measured using the same monochrome multiplex quantitative PCR method in all three studies. We used conditional logistic regression models to calculate odds ratios (OR) and their 95% confidence intervals (CI) for the association between telomere length and lung cancer risk adjusted for age, to account for residual confounding, and pack-years of smoking as continuous variables. Analyses by telomere length quartile retaining the initial categorization used in each study, and using categorization based on telomere length in pooled controls, produced similar findings and results are presented for the former. Results: In the PLCO Trial, increasing telomere length was significantly associated with lung cancer risk (adjusted OR [95% CI] by quartile: 1.00; 1.11 [0.65-1.92]; 1.20 [0.66-2.15]; and 1.83 [1.05-3.19]; P-trend = 0.011), consistent with results from the ATBC and SWHS studies. In the pooled analyses, the adjusted OR (95% CI) by quartile was 1.00; 1.24 (0.90-1.72); 1.27 (0.91-1.77); and 1.87 (1.33-2.63); P-trend = 0.000022. This positive association was particularly evident for adenocarcinoma cases, especially those diagnosed more than 6 years after blood collection (n=115; adjusted OR [95% CI] by quartile: 1.00; 2.48 [0.85-7.23]; 2.05 [0.81-5.15]; and 3.59 [1.38-9.34]; P-trend = 0.0027). Conclusion: Telomere length in white blood cell DNA may be an important biomarker of future increased risk of lung cancer in diverse populations. Citation Format: Wei Jie Seow, Richard Cawthon, Mark Purdue, Wei Hu, Yu-Tang Gao, Wen-Yi Huang, Stephanie J. Weinstein, Bu-Tian Ji, Jarmo Virtamo, Dean Hosgood, Bryan Bassig, Xiaoou Shu, Qiuyin Cai, Yongbin Xiang, Shen Min, Wong-Ho Chow, Sonja Berndt, Christopher Kim, Unhee Lim, Demetrius Albanes, Neil E. Caporaso, Stephen Chanock, Wei Zheng, Nathaniel Rothman, Qing Lan. Telomere length in white blood cell DNA and lung cancer: a pooled analysis of three prospective cohorts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4160. doi:10.1158/1538-7445.AM2014-4160

Introduction: Indoor air pollution (IAP), mostly from coal burning, was responsible for approximately 3.5 million deaths from all-causes and over 100,000 disability-adjusted life years in 2010. The majority of studies conducted in the past have been retrospective, in rural and under developed populations with recent and high levels of exposure. We assessed the association between historic kitchen coal use and various causes of mortality in the prospective Shanghai Women's Health Study cohort. Methods: A cohort of 73,363 women was followed through December 2009 with a combination of in-person surveys every 2-3 years and annual linkage to a vital statistics registry database where all causes of mortality was recorded. A total of 3808 deaths were identified during the follow-up period. Cox proportional hazards models were used to estimate risk of mortality associated with in-home coal use. Models were adjusted for smoking status, family income, environmental tobacco smoke, occupational history, shift work, BMI, hormone therapy, and parity. Results: All-cause mortality was elevated 13% among ever coal users (Hazard Ratio (HR): 1.13; 95% CI: 1.04-1.23) compared to never-coal users. Coal use was most strongly associated with all-cause mortality among women who had more than 15 years of coal use (15-30 years: HR: 1.14; 95% CI: 1.02-1.26; >30 years: HR: 1.15; 95% CI: 1.04-1.26). Women with 15-30 years of coal use had a 21% elevation of cancer mortality (95% CI: 1.04-1.42), but no elevation was observed in women with >30 years of coal use (HR: 1.06; 95% CI: 0.91-1.24) compared to never-coal users. More than 30 years of coal use was associated with a 32% elevated risk of cardiovascular mortality (HR: 1.32; 95% CI: 1.11-1.57), and 62% elevated risk of myocardial infarction mortality (HR: 1.62; 95% CI: 1.01-2.63) compared to never-coal users. All-cause mortality was elevated in women who last lived in a coal burning home up to 20 years ago (>0-10 years: HR: 1.16; 95% CI: 1.04-1.28; >10-20 years: HR: 1.21; 95% CI: 1.09-1.35). Discussion: This is the first study of mortality and in-home coal use in a prospective study after much of Shanghai transitioned into a developed and urban city. Evidence from this study suggests that previous coal use could be related to excess cardiovascular and cancer deaths among women in Shanghai. Citation Format: Christopher Kim, Xiao-Ou Shu, H. Dean Hosgood, Bryan A. Bassig, Wei Jie Seow, Yongbin Xiang, Bu-Tian Ji, Wei Hu, Wong-Ho Chow, Yutang Gao, Nathaniel Rothman, Qing Lan. Past use of coal for cooking is associated with all-cause mortality in the prospective Shanghai Women's Health Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2184. doi:10.1158/1538-7445.AM2014-2184

Lung cancer incidence has been on the rise in less-developed countries. Indoor air pollution caused by poor ventilation, burning of solid fuels, and cooking oils has been associated with lung cancer risk in developing poor and rural countries in many retrospective case-control studies. However, few studies have been conducted in more urban and more economically developed populations, even less in prospective studies. To assess the relationship of indoor air quality and risk of lung cancer in a modern population, a prospective cohort study was conducted in the Shanghai Women's Health Study. 73,442 women were followed through December 2009. A total of 469 lung cancer patients were diagnosed during the follow-up period, but after excluding ever smokers, 71,320 women in the cohort and 429 women with lung cancer were included in this analysis. Standardized and structured questionnaires were used to collect information on all household living and cooking practices: past three residences lived, cooking fuel utilized, cooking oil utilized, ventilation conditions, smoking patterns of family at home, and coworker smoking at work. Effect estimates for household ventilation conditions, cooking fuels, and cooking oils use for the risk of lung cancer are presented as hazard ratios (HR) with 95% confidence intervals (95% CI) from Cox proportional hazards regression. Ever having poor household ventilation was associated with a 61% increase in lung cancer risk (HR: 1.61; 95% CI: 1.19-2.18), and more than 20 years was associated with a 100% increase in risk (HR: 2.00; 95% CI: 1.32-3.01) compared to always having good ventilation. Ever use of coal with poor ventilation was associated with a 71% increased risk of lung cancer (HR: 1.71; 95% CI: 1.19-2.46), and more than 20 years of using coal with poor ventilation was associated with an 83% increase (HR: 1.83; 95% CI: 1.16-2.89) compared to gas users with good ventilation. There was some suggestion of lung cancer risk with vegetable oil use compared to soybean oil use, although the number of lung cancer cases was few and not statistically stable. In summary, this prospective cohort study of non-smoking Chinese women suggests that exposure to poor ventilation and poorly vented cooking coal increases the risk of lung cancer. These findings were consistent with past retrospective case-control studies and suggesting that past exposure to coal use with poorly ventilated conditions pose a health risk. These results suggest that current modern day cooking conditions, particularly in poorly ventilated homes, is still a public health issue. Citation Format: Christopher Kim, Yutang Gao, Yongbing Xiang, Francesco Barone-Adesi, Yawei Zhang, H. Dean Hosgood, Shuangge Ma, Xiao-ou Shu, Bu-Tian Ji, Wong-Ho Chow, Qiuyin Cai, Wei Zheng, Nathaniel Rothman, Qing Lan. Household ventilation, cooking fuels and oils, and lung cancer risk in a prospective cohort of non-smoking Chinese women. [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 3629. doi:10.1158/1538-7445.AM2013-3629

RATIONALE: Human exposure to indoor smoke emissions from the domestic burning of solid fuels (e.g. coal, wood, plant materials) is a major cause of morbidity and mortality that affects nearly half of the world's population. While epidemiologic studies on the health impact of indoor air pollution (IAP) have yielded valuable insights from the use of various exposure assessments (e.g. personal and area air sampling, urinary metabolites), there is a need to connect these exposure measures to biomarkers of the host's physiologic response to exposure. We have previously shown that gene-expression (GE) profiles in the upper airway epithelium are affected by tobacco smoke. Thus, we sought to determine whether transcriptomic changes in the oral mucosal epithelium might also capture physiologic responses to IAP from the burning of solid fuels. METHODS: Buccal mucosa epithelial cell scrapings were collected from healthy, non-smoking female subjects in rural Xuanwei, China, where female lung cancer rates are among the highest in the world. Benzo(a)pyrene (BaP) exposure levels from indoor burning of solid fuels (primarily coal) for cooking and heating were measured by personal in-home air monitoring. RNA from 18 samples was extracted and processed onto Affymetrix Gene 1.0 ST arrays. Student's t-test and DAVID were used to identify and characterize genes that vary between relatively high levels of BaP exposure (n=8; BaP 99.0 +/- 45.9) and low (n=10; BaP 16.2 +/- 6.1) exposure. Using GSEA, results were compared to independent airway epithelial GE profiles that distinguish current smokers from never smokers and bronchial GE profiles in subjects with and without lung cancer. RESULTS: We identified 227 genes that were differentially expressed between subjects with high and low BaP exposure (p Citation Format: Teresa W. Wang, Qing Lan, Bozena Krystyna, Nathaniel Rothman, Roberta Florido, Wei Hu, Katrina Steiling, Gang Liu, Ji Xiao, Yuriy Alekseyev, Jun Xu, Fusheng Wei, H. Dean Hosgood, Boris Reiss, George Downward, Marc Lenburg, Roel Vermeulen, Avrum Spira. Transcriptomic changes in the oral mucosal epithelium reflect the physiologic response to indoor burning of solid fuels. [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 112. doi:10.1158/1538-7445.AM2013-112

Background: Mitochondrial DNA (mtDNA) is vulnerable to mutations, and the number of copies of mtDNA per cell may increase to compensate for DNA damage. Recent studies have evaluated blood leukocyte mtDNA copy number and risk of various types of cancer, including renal cell carcinoma (RCC). Although alterations in mtDNA copy number have been associated with cancer risk, the direction of this association has been inconsistent between studies with prospective and retrospective blood collection. One case-control study found that low mtDNA copy number was associated with an increased risk of RCC; however, this association has not been investigated prospectively. Methods: We conducted a nested case-control study of RCC risk in relation to mtDNA copy number in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 230 cases and 469 controls matched on age, sex, race, date of blood collection and specimen type were included. Measurements of mtDNA copy number were performed in triplicate using a fluorescence-based QPCR assay. Assay results were highly reproducible, with a coefficient of variation of 5.3% for replicate QC samples from a single individual and an intraclass correlation coefficient of 0.69 for duplicate samples collected an average of 3.6 years apart from 45 controls. To evaluate risk of RCC in relation to mtDNA copy number, we calculated odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression models adjusted for all matching variables as well as history of hypertension, body mass index, smoking history, and family history of kidney cancer. Subjects were assigned to quartiles of mtDNA copy number based on the distribution among controls. Results: Median mtDNA copy number was higher for cases than for controls (131 vs. 121; P=0.001, Wilcoxon rank-sum test). Relative to subjects in the lowest quartile of mtDNA copy number, the ORs for subjects in the 2nd, 3rd, and 4th quartiles were 1.0 (95% CI 0.6-1.6), 1.5 (95% 0.9-2.3), and 1.9 (95% CI 1.2-3.1), respectively (Ptrend = 0.003). The association between mtDNA copy number and RCC was stronger among men (highest vs. lowest quartile, OR 2.4, 95% CI 1.3-4.4) than among women (OR 1.3, 95% CI 0.5-3.2; Pint = 0.24). Results were similar in conditional logistic regression analyses of matched sets, and when we restricted to subjects with mtDNA from buffy coat specimens and to cases diagnosed more than two years after sample collection. Conclusions: Results of this study, to our knowledge the first prospective investigation of mtDNA copy number and RCC risk, suggest that high mtDNA copy number is associated with an increased risk of RCC, particularly among men. Although our findings were inconsistent with prior case-control evidence, most prospective studies of other cancers (e.g., lung, pancreas, non-Hodgkin lymphoma) have reported positive associations. Replication of these findings in other prospective cohorts is needed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4461. doi:1538-7445.AM2012-4461

The pattern recognition pathway plays an important role in infection recognition and immune responses, and previous studies have suggested an association between genetic variation in innate immunity genes and non-Hodgkin lymphoma (NHL). We evaluated NHL risk associated with the common genetic variation in pattern recognition genes using data from a case-control study of NHL conducted in Connecticut women. Single nucleotide polymorphisms (SNPs) in 27 pattern recognition genes were genotyped in 432 Caucasian incident NHL cases and 494 frequency-matched controls. Unconditional logistic regression was used to compute odds ratios (ORs) for NHL and four major NHL subtypes in relation to individual SNPs and haplotypes. A gene-based analysis that adjusted for the number of tagSNPs genotyped in each gene showed significant association with overall NHL for the MBP gene (p=0.028), with DLBCL subtype for the MASP2 gene (p=0.011), and with FL subtype for the DEFB126 (p=0.041). A SNP-based analysis showed that MBP rs8094402 was associated with decreased risks of overall NHL (allele risk OR=0.72, p-trend=0.0018), DLBCL (allele risk OR=0.72, p-trend=0.036), and FL (allele risk OR=0.67, p-trend=0.021). MASP2 rs12711521 was associated with a decreased risk of DLBCL (allele risk OR=0.57, p-trend=0.0042). We also observed an increased risk of FL for DEFB126 rs6054706 (allele risk OR=1.39, p-trend=0.033). Our results are suggestive of a potential role of the pattern recognition in susceptibility to NHL but require replication in larger studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2641. doi:1538-7445.AM2012-2641

Introduction: Lung cancer rates in Xuanwei County, Yunnan Province are among the highest in China. We have previously reported that indoor combustion of smoky coal for home heating and cooking was associated with increased risk of lung cancer and that this effect varies markedly by coal type. Further, improved stove ventilation is followed by reduction in lung cancer risk. We explored the joint relationship between tobacco use and coal use in Xuanwei men. Methods: We analyzed data from a population-based case-control study of lung cancer in Xuanwei. Cases were identified from four Xuanwei hospitals and controls were selected from the general population by probability sampling. Controls were matched one-to-one with cases on age. In total, 260 cases and 260 controls were analyzed in this study. Tobacco, coal, and solid fuel exposures were tabulated from questionnaires and reported in cigarette pack-years, duration of smoking, and average tons of coal used annually. Odds ratios and 95% confidence intervals were estimated by conditional logistic regression with the main effects of coal, smoking, and coal-smoking interaction terms. Results: Overall, smoking was positively and significantly, although only modestly, associated with lung cancer risk (OR per pack-year: 1.02; 95% CI: 1.01-1.04). The risk of lung cancer per pack-year of smoking decreased as cumulative lifetime use of smoky coal increased (0-50 tons coal: OR: 1.07; 95% CI: 1.01-1.15; >50-150 tons coal: OR: 1.05; 95% CI: 1.01-1.10; >150 tons coal: OR: 1.00; 95% CI: 0.99-1.03; P-interaction: 0.041). Discussion: Our results suggest that the effect of tobacco on lung cancer risk was weaker in men exposed to higher amounts of coal. Results are consistent with previous cohort study findings in Xuanwei. Constituents of coal combustion, such as polycyclic aromatic hydrocarbons, could plausibly act to diminish the carcinogenicity of tobacco through metabolic competition or other possible mechanisms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5478. doi:1538-7445.AM2012-5478

Trichloroethylene (TCE) is a volatile chlorinated organic compound that is commonly used in the workplace as a degreaser for metal parts and general-purpose solvent for lipophilic compounds. Although TCE is considered an animal carcinogen, its carcinogenic potential in humans is uncertain. Occupational exposure to TCE has been associated with increased risk of kidney cancer and non-Hodgkin lymphoma in some studies, but findings are not fully consistent. We have carried out a cross-sectional study of 80 workers exposed to TCE and 96 unexposed controls matched on age and sex in Guangdong, China to study TCE's early biologic effects. We previously reported that the total lymphocyte count (but not the granulocyte count) and each of the major lymphocyte subsets (i.e., CD4+ T cells, CD8+ T cells, natural killer (NK) cells, and B cells) were decreased in TCE-exposed workers compared to controls. These findings suggested a selective effect of TCE exposure on lymphoid progenitors and/or lymphocyte survival. To further study which subsets of lymphocytes are affected specifically, we investigated the effect of TCE exposure on the numbers of CD4+ naïve and memory T cells, CD8+ naïve and memory T cells, and regulatory T cells by FACS analysis. Linear regression using the natural logarithm (ln) of each subset was used to test for differences between exposed workers and controls adjusting for potential confounders such as age, sex, smoking status, alcohol consumption, recent infections, and body mass index. We observed that CD4+ and CD8+ naïve T cell counts were about 8% (p = 0.056) and 17% (p = 0.0002) lower, respectively, among exposed workers. Strikingly, CD4+ effector memory T cell counts were decreased by about 20% among TCE exposed workers compared to controls (p = 0.001) whereas the CD4+ central memory T cell population was not significantly changed. Intriguingly, the numbers of CD4+ central memory T cells, and CD8+ memory T cells including central and effector memory population, as well as regulatory T cells were not significantly different between the controls and exposed workers. Thus, TCE selectively targets CD4+ naïve and CD4+ effector memory T cells, and CD8+ naïve T cells. These findings provide further insights into the biologic response of human immune cells upon exposure to TCE, which may include immunosuppression through reduced capacity to respond to antigens. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4645. doi:10.1158/1538-7445.AM2011-4645

The degree of activation of peritoneal macrophages elicited by pyran copolymer (MVE-2) was studied in C57BL/6J mice. When cytotoxicity was examined under endotoxin-free culture conditions, the pyran-elicited macrophages could not complete cytolysis of tumor target cells. The macrophages, however, completed cytolysis when pulsed with endotoxin. These results were obtained when either the interval between injection of the pyran copolymer and harvest of the macrophage or the dose of pyran was varied. The pyran-elicited macrophages expressed five markers considered to be typical of inflammatory macrophages, and bound tumor cells to an augmented degree. The pyran-elicited macrophages were capable of secreting a potent cytolytic proteinase when pulsed with endotoxin, but did not secrete cytolytic proteinase spontaneously. The pyran-elicited macrophages, in contrast to inflammatory macrophages, could effect cytostasis of tumor cells; their cytostatic potential was also augmented by addition of endotoxin. Taken together, the results indicated that pyran copolymer elicits primed but not fully activated murine macrophages.