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Background: Genome-wide association studies have identified multiple genetic variants associated with susceptibility to prostate cancer (PrCa). In the two-stage Cancer Genetic Markers of Susceptibility prostate cancer scan, a single-nucleotide polymorphism (SNP), rs10486567, located within intron 2 of JAZF1 gene on chromosome 7p15.2, showed a promising association with PrCa overall (P = 2.14 × 10−6), with a suggestion of stronger association with aggressive disease (P = 1.2 × 10−7).Methods: In the third stage of genome-wide association studies, we genotyped 106 JAZF1 SNPs in 10,286 PrCa cases and 9,135 controls of European ancestry.Results: The strongest association was observed with the initial marker rs10486567, which now achieves genome-wide significance [P = 7.79 × 10−11; ORHET, 1.19 (95% confidence interval, 1.12-1.27); ORHOM, 1.37 (95% confidence interval, 1.20-1.56)]. We did not confirm a previous suggestion of a stronger association of rs10486567 with aggressive disease (P = 1.60 × 10−4 for aggressive cancer, n = 4,597; P = 3.25 × 10−8 for nonaggressive cancer, n = 4,514). Based on a multilocus model with adjustment for rs10486567, no additional independent signals were observed at chromosome 7p15.2. There was no association between PrCa risk and SNPs in JAZF1 previously associated with height (rs849140; P = 0.587), body stature (rs849141, tagged by rs849136; P = 0.171), and risk of type 2 diabetes and systemic lupus erythematosus (rs864745, tagged by rs849142; P = 0.657).Conclusion: rs10486567 remains the most significant marker for PrCa risk within JAZF1 in individuals of European ancestry.Impact: Future studies should identify all variants in high linkage disequilibrium with rs10486567 and evaluate their functional significance for PrCa. Cancer Epidemiol Biomarkers Prev; 19(5); 1349–55. ©2010 AACR.

SUPPLEMENTAL TABLE: Effect of homozygosity at the three HLA class I loci -A, -B and -C and five HLA class I loci -DRB1, DQA1, DQB1, DPA1, and DPB1 on susceptibility to four NHL subtypes (DLBCL, FL, CLL/SLL, and MZL) stratified by GWAS platform (analyses adjusted for sex, age, and ancestry/principal components)

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Background: One of the goals of personalized medicine is to generate individual risk profiles that could identify individuals in the population that exhibit high risk. The discovery of more than two-dozen independent single-nucleotide polymorphism markers in prostate cancer has raised the possibility for such risk stratification. In this study, we evaluated the discriminative and predictive ability for prostate cancer risk models incorporating 25 common prostate cancer genetic markers, family history of prostate cancer, and age.Methods: We fit a series of risk models and estimated their performance in 7,509 prostate cancer cases and 7,652 controls within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also calculated absolute risks based on SEER incidence data.Results: The best risk model (C-statistic = 0.642) included individual genetic markers and family history of prostate cancer. We observed a decreasing trend in discriminative ability with advancing age (P = 0.009), with highest accuracy in men younger than 60 years (C-statistic = 0.679). The absolute ten-year risk for 50-year-old men with a family history ranged from 1.6% (10th percentile of genetic risk) to 6.7% (90th percentile of genetic risk). For men without family history, the risk ranged from 0.8% (10th percentile) to 3.4% (90th percentile).Conclusions: Our results indicate that incorporating genetic information and family history in prostate cancer risk models can be particularly useful for identifying younger men that might benefit from prostate-specific antigen screening.Impact: Although adding genetic risk markers improves model performance, the clinical utility of these genetic risk models is limited. Cancer Epidemiol Biomarkers Prev; 21(3); 437–44. ©2012 AACR.

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Supplementary Table 3 from Refining the Prostate Cancer Genetic Association within the JAZF1 Gene on Chromosome 7p15.2

Supplementary Table 1 from Refining the Prostate Cancer Genetic Association within the JAZF1 Gene on Chromosome 7p15.2

Supplementary Table Legends from Refining the Prostate Cancer Genetic Association within the JAZF1 Gene on Chromosome 7p15.2

Association between CCNE1 variants and bladder cancer

Supplementary Tables 1S-7S, Figure 1S from Haplotype Analysis of the HSD17B1 Gene and Risk of Breast Cancer: A Comprehensive Approach to Multicenter Analyses of Prospective Cohort Studies

Supplementary Figure 1: Electrophoretic mobility shift assays (EMSA) for CCNE1 SNPs rs8102137 and rs7257330. Supplementary Figure 2: Alignment of cyclin E protein isoforms - WT1, WT2 and ES and ET. Supplementary Figure 3: Functional analysis of cyclin E isoforms.Supplementary Table 1: Description of sub-studies included in NCI-GWAS1 and GWAS2 of bladder cancer. Supplementary Table 2: Characteristics of bladder tissue samples used for mRNA expression analysis. Supplementary Table 3: PCR primers, genotyping and gene expression assays, EMSA probes and antibodies. Supplementary Table 4: Bladder cancer stage and grade information for patients in the combined GWAS1+2 set. Supplementary Table 6: Association with bladder cancer risk with mutual adjustment for CCNE1 variants. Supplementary Table 7: Association with bladder cancer risk for CCNE1 variants previously associated with other cancers and for two non-synonymous coding variants. Supplementary Table 8: Association between cyclin E protein expression (IHC scores), bladder cancer patient characteristics and CCNE1 variants.

Background: Cannabis use is increasing, including among smokers, an at-risk population for cancer. Research is equivocal on whether using cannabis inhibits quitting cigarettes. The current longitudinal study investigated associations between smoking cannabis and subsequently quitting cigarettes. Methods: Participants were 4,535 adult cigarette smokers from a cohort enrolled in the American Cancer Society's Cancer Prevention Study-3 in 2009–2013. Cigarette quitting was assessed on a follow-up survey in 2015–2017, an average of 3.1 years later. Rates of quitting cigarettes at follow-up were examined by retrospectively assessed baseline cannabis smoking status (never, former, recent), and by frequency of cannabis smoking among recent cannabis smokers (low: ≤3 days/month; medium: 4–19 days/month; high: ≥20 days/month). Logistic regression models adjusted for sociodemographic factors, smoking- and health-related behaviors, and time between baseline and follow-up. Results: Adjusted cigarette quitting rates at follow-up did not differ significantly by baseline cannabis smoking status [never 36.2%, 95% confidence interval (CI), 34.5–37.8; former 34.1%, CI, 31.4–37.0; recent 33.6%, CI, 30.1–37.3], nor by frequency of cannabis smoking (low 31.4%, CI, 25.6–37.3; moderate 36.7%, CI, 30.7–42.3; high 34.4%, CI, 28.3–40.2) among recent baseline cannabis smokers. In cross-sectional analyses conducted at follow-up, the proportion of cigarette smokers intending to quit smoking cigarettes in the next 30 days did not differ by cannabis smoking status (P = 0.83). Conclusions: Results do not support the hypothesis that cannabis smoking inhibits quitting cigarette smoking among adults. Impact: Future longitudinal research should include follow-ups of >1 year, and assess effects of intensity/frequency of cannabis use and motivation to quit on smoking cessation.

Identifying risk factors for women at high risk of symptom-detected breast cancers that were missed by screening would enable targeting of enhanced screening regimens. To this end, we examined associations of breast cancer risk factors by mode of detection in screened women from the Cancer Prevention Study (CPS)-II Nutrition Cohort. Among 77,206 women followed for a median of 14.8 years, 2711 screen-detected and 1281 symptom-detected breast cancer cases were diagnosed. Multivariable-adjusted associations were estimated using joint Cox proportional hazards regression models with person-time calculated contingent on screening. Factors associated with higher risks of symptom-detected and screen-detected breast cancer included current combined hormone therapy (HT) use (HR 2.07, 95% CI 1.72–2.48 and 1.45, 1.27–1.65, respectively) and history of benign breast disease (1.85, 1.64–2.08 and 1.43, 1.31–1.55, respectively). Current estrogen-only HT use was associated with symptom-detected (1.40, 1.15–1.71) but not screen-detected (0.95, 0.83–1.09) breast cancer. Higher risk of screen-detected but not symptom-detected breast cancer was observed for obese vs. normal body mass index (1.22, 1.01–1.48 and 0.76, 0.56–1.01, respectively), per 3 h/day sitting time (1.10, 1.04–1.16 and 0.97, 0.89–1.06, respectively), and ≥ 2 drinks per day vs. nondrinker (1.40, 1.16–1.69 and 1.27, 0.97–1.66, respectively). Differences in risk factors for symptom-detected vs. screen-detected breast cancer were observed and most notably, use of combined and estrogen-only HT and a history of benign breast disease were associated with increased risk of symptomatic detected breast cancer. If confirmed, these data suggest that such women may benefit from more intensive screening to facilitate early detection.

Cadmium and lead are persistent environmental toxins that are known or probable carcinogens, based on evidence for causality for nonhematologic cancers. Associations of these metals with risk of non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are unknown but biologically plausible. To examine the associations of circulating levels of lead and cadmium exposure with risk of B-cell NHL (B-NHL) and multiple myeloma, we conducted a nested case-control study among 299 incident B-cell NHLs and 76 MM cases within the Cancer Prevention Study-II Nutrition Cohort (CPS-II NC). Each case was incidence-density matched to two eligible controls on age, race, sex and blood draw date. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) for lymphoid malignancies overall and stratified by subtype. We observed a significant positive association between high erythrocyte lead concentration and risk of lymphoid malignancies overall (RR = 1.16, 95% CI: 1.02-1.33 per 17.6 μg/L (1 standard deviation [SD])) and follicular lymphoma in particular (RR = 1.80, 95% CI: 1.15-2.80 per SD). In contrast, there was no association between erythrocyte cadmium and risk of B-NHL (RR = 0.89, 95% CI: 0.75-1.06 per 0.37 μg/L [1 SD]), or any B-NHL subtypes; but a strong inverse association with MM risk (RR = 0.59, 95% CI: 0.38-0.89, per SD). Results from our study suggest a positive association between erythrocyte lead level and risk of lymphoid malignancies and a possible inverse association between cadmium and myeloma. Additional research is needed to confirm and further explore these findings.

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10−6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10−12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

Nighttime light exposure may increase cancer risk by disrupting the circadian system. However, there is no well-established survey method for measuring ambient light. In the Cancer Prevention Study-3, 732 men and women answered a light survey based on seven environments. The light environment in the past year was assessed twice, one year apart, and four one-week diaries were collected between the annual surveys. A total of 170 participants wore a meter to measure photopic illuminance and circadian stimulus (CS). Illuminance and CS values were estimated for lighting environments from measured values and evaluated with a cross validation approach. The kappas for self-reported light environment comparing the two annual surveys were 0.61 on workdays and 0.49 on non-workdays. Kappas comparing the annual survey to weekly diaries were 0.71 and 0.57 for work and non-workdays, respectively. Agreement was highest for reporting of darkness (95.3%), non-residential light (86.5%), and household light (75.6%) on workdays. Measured illuminance and CS identified three peaks of light (darkness, indoor lighting, and outdoor daytime light). Estimated illuminance and CS were correlated with the measured values overall (r = 0.77 and r = 0.67, respectively) but were less correlated within each light environment (r = 0.23–0.43). The survey has good validity to assess ambient light for studies of human health.

ImportanceThe number of cancer survivors living in the US is projected to be 26.1 million by 2040. Cancer survivors may be at increased risk of bone fractures, but research is limited in several important ways.ObjectiveTo investigate the associations of cancer diagnoses, including time since diagnosis and stage at diagnosis, with risks of pelvic, radial, and vertebral fractures (separately and combined) among older cancer survivors and compared with fracture risk among older adults without a history of cancer. Secondarily, to examine differences in risk of fracture stratified by modifiable behaviors, treatment, and cancer type.Design, Setting, and ParticipantsThis longitudinal cohort study used data from 92 431 older adults in the US Cancer Prevention Study II Nutrition Cohort linked with 1999 to 2017 Medicare claims. Data were analyzed from July 15, 2021, to May 3, 2022.ExposuresCancer history, time since cancer diagnosis, and stage at cancer diagnosis.Main Outcomes and MeasuresHazard ratios (HRs) and 95% CIs for the risk of pelvic, radial, vertebral, and total frailty-related fractures were estimated using multivariate Cox proportional hazards regression. Stratification was used for secondary aims.ResultsAmong 92 431 participants (mean [SD] age, was 69.4 [6.0] years, 51 820 [56%] women, and 90 458 [97.9%] White], 12 943 participants experienced a frailty-related bone fracture. Compared with participants without a history of cancer, cancer survivors who were diagnosed 1 to less than 5 years earlier with advanced stage cancer had higher risk of fracture (HR, 2.12; 95% CI, 1.75-2.58). The higher fracture risk in cancer survivors with recent advanced stage diagnosis (vs no cancer) was driven largely by vertebral (HR, 2.46; 95% CI, 1.93-3.13) and pelvic (HR, 2.46; 95% CI, 1.84-3.29) fracture sites. Compared with cancer survivors who did not receive chemotherapy, survivors who received chemotherapy were more likely to have a fracture; this association was stronger within 5 years of diagnosis (HR, 1.31; 95% CI, 1.09-1.57) than 5 or more years after diagnosis (HR, 1.22; 95% CI, 0.99-1.51). Although the HR for risk of fracture was lower among physically active cancer survivors 5 or more years after diagnosis (HR, 0.76; 95% CI, 0.54-1.07), this result was not statistically significant, whereas current smoking was significantly associated with higher risk of fracture (HR, 2.27; 95% CI, 1.55-3.33).Conclusions and RelevanceFindings from this cohort study suggest that older adults with a history of cancer may benefit from clinical guidance on prevention of frailty-related fractures. If study findings are replicated, fracture prevention programs for survivors might include referrals for physical activity with cancer exercise professionals and smoking cessation programs.

Background Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic or likely pathogenic (P/LP) variants in 5451 long-term pediatric cancer survivors from the Childhood Cancer Survivor Study. Methods Exome sequencing was conducted on germline DNA from 5451 pediatric cancer survivors (cases who survived ≥5 years from diagnosis; n = 5105 European) and 597 European cancer-free adults (controls). Analyses focused on comparing the frequency of rare P/LP variants in 237 cancer-susceptibility genes and a subset of 60 autosomal dominant high-to-moderate penetrance genes, for both case-case and case-control comparisons. Results Of European cases, 4.1% harbored a P/LP variant in high-to-moderate penetrance autosomal dominant genes compared with 1.3% in controls (2-sided P = 3 × 10-4). The highest frequency of P/LP variants was in genes typically associated with adult onset rather than pediatric cancers, including BRCA1/2, FH, PALB2, PMS2, and CDKN2A. A statistically significant excess of P/LP variants, after correction for multiple tests, was detected in patients with central nervous system cancers (NF1, SUFU, TSC1, PTCH2), Wilms tumor (WT1, REST), non-Hodgkin lymphoma (PMS2), and soft tissue sarcomas (SDHB, DICER1, TP53, ERCC4, FGFR3) compared with other pediatric cancers. Conclusion In long-term pediatric cancer survivors, we identified P/LP variants in cancer-susceptibility genes not previously associated with pediatric cancer as well as confirmed known associations. Further characterization of variants in these genes in pediatric cancer will be important to provide optimal genetic counseling for patients and their families.

Background The risk of infection and severity of illness by SARS-CoV-2 infection is elevated for people who smoke cigarettes and may motivate quitting. Organic public conversations on Twitter about quitting smoking could provide insight into quitting motivations or behaviors associated with the pandemic. Objective This study explored key topics of conversation about quitting cigarette smoking and examined their trajectory during 2018-2020. Methods Topic model analysis with latent Dirichlet allocation (LDA) identified themes in US tweets with the term “quit smoking.” The model was trained on posts from 2018 and was then applied to tweets posted in 2019 and 2020. Analysis of variance and follow-up pairwise tests were used to compare the daily frequency of tweets within and across years by quarter. Results The mean numbers of daily tweets on quitting smoking in 2018, 2019, and 2020 were 133 (SD 36.2), 145 (SD 69.4), and 127 (SD 32.6), respectively. Six topics were extracted: (1) need to quit, (2) personal experiences, (3) electronic cigarettes (e-cigarettes), (4) advice/success, (5) quitting as a component of general health behavior change, and (6) clinics/services. Overall, the pandemic was not associated with changes in posts about quitting; instead, New Year’s resolutions and the 2019 e-cigarette or vaping use–associated lung injury (EVALI) epidemic were more plausible explanations for observed changes within and across years. Fewer second-quarter posts in 2020 for the topic e-cigarettes may reflect lower pandemic-related quitting interest, whereas fourth-quarter increases in 2020 for other topics pointed to a late-year upswing. Conclusions Twitter posts suggest that the pandemic did not generate greater interest in quitting smoking, but possibly a decrease in motivation when the rate of infections was increasing in the second quarter of 2020. Public health authorities may wish to craft messages for specific Twitter audiences (eg, using hashtags) to motivate quitting during pandemics.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

Outdoor air pollution is a major contributor to the burden of disease worldwide. Most of the global population resides in places where air pollution levels, because of emissions from industry, power generation, transportation, and domestic burning, considerably exceed the World Health Organization's health-based air-quality guidelines. Outdoor air pollution poses an urgent worldwide public health challenge because it is ubiquitous and has numerous serious adverse human health effects, including cancer. Currently, there is substantial evidence from studies of humans and experimental animals as well as mechanistic evidence to support a causal link between outdoor (ambient) air pollution, and especially particulate matter (PM) in outdoor air, with lung cancer incidence and mortality. It is estimated that hundreds of thousands of lung cancer deaths annually worldwide are attributable to PM air pollution. Epidemiological evidence on outdoor air pollution and the risk of other types of cancer, such as bladder cancer or breast cancer, is more limited. Outdoor air pollution may also be associated with poorer cancer survival, although further research is needed. This report presents an overview of outdoor air pollutants, sources, and global levels, as well as a description of epidemiological evidence linking outdoor air pollution with cancer incidence and mortality. Biological mechanisms of air pollution-derived carcinogenesis are also described. This report concludes by summarizing public health/policy recommendations, including multilevel interventions aimed at individual, community, and regional scales. Specific roles for medical and health care communities with regard to prevention and advocacy and recommendations for further research are also described.

Identifying risk factors for women at high risk of symptom-detected breast cancers that were missed by screening would enable targeting of enhanced screening regimens. To this end, we examined associations of breast cancer risk factors by mode of detection in screened women from the Cancer Prevention Study (CPS)-II Nutrition Cohort.Among 77,206 women followed for a median of 14.8 years, 2711 screen-detected and 1281 symptom-detected breast cancer cases were diagnosed. Multivariable-adjusted associations were estimated using joint Cox proportional hazards regression models with person-time calculated contingent on screening.Factors associated with higher risks of symptom-detected and screen-detected breast cancer included current combined hormone therapy (HT) use (HR 2.07, 95% CI 1.72-2.48 and 1.45, 1.27-1.65, respectively) and history of benign breast disease (1.85, 1.64-2.08 and 1.43, 1.31-1.55, respectively). Current estrogen-only HT use was associated with symptom-detected (1.40, 1.15-1.71) but not screen-detected (0.95, 0.83-1.09) breast cancer. Higher risk of screen-detected but not symptom-detected breast cancer was observed for obese vs. normal body mass index (1.22, 1.01-1.48 and 0.76, 0.56-1.01, respectively), per 3 h/day sitting time (1.10, 1.04-1.16 and 0.97, 0.89-1.06, respectively), and ≥ 2 drinks per day vs. nondrinker (1.40, 1.16-1.69 and 1.27, 0.97-1.66, respectively).Differences in risk factors for symptom-detected vs. screen-detected breast cancer were observed and most notably, use of combined and estrogen-only HT and a history of benign breast disease were associated with increased risk of symptomatic detected breast cancer.If confirmed, these data suggest that such women may benefit from more intensive screening to facilitate early detection.

Cadmium and lead have been classified as carcinogens by the International Agency for Research on Cancer. However, their associations with breast cancer risk are unknown despite their persistence in ...

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Associations between long-term exposure to ambient fine particulate matter (PM2.5) and all-cause and cardiovascular mortality are well documented however less is known regarding possible interactions with cigarette smoking. We previously reported a supra-additive synergistic relationship between PM2.5 and cigarette smoking for lung cancer mortality. Here we examine interactions for all-cause and cardiovascular mortality among 429,406 current or never smoking participants in the prospective American Cancer Society Cancer Prevention Study-II with modeled PM2.5 concentrations. Cox proportional and additive hazards models were used to estimate mortality associations and interactions on the multiplicative and additive scales. A total of 146,495 all-cause and 64,339 cardiovascular (plus diabetes) deaths were observed. The hazard ratio (HR) (95% confidence interval (CI)) for cardiovascular mortality for high vs. low PM2.5 exposure (>14.44µg/m3 vs ≤10.59µg/m3, 75th vs 25th percentile) was 1.09 (95% CI 1.05, 1.12) in never smokers. The HR for cigarette smoking was 1.89 (95% CI 1.82, 1.96) in those with low PM2.5. The HR for both high PM2.5 and cigarette smoking was 2.08 (95% CI 2.00, 2.17). A small significant excess relative risk due to interaction (0.10; 95% CI 0.02, 0.19) was observed. Quantification of the public health burden attributed to the interaction between PM2.5 and cigarette smoking indicated a total of 32 (95% CI -6, 71) additional cardiovascular deaths per 100,000 person-years due to this interaction. In conclusion, PM2.5 was associated with all-cause and cardiovascular mortality in both smokers and never smokers, with some evidence for a small additive interaction with cigarette smoking. Reductions in cigarette smoking will result in the greatest impact on reducing all-cause and cardiovascular death at the levels of PM2.5 observed in this study. However, reductions in PM2.5 will also contribute to preventing a proportion of mortality attributed to cigarette smoking.

BACKGROUND Prospective cohort studies contribute importantly to understanding the role of lifestyle, genetic, and other factors in chronic disease etiology. METHODS The American Cancer Society (ACS) recruited a new prospective cohort study, Cancer Prevention Study 3 (CPS-3), between 2006 and 2013 from 35 states and Puerto Rico. Enrollment took place primarily at ACS community events and at community enrollment “drives.” At enrollment sites, participants completed a brief survey that included an informed consent, identifying information necessary for follow-up, and key exposure information. They also provided a waist measure and a nonfasting blood sample. Most participants also completed a more comprehensive baseline survey at home that included extensive medical, lifestyle, and other information. Participants will be followed for incident cancers through linkage with state cancer registries and for cause-specific mortality through linkage with the National Death Index. RESULTS In total, 303,682 participants were enrolled. Of these, 254,650 completed the baseline survey and are considered “fully” enrolled; they will be sent repeat surveys periodically for at least the next 20 years to update exposure information. The remaining participants (n = 49,032) will not be asked to update exposure information but will be followed for outcomes. Twenty-three percent of participants were men, 17.3% reported a race or ethnicity other than “white,” and the median age at enrollment was 47 years. CONCLUSIONS CPS-3 will be a valuable resource for studies of cancer and other outcomes because of its size; its diversity with respect to age, ethnicity, and geography; and the availability of blood samples and detailed questionnaire information collected over time. Cancer 2017;123:2014–2024. © 2017 American Cancer Society.

Background: Fine particulate matter (PM2.5) air pollution exposure has been identified as a global health threat. However, the types and sources of particles most responsible are not yet known. Objectives: We sought to identify the causal characteristics and sources of air pollution underlying past associations between long-term PM2.5 exposure and ischemic heart disease (IHD) mortality, as established in the American Cancer Society’s Cancer Prevention Study-II cohort. Methods: Individual risk factor data were evaluated for 445,860 adults in 100 U.S. metropolitan areas followed from 1982 through 2004 for vital status and cause of death. Using Cox proportional hazard models, we estimated IHD mortality hazard ratios (HRs) for PM2.5, trace constituents, and pollution source–associated PM2.5, as derived from air monitoring at central stations throughout the nation during 2000–2005. Results: Associations with IHD mortality varied by PM2.5 mass constituent and source. A coal combustion PM2.5 IHD HR = 1.05 (95% CI: 1.02, 1.08) per microgram/cubic meter, versus an IHD HR = 1.01 (95% CI: 1.00, 1.02) per microgram/cubic meter PM2.5 mass, indicated a risk roughly five times higher for coal combustion PM2.5 than for PM2.5 mass in general, on a per microgram/cubic meter PM2.5 basis. Diesel traffic–related elemental carbon (EC) soot was also associated with IHD mortality (HR = 1.03; 95% CI: 1.00, 1.06 per 0.26-μg/m3 EC increase). However, PM2.5 from both wind-blown soil and biomass combustion was not associated with IHD mortality. Conclusions: Long-term PM2.5 exposures from fossil fuel combustion, especially coal burning but also from diesel traffic, were associated with increases in IHD mortality in this nationwide population. Results suggest that PM2.5–mortality associations can vary greatly by source, and that the largest IHD health benefits per microgram/cubic meter from PM2.5 air pollution control may be achieved via reductions of fossil fuel combustion exposures, especially from coal-burning sources. Citation: Thurston GD, Burnett RT, Turner MC, Shi Y, Krewski D, Lall R, Ito K, Jerrett M, Gapstur SM, Diver WR, Pope CA III. 2016. Ischemic heart disease mortality and long-term exposure to source-related components of U.S. fine particle air pollution. Environ Health Perspect 124:785–794; http://dx.doi.org/10.1289/ehp.1509777

The effectiveness of regulatory actions designed to improve air quality is often assessed by predicting changes in public health resulting from their implementation. Risk of premature mortality from long-term exposure to ambient air pollution is the single most important contributor to such assessments and is estimated from observational studies generally assuming a log-linear, no-threshold association between ambient concentrations and death. There has been only limited assessment of this assumption in part because of a lack of methods to estimate the shape of the exposure-response function in very large study populations. In this paper, we propose a new class of variable coefficient risk functions capable of capturing a variety of potentially non-linear associations which are suitable for health impact assessment. We construct the class by defining transformations of concentration as the product of either a linear or log-linear function of concentration multiplied by a logistic weighting function. These risk functions can be estimated using hazard regression survival models with currently available computer software and can accommodate large population-based cohorts which are increasingly being used for this purpose. We illustrate our modeling approach with two large cohort studies of long-term concentrations of ambient air pollution and mortality: the American Cancer Society Cancer Prevention Study II (CPS II) cohort and the Canadian Census Health and Environment Cohort (CanCHEC). We then estimate the number of deaths attributable to changes in fine particulate matter concentrations over the 2000 to 2010 time period in both Canada and the USA using both linear and non-linear hazard function models. Electronic supplementary material The online version of this article (doi:10.1007/s11869-016-0398-z) contains supplementary material, which is available to authorized users.

Background: Persons of African ancestry (AA) experience a 1.5-2-fold risk of multiple myeloma (MM) compared to persons of European ancestry (EA). We assembled a set of MM patients with self-reported AA in order to evaluate the contribution of genetics to etiology in this high-risk group. Methods: Here we present the results of a meta-analysis of two GWAS in 1,813 cases and 8,871 controls of AA. We also conducted an admixture mapping scan to identify risk alleles associated with local ancestry, fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA, and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. Finally, we conducted an eQTL analysis measuring gene expression in those genes harboring a risk variant in malignant plasma cells from 292 of the patients from a single site. Results: In GWAS analysis, we identified two suggestive novel loci located at 9p24.3 and 9p13.1 at P Conclusion: Our study shows that common genetic variation contributes to MM risk individuals of AA. This abstract is also being presented as Poster C040. Citation Format: Zhaohui Du, Niels Weinhold, Gregory Chi Song, Kristen A. Rand, David J. Van Den Berg, Amie E. Hwang, Xin Sheng, Victor Hom, Sikander Ailawadhi, Ajay K. Nooka, Seema Singhal, Karen Pawlish, Edward Peters, Cathryn Bock, Ann Mohrbacher, Alexander Stram, Sonja I. Berndt, William J. Blot, Graham Casey, Victoria L. Stevens, Rick Kittles, Phyllis J. Goodman, W. Ryan Diver, Anselm Hennis, Barbara Nemesure, Eric A. Klein, Benjamin A. Rybicki, Janet L. Stanford, John S. Witte, Lisa Signorello, Esther M. John, Leslie Bernstein, Antoinette Stroup, Owen W. Stephens, Maurizio Zangari, Frits Van Rhee, Andrew Olshan, Wei Zheng, Jennifer J. Hu, Regina Ziegler, Sarah J. Nyante, Sue Ann Ingles, Michael Press, John David Carpten, Stephen Chanock, Jayesh Mehta, Graham A Colditz, Jeffrey Wolf, Thomas G. Martin, Michael Tomasson, Mark A. Fiala, Howard Terebelo, Nalini Janakiraman, Laurence Kolonel, Kenneth C. Anderson, Loic Le Marchand, Daniel Auclair, Brian C.-H. Chiu, Elad Ziv, Daniel Stram, Ravi Vij, Leon Bernal-Mizrachi, Gareth J. Morgan, Jeffrey A. Zonder, Carol Ann Huff, Sagar Lonial, Robert Z. Orlowski, David V. Conti, Christopher A. Haiman, Wendy Cozen. A meta-analysis of genome-wide association study and eQTL analysis of multiple myeloma among African Americans [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr PR05.

Exposure to ambient fine particulate matter (PM 2.5 ) is a major global health concern. Quantitative estimates of attributable mortality are based on disease-specific hazard ratio models that incorporate risk information from multiple PM 2.5 sources (outdoor and indoor air pollution from use of solid fuels and secondhand and active smoking), requiring assumptions about equivalent exposure and toxicity. We relax these contentious assumptions by constructing a PM 2.5 -mortality hazard ratio function based only on cohort studies of outdoor air pollution that covers the global exposure range. We modeled the shape of the association between PM 2.5 and nonaccidental mortality using data from 41 cohorts from 16 countries—the Global Exposure Mortality Model (GEMM). We then constructed GEMMs for five specific causes of death examined by the global burden of disease (GBD). The GEMM predicts 8.9 million [95% confidence interval (CI): 7.5–10.3] deaths in 2015, a figure 30% larger than that predicted by the sum of deaths among the five specific causes (6.9; 95% CI: 4.9–8.5) and 120% larger than the risk function used in the GBD (4.0; 95% CI: 3.3–4.8). Differences between the GEMM and GBD risk functions are larger for a 20% reduction in concentrations, with the GEMM predicting 220% higher excess deaths. These results suggest that PM 2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations.

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40–31.03, P = 1.36 × 10−54) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45–6.96, P = 8.75 × 10−19). Both risk alleles are observed at a low frequency among controls (~2–3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy., Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a non-Hodgkin-type B cell lymphoma. Here, the authors identify two risk loci for WM/LPL in a two-stage GWAS involving a family-oversampling approach and provide evidence for a functional role of the non-coding SNP rs116446171.

The survival of breast cancer patients is largely influenced by tumor characteristics, such as TNM stage, tumor grade and hormone receptor status. However, there is growing evidence that inherited ...

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1. ispartof: Nature Genetics vol:47 issue:4 pages:373-80 ispartof: location:United States status: published

Rationale: Growing evidence suggests that long-term exposure to fine particulate matter (PM 2.5 ) air pollution contributes to risk of cardiovascular disease (CVD) morbidity and mortality. There is uncertainty about who are most susceptible. Individuals with underlying cardiometabolic disorders, including hypertension, diabetes mellitus, and obesity, may be at greater risk. PM 2.5 pollution may also contribute to cardiometabolic disorders, augmenting CVD risk. Objective: This analysis evaluates relationships between long-term PM 2.5 exposure and cardiometabolic disease on risk of death from CVD and cardiometabolic conditions. Methods and Results: Data on 669 046 participants from the American Cancer Society Cancer Prevention Study II cohort were linked to modeled PM 2.5 concentrations at geocoded home addresses. Cox proportional hazards regression models were used to estimate adjusted hazards ratios for death from CVD and cardiometabolic diseases based on death-certificate information. Effect modification by pre-existing cardiometabolic risk factors on the PM 2.5 –CVD mortality association was examined. PM 2.5 exposure was associated with CVD mortality, with the hazards ratios (95% confidence interval) per 10 μg/m 3 increase in PM 2.5 equal to 1.12 (1.10–1.15). Deaths linked to hypertension and diabetes mellitus (mentioned on death certificate as either primary or contributing cause of death) were also associated with PM 2.5 . There was no consistent evidence of effect modification by cardiometabolic disease risk factors on the PM 2.5 –CVD mortality association. Conclusions: Pollution-induced CVD mortality risk is observed for those with and without existing cardiometabolic disorders. Long-term exposure may also contribute to the development or exacerbation of cardiometabolic disorders, increasing risk of CVD, and cardiometabolic disease mortality.

Background Concern about the carcinogenic potential of aspartame was raised after an increase in lymphomas and leukemia was reported in an animal study at doses similar to human exposure. Two prospective cohort studies published after the report found inconsistent results for estimated aspartame intake, artificially sweetened beverage consumption, and risk of lymphoid neoplasms. Objective The objective of this study was to examine associations of artificially and sugar-sweetened carbonated beverage consumption (for comparison) and aspartame intake with risk of non-Hodgkin lymphoma (NHL) overall and by major histologic subtype in the Cancer Prevention Study-II Nutrition Cohort. Methods Among 100,442 adult men and women who provided information on diet and lifestyle factors in 1999, 1196 NHL cases were verified during a 10-y follow-up period. Cox proportional hazards regression was used to estimate multivariable-adjusted RRs and 95% CIs. Results In women and men combined, there were no associations of consumption of ≥1 (355 mL) servings/d of artificially (RR: 0.92; 95% CI: 0.73, 1.17; P-trend: 0.14) or sugar- (RR: 1.10; 95% CI: 0.77, 1.58; P-trend: 0.62) sweetened carbonated beverages with NHL risk, compared to no consumption (P-heterogeneity by gender: 0.11-1.00). Similarly, aspartame intake was not associated with NHL risk (RR: 1.02; 95% CI: 0.84, 1.24; P-trend: 0.69, top vs. bottom quintile). Associations with NHL subtype (multiple myeloma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular and other B-cell lymphoma) were generally null. Conclusion These findings do not support associations of daily consumption of artificially or sugar-sweetened carbonated beverages, or aspartame, with NHL risk.

Introduction Secondhand smoke is known to have adverse effects on the lung and vascular systems in both children and adults. It is unknown if childhood exposure to secondhand smoke is associated with adult mortality. Methods The authors examined associations of childhood and adult secondhand smoke exposure with death from all causes, ischemic heart disease, stroke, and chronic obstructive pulmonary disease among 70,900 never smoking men and women, predominantly aged ≥50 years, from the Cancer Prevention Study–II Nutrition Cohort in 1992–1993. There were 25,899 participant deaths during follow-up through 2014. During 2016–2017, Cox proportional hazards regression models were used to calculate multivariable-adjusted hazard ratios and 95% CIs. Results Childhood secondhand smoke exposure was not associated with all-cause mortality. However, childhood secondhand smoke (living with a smoker for 16–18 years during childhood) was associated with higher mortality from chronic obstructive pulmonary disease (hazard ratio=1.31, 95% CI=1.05, 1.65). Adult secondhand smoke exposure of ≥10 hours/week at enrollment was associated with a higher risk of all-cause (hazard ratio=1.09, 95% CI=1.04, 1.14); ischemic heart disease (hazard ratio=1.27, 95% CI=1.14, 1.42); stroke (hazard ratio=1.23, 95% CI=1.04, 1.45); and chronic obstructive pulmonary disease (hazard ratio=1.42, 95% CI=0.97, 2.09) mortality. Conclusions These results suggest that childhood secondhand smoke exposure, as well as adult secondhand smoke exposure, increase the risk of chronic obstructive pulmonary disease death in adulthood. Consistent with previous studies, the results also show that adult secondhand smoke is meaningfully associated with higher mortality from vascular disease and all causes. Overall, these findings provide further evidence for reducing secondhand smoke exposure throughout life.