Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions.

Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals.

Age at lung cancer diagnosis in females versus males who never smoke by race and ethnicity.

BACKGROUND: We characterized age at diagnosis and estimated sex differences for lung cancer and its histological subtypes among individuals who never smoke. METHODS: We analyzed the distribution of age at lung cancer diagnosis in 33,793 individuals across 8 cohort studies and two national registries from East Asia, the United States (US) and the United Kingdom (UK). Student's t-tests were used to assess the study population differences (Δ years) in age at diagnosis comparing females and males who never smoke across subgroups defined by race/ethnicity, geographic location, and histological subtypes. RESULTS: We found that among Chinese individuals diagnosed with lung cancer who never smoke, females were diagnosed with lung cancer younger than males in the Taiwan Cancer Registry (n = 29,832) (Δ years = -2.2 (95% confidence interval (CI):-2.5, -1.9), in Shanghai (n = 1049) (Δ years = -1.6 (95% CI:-2.9, -0.3), and in Sutter Health and Kaiser Permanente Hawai'i in the US (n = 82) (Δ years = -11.3 (95% CI: -17.7, -4.9). While there was a suggestion of similar patterns in African American and non-Hispanic White individuals. the estimated differences were not consistent across studies and were not statistically significant. CONCLUSIONS: We found evidence of sex differences for age at lung cancer diagnosis among individuals who never smoke.

Long-term multimorbidity trajectories in older adults: The role of cancer, demographics, and health behaviors.

BACKGROUND: Multimorbidity is associated with premature mortality and excess health care costs. The burden of multimorbidity is highest among patients with cancer, yet trends and determinants of multimorbidity over time are poorly understood. METHODS: Via Medicare claims linked to Cancer Prevention Study II data, group-based trajectory modeling was used to compare National Cancer Institute comorbidity index score trends for cancer survivors and older adults without a cancer history. Among cancer survivors, multinomial logistic regression analyses evaluated associations between demographics, health behaviors, and comorbidity trajectories. RESULTS: In 82,754 participants (mean age, 71.6 years [SD, 5.1 years]; 56.9% female), cancer survivors (n = 11,265) were more likely than older adults without a cancer history to experience the riskiest comorbidity trajectories: (1) steady, high comorbidity scores (remain high; odds ratio [OR], 1.36; 95% CI, 1.29-1.45), and (2) high scores that increased over time (start high and increase; OR, 1.51; 95% CI, 1.38-1.65). Cancer survivors who were physically active postdiagnosis were less likely to fall into these two trajectories (OR, 0.73; 95% CI, 0.64-0.84, remain high; OR, 0.42; 95% CI, 0.33-0.53, start high and increase) compared to inactive survivors. Cancer survivors with obesity were more likely to have a trajectory that started high and increased (OR, 2.83; 95% CI, 2.32-3.45 vs. normal weight), although being physically active offset some obesity-related risk. Cancer survivors who smoked postdiagnosis were also six times more likely to have trajectories that started high and increased (OR, 6.86; 95% CI, 4.41-10.66 vs. never smokers). CONCLUSIONS: Older cancer survivors are more likely to have multiple comorbidities accumulated at a faster pace than older adults without a history of cancer. Weight management, physical activity, and smoking avoidance postdiagnosis may attenuate that trend.

Case-Cohort Study of the Association between PFAS and Selected Cancers among Participants in the American Cancer Society's Cancer Prevention Study II LifeLink Cohort.

BACKGROUND: Previous epidemiological studies found associations between exposure to per- and polyfluoroalkyl substances (PFAS) and some cancer types. Many studies considered highly exposed populations, so relevance to less-exposed populations can be uncertain. Additionally, many studies considered only cancer site, not histology. OBJECTIVES: We conducted a case-cohort study within the American Cancer Society's prospective Cancer Prevention Study II (CPS-II) LifeLink cohort to examine associations between PFAS exposure and risk of selected cancers, considering histologic subtypes. METHODS: Serum specimens were collected from cohort participants during the period 1998-2001. This study included a subcohort (500 men, 499 women) randomly selected from participants without prior cancer diagnoses at serum collection, and all participants with incident (after serum collection) first cancers of the breast (females only, n=786), bladder (n=401), kidney (n=158), pancreas (n=172), prostate (males only, n=1,610) or hematologic system (n=635). PFAS concentrations [perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA)] were measured in stored serum. We assessed associations between PFAS concentrations and incident cancers, by site and histologic subtype, using multivariable Cox proportional hazards models stratified by sex and controlling for age and year at blood draw, education, race/ethnicity, smoking, and alcohol use. RESULTS: Serum PFOA concentrations were positively associated with renal cell carcinoma of the kidney among women [hazard ratio (HR) and 95% confidence interval (CI) per PFOA doubling: 1.54 (95% CI: 1.05, 2.26)] but not men. Among men, we observed a positive association between PFHxS concentrations and chronic lymphocytic leukemia/small lymphocytic lymphoma [CLL/SLL, HR and 95% CI per PFHxS doubling: 1.34 (95% CI: 1.02, 1.75)]. We observed some heterogeneity of associations by histologic subtype within sites. DISCUSSION: This study supports the previously observed association between PFOA and renal cell carcinoma among women and suggests an association between PFHxS and CLL/SLL among men. Consideration of histologic subtypes might be important in future studies of PFAS-cancer associations. https://doi.org/10.1289/EHP13174.

Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding.

Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose that germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed that EwS-affected individuals had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation.

Evaluation of a Novel Ambient Light Survey Question in the Cancer Prevention Study-3.

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.

Fracture Risk Among Older Cancer Survivors Compared With Older Adults Without a History of Cancer.

Importance: The 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. Objective: To 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 Participants: This 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. Exposures: Cancer history, time since cancer diagnosis, and stage at cancer diagnosis. Main Outcomes and Measures: Hazard 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. Results: Among 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 Relevance: Findings 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.

Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes.

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10-8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10-9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10-8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.

COVID-19 and Tweets About Quitting Cigarette Smoking: Topic Model Analysis of Twitter Posts 2018-2020.

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.

The Role of Individual-Level Factors in Rural Mortality Disparities.

Introduction: The role of individual risk factors in the rural‒urban mortality disparity is poorly understood. The purpose of this study was to explore the role of individual-level demographics and health behaviors on the association between rural residence and the risk of mortality. Methods: Cancer Prevention Study-II participants provided updated addresses throughout the study period. Rural‒Urban Commuting Area codes were assigned to participants' geocoded addresses as a time-varying exposure. Cox proportional hazards regression was used to estimate hazard ratios and 95% CIs for mortality associated with Rural‒Urban Commuting Area groups. Results: After adjustment for age and sex, residents of rural areas/small towns had a small but statistically significant elevated risk of all-cause mortality compared with metropolitan residents (hazard ratio=1.04; 95% CI=1.01, 1.06). Adjustment for additional covariates attenuated the association entirely (hazard ratio=0.99; 95% CI=0.97, 1.01). Individually, adjustment for education (hazard ratio=0.99; 95% CI=0.97, 1.01), alcohol use (hazard ratio=1.01; 95% CI=0.99, 1.04), and moderate-to-vigorous intensity aerobic physical activity (hazard ratio=1.00; 95% CI=0.97, 1.02) eliminated the elevated risk. Conclusions: The elevated risk of death for rural compared with that for metropolitan residents appeared to be largely explained by individual-level demographics and health behaviors. If replicated in other subpopulations, these results suggest that modifiable factors may play an important role in reducing the rural mortality disparity.

Association between Smoking Cannabis and Quitting Cigarettes in a Large American Cancer Society Cohort.

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.

Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study.

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.

Breast cancer risk factors by mode of detection among screened women in the Cancer Prevention Study-II.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. IMPACT: If confirmed, these data suggest that such women may benefit from more intensive screening to facilitate early detection.

Outdoor air pollution and cancer: An overview of the current evidence and public health recommendations.

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.

Erythrocyte levels of cadmium and lead and risk of B-cell non-Hodgkin lymphoma and multiple myeloma.

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.

A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry.

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.

Residential ambient benzene exposure in the United States and subsequent risk of hematologic malignancies.

Benzene is considered a carcinogen, mostly based on evidence of causality for myeloid leukemia from high levels of exposure in occupational studies. We used United States Environmental Protection Agency National Ambient Toxics Assessment (NATA) estimates of low-level ambient benzene to examine potential associations for the general public between benzene exposure and risk of hematologic cancers. Exposure was estimated by linking participants' residential address to the NATA benzene estimates for that census tract. Among 115,996 American Cancer Society Cancer Prevention Study-II Nutrition cohort participants (52,554 men, 63,442 women), 2,595 were diagnosed with incident hematologic cancer between 1997 and 2013. Extended Cox regression modeling was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Among all participants, ambient benzene was positively associated with myelodysplastic syndromes (HR = 1.16, 95% CI: 1.01-1.33 per µg/m3 ) and T-cell lymphoma (HR = 1.29, 95% CI: 1.08-1.53 per µg/m3 ). Among men, ambient benzene was also positively associated with any hematologic malignancy (HR = 1.07, 95% CI: 1.01-1.15 per µg/m3 ) and follicular lymphoma (HR = 1.28, 95% CI: 1.09-1.50 per µg/m3 ). No significant associations were observed for women only, but associations were suggestive for MDS and T-cell lymphoma. It is possible that the NATA ambient benzene estimates are a better proxy for benzene exposure for men than women in this cohort. The results of this study support an association between ambient benzene and risk of hematologic malignancies, particularly MDS, T-cell lymphoma and follicular lymphoma. More research in large scale or pooled studies is needed to further explore these associations.

Social Isolation and Mortality in US Black and White Men and Women.

Social isolation is associated with higher mortality in studies comprising mostly white adults, yet associations among black adults are unclear. In this prospective cohort study, we evaluated whether associations of social isolation with all-cause, cardiovascular disease, and cancer mortality differed by race and sex. Adults enrolled in Cancer Prevention Study II in 1982/1983 were followed for mortality through 2012 (n = 580,182). Sex- and race-specific multivariable-adjusted hazard ratios and 95% confidence intervals were estimated for associations of a 5-point social isolation score with risk of death. Social isolation was associated with all-cause mortality in all subgroups (P for trend ≤ 0.005); for the most isolated versus the least isolated, the hazard ratios were 2.34 (95% confidence interval (CI): 1.58, 3.46) and 1.60 (95% CI: 1.41, 1.82) among black men and white men, respectively (P for interaction = 0.40) and 2.13 (95% CI: 1.44, 3.15) and 1.84 (95% CI: 1.68, 2.01) among black women and white women, respectively (P for interaction = 0.89). The association did not differ between black men and black women (P for interaction = 0.33) but was slightly stronger in white women than in white men (P for interaction = 0.01). Social isolation was associated with cardiovascular disease mortality in each subgroup (P for trend < 0.03) but with cancer mortality only among whites (P for trend < 0.0001). Subgroup differences in the influence of specific social isolation components were identified. Identifying and intervening with socially isolated adults could improve health outcomes.

Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia.

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.