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Supplementary Table S1. Cohorts Participating in the Liver Cancer Pooling Project with Information on Aspirin Use. Supplementary Table S2. Assessment of aspirin and ibuprofen use, Liver Cancer Pooling Project. Supplemental Table S3. Adjusted* Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between NSAID Use and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Sex, Cigarette Use, Alcohol Consumption, and Ibuprofen Use, Liver Cancer Pooling Project. Supplemental Table S4. Adjusted* Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between NSAID Use and Confirmed or Suspected Hepatocellular Carcinoma, Liver Cancer Pooling Project.

Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC = 679, ICC = 225) from 10 U.S.-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted HRs and 95% confidence intervals (CI). Current aspirin use, versus nonuse, was inversely associated with HCC (HR, 0.68; 95% CI, 0.57–0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5- and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR, 0.64; 95% CI, 0.42–0.98) but not women (HR, 1.34; 95% CI, 0.89–2.01; Pinteraction = 0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggests the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC. Cancer Prev Res; 8(12); 1156–62. ©2015 AACR.

Although NSAIDs have been associated with both reduced and increased cutaneous melanoma risk, few studies have examined these associations by ultraviolet radiation (UVR) or personal sun-sensitivity. We examined the associations between NSAID use and first primary invasive cutaneous melanoma among 58,227 non-Hispanic white participants in the United States Radiologic Technologists cohort study. Poisson regression was used to calculate rate ratios (RR) and 95% likelihood-based confidence intervals (CI), adjusting for attained age, birth cohort, and ambient UVR. No significant association of melanoma was observed for any use of NSAIDs (RR, 0.87; 95% CI, 0.71–1.09). The relative risks of melanoma for the highest categories of aspirin and other NSAID use (≥5 times per month vs. none) were 0.93 (95% CI, 0.74–1.16) and 1.02 (95% CI, 0.83–1.25), respectively. Further analyses did not reveal dose–response for trends in frequency of NSAID use or interactions with sex, UVR, eye and hair color, and skin complexion. In this large nationwide study, NSAID use was not associated with melanoma risk.Prevention Relevance:NSAIDs have been associated with both reduced and increased melanoma risk. However, few studies have examined the role of UVR or personal sun-sensitivity on these associations. Our findings strengthen the evidence that NSAID use is not associated with melanoma risk, even in sun-sensitive subgroups.

Tables 1-17, Figure S1, and acknowledgements.

Background: Thyroid cancer incidence has risen dramatically in the United States since the early 1980s. Although the prevalence of obesity has doubled during this time period, the relationship between obesity and thyroid cancer is uncertain.Methods: We examined the association between body mass index (BMI) and thyroid cancer risk in a pooled analysis of five prospective U.S. studies, including 413,979 women and 434,953 men. Proportional hazards models with attained age as the time metric were adjusted for education, race, marital status, smoking, alcohol intake, and (where appropriate) cohort and sex.Results: Over follow-up (mean = 10.3 years), 768 women and 388 men were diagnosed with thyroid cancer. The risk of thyroid cancer was greater with increasing BMI [per 5 kg/m2: HR in women, 1.16 (95% CI, 1.08–1.24); HR in men, 1.21 (95% CI, 0.97–1.49)]. There was no significant heterogeneity between studies (both P > 0.05). For women and men combined, the HRs for overweight (25.0–29.9 kg/m2) and obesity (≥30 kg/m2) compared with normal-weight (18.5–24.9 kg/m2) were 1.20 (95% CI, 1.04–1.38) and 1.53 (95% CI, 1.31–1.79), respectively. We found no significant effect modification by other factors, and the results did not differ significantly by histologic type. A significant positive association for BMI in young adulthood (ages 18–20) with thyroid cancer risk was also observed [per 5-kg/m2 increase: HR, 1.18 (95% CI, 1.03–1.35)].Conclusion: BMI was positively associated with thyroid cancer risk in both men and women.Impact: Our study provides strong evidence that obesity is an independent risk factor for thyroid cancer. Cancer Epidemiol Biomarkers Prev; 20(3); 464–72. ©2011 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)

Background: Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee–HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer.Methods: In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC, n = 860; ICC, n = 260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards regression.Results: Higher coffee consumption was associated with lower risk of HCC (HR>3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53–0.99; Ptrend cups/day = Pinteraction = 0.07). Women who consumed more than three cups of coffee per day were at a 54% lower risk of HCC (HR, 0.46; 95% CI, 0.26–0.81), whereas men had more modest reduced risk of HCC (HR, 0.93; 95% CI, 0.63–1.37). The associations were stronger for caffeinated coffee (HR>3 cups/day vs. non-drinker, 0.71; 95% CI, 0.50–1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55–1.54). There was no association between coffee consumption and ICC.Conclusions: These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC.Impact: Further research into specific coffee compounds and mechanisms that may account for these associations is needed. Cancer Epidemiol Biomarkers Prev; 24(9); 1398–406. ©2015 AACR.

Background: For decades, non–Hodgkin lymphoma (NHL) incidence has been increasing worldwide. NHL risk is strongly increased among HIV-infected people. Our understanding of trends in NHL incidence has been hampered by difficulties in separating HIV-infected NHL cases from general population rates.Methods: NHL incidence data during 1992–2009 were derived from 10 U.S. SEER cancer registries with information on HIV status at NHL diagnosis. The CDC estimated the number of people living with HIV in the registry areas. The proportion of NHL cases with HIV and NHL rates in the total and the HIV-uninfected populations were estimated. Time trends were assessed with Joinpoint analyses.Results: Of 115,643 NHL cases diagnosed during 1992–2009, 5.9% were HIV-infected. The proportions of NHL cases with HIV were highest for diffuse large B-cell (DLBCL; 7.8%), Burkitt (26.9%), and peripheral T-cell lymphomas (3.2%) with low proportions (≤1.1%) in the other subtypes. NHL rates in the total population increased 0.3% per year during 1992–2009. However, rates of NHL in HIV-uninfected people increased 1.4% per year during 1992–2003, before becoming stable through 2009. Similar trends were observed for DLBCLs and follicular lymphoma in HIV-uninfected people; rates increased 2.7% per year until 2003 and 1.7% per year until 2005, respectively, before stabilizing.Conclusions: NHL incidence rates in the United States have plateaued over the last 5–10 years, independent of HIV infection.Impact: Although the causes of the long-term increase in NHL incidence rates in the United States remain unknown, general population rates of NHL have stabilized since the early 2000s, independent of HIV. Cancer Epidemiol Biomarkers Prev; 22(6); 1069–78. ©2013 AACR.

Supplementary Table 1 from Obesity and Thyroid Cancer Risk among U.S. Men and Women: A Pooled Analysis of Five Prospective Studies

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.

figure legends for supp. figures 1, 2, and 3

Descriptive table or cohorts and results from sensitivity analyses

Supplementary Table - PDF file 46K, NHL rates excluding persons with HIV with 1) the SEER population as the denominator; 2) the SEER population excluding persons with AIDS as the denominator; and 3) the SEER population excluding persons with HIV as the denominator, 2006-2009.

Results from individual participant meta-analysis of WC. Footnote to Supplementary Figure 2. Multivariable models include age, sex, study, alcohol, smoking, race and body mass index.

Supplementary Table S1: Cohorts participating in analysis of coffee variables, Liver Cancer Pooling Project. Supplementary Table S2: Assessment of coffee consumption, Liver Cancer Pooling Project. Supplementary Table S3: Characteristics of participants in the Liver Cancer Pooling Project by coffee drinking. Supplementary Table S4: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Intrahepatic Cholangiocarcinoma Incidence by Sex, Smoking Status, Body Mass Index, and Diabetes, Liver Cancer Pooling Project. Supplementary Table S5: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Caffeine Content; Sensitivity Analysis Excluding WHI and Jointly Modeling Caffeine Content and Drinking Intensity, Liver Cancer Pooling Project. Supplementary Table S6: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Suspected Hepatocellular Carcinoma Incidence by Caffeine Content, Liver Cancer Pooling Project. Supplementary Table S7: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Caffeine Content in the AARP Study, Liver Cancer Pooling Project. Supplementary Table S8: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Sex in the AARP Study, Liver Cancer Pooling Project. Supplementary Table S9: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Caffeine Content excluding the AARP Study, Liver Cancer Pooling Project. Supplementary Table S10: Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Associations Between Coffee Consumption and Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma Incidence by Sex excluding the AARP Study, Liver Cancer Pooling Project. Supplementary Figure S1: Meta-influence Graph of the Influence of Individuals Studies for Associations between Coffee Consumption versus No Consumption and Hepatocellular Carcinoma, Liver Cancer Pooling Project.

The average age at menarche declined in European and U.S. populations during the 19th and 20th centuries. The timing of pubertal events may have broad implications for chronic disease risks in aging women. Here we tested for associations of recalled menarcheal age with risks of 19 cancers in 536,450 women [median age, 60 years (range, 31–39 years)] in nine prospective U.S. and European cohorts that enrolled participants from 1981 to 1998. Cox regression estimated multivariable-adjusted HRs and 95% confidence intervals (CI) for associations of the age at menarche with risk of each cancer in each cohort and random-effects meta-analysis was used to generate summary estimates for each cancer. Over a median 10 years of follow-up, 60,968 women were diagnosed with a first primary incident cancer. Inverse linear associations were observed for seven of 19 cancers studied. Each additional year in the age at menarche was associated with reduced risks of endometrial cancer (HR = 0.91; 95% CI, 0.89–0.94), liver cancer (HR = 0.92; 95% CI, 0.85–0.99), melanoma (HR = 0.95; 95% CI, 0.93–0.98), bladder cancer (HR = 0.96; 95% CI, 0.93–0.99), and cancers of the colon (HR = 0.97; 95% CI, 0.96–0.99), lung (HR = 0.98; 95% CI, 0.96–0.99), and breast (HR = 0.98; 95% CI, 0.93–0.99). All but one of these associations remained statistically significant following adjustment for baseline body mass index. Similarities in the observed associations between menarche and seven cancers suggest shared underlying causes rooted early in life. We propose as a testable hypothesis that early exposure to sex hormones increases mid-life cancer risks by altering functional capacities of stem cells with roles in systemic energy balance and tissue homeostasis.Significance:Age at menarche is associated with risk for seven cancers in middle-aged women, and understanding the shared underlying causal pathways across these cancers may suggest new avenues for cancer prevention.

Results from individual participant meta-analysis of diabetes. Multivariable models include age, sex, study, alcohol, smoking, race and body mass index.

Results from individual participant meta-analysis of BMI. Multivariable models include age, sex, study, alcohol, smoking, and race.

Data on incidence rates of myeloid malignancies for subtypes based on the World Health Organization (WHO) classification are lacking in Asian populations. We compared age-adjusted incidence rates for 27 myeloid malignancy WHO-defined subtypes in Hong Kong (HK) (2014–2016) with those for Asian and white individuals living in the United States (U.S.) (2010–2016). Except for overall acute myeloid leukemia (AML) (2.23 cases per 100,000) and myeloproliferative neoplasms (MPNs) (2.10 cases per 100,000), rates of all subtypes were

BACKGROUND: Adult survivors of childhood cancer are at increased risk of cardiac late effects. METHODS: Using whole-genome sequencing data from 1870 survivors of European ancestry in the St. Jude Lifetime Cohort (SJLIFE) study, genetic variants were examined for association with ejection fraction (EF) and clinically assessed cancer therapy–induced cardiac dysfunction (CCD). Statistically significant findings were validated in 301 SJLIFE survivors of African ancestry and 4020 survivors of European ancestry from the Childhood Cancer Survivor Study. All statistical tests were 2-sided. RESULTS: A variant near KCNK17 showed genome-wide significant association with EF (rs2815063-A: EF reduction = 1.6%; P = 2.1 × 10(-8)) in SJLIFE survivors of European ancestry, which replicated in SJLIFE survivors of African ancestry (EF reduction = 1.5%; P = .004). The rs2815063-A also showed a 1.80-fold (P = .008) risk of severe or disabling or life-threatening CCD and replicated in 4020 Childhood Cancer Survivor Study survivors of European ancestry (odds ratio = 1.40; P = .04). Notably, rs2815063-A was specifically associated among survivors exposed to doxorubicin only, with a stronger effect on EF (3.3% EF reduction) and CCD (2.97-fold). Whole blood DNA methylation data in 1651 SJLIFE survivors of European ancestry showed statistically significant correlation of rs2815063-A with dysregulation of KCNK17 enhancers (false discovery rate

Background Previous epidemiological studies have found positive associations between maternal infections and childhood leukaemia; however, evidence from prospective cohort studies is scarce. We aimed to examine the associations using large-scale prospective data. Methods Data were pooled from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA (recruitment 1950s-2000s). Primary outcomes were any childhood leukaemia and acute lymphoblastic leukaemia (ALL); secondary outcomes were acute myeloid leukaemia (AML) and any childhood cancer. Exposures included maternal self-reported infections [influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections and urinary tract infection (including cystitis)] and infection-associated symptoms (fever and diarrhoea) during pregnancy. Covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using multilevel Cox models. Results Among 312 879 children with a median follow-up of 13.6 years, 167 leukaemias, including 129 ALL and 33 AML, were identified. Maternal urinary tract infection was associated with increased risk of any leukaemia [HR (95% CI) 1.68 (1.10–2.58)] and subtypes ALL [1.49 (0.87–2.56)] and AML [2.70 ([0.93–7.86)], but not with any cancer [1.13 (0.85–1.51)]. Respiratory tract infection was associated with increased risk of any leukaemia [1.57 (1.06–2.34)], ALL [1.43 (0.94–2.19)], AML [2.37 (1.10–5.12)] and any cancer [1.33 (1.09–1.63)]; influenza-like illness showed a similar pattern but with less precise estimates. There was no evidence of a link between other infections and any outcomes. Conclusions Urinary tract and respiratory tract infections during pregnancy may be associated with childhood leukaemia, but the absolute risk is small given the rarity of the outcome.

Although NSAIDs have been associated with both reduced and increased cutaneous melanoma risk, few studies have examined these associations by ultraviolet radiation (UVR) or personal sun-sensitivity. We examined the associations between NSAID use and first primary invasive cutaneous melanoma among 58,227 non-Hispanic white participants in the United States Radiologic Technologists cohort study. Poisson regression was used to calculate rate ratios (RR) and 95% likelihood-based confidence intervals (CI), adjusting for attained age, birth cohort, and ambient UVR. No significant association of melanoma was observed for any use of NSAIDs (RR, 0.87; 95% CI, 0.71–1.09). The relative risks of melanoma for the highest categories of aspirin and other NSAID use (≥5 times per month vs. none) were 0.93 (95% CI, 0.74–1.16) and 1.02 (95% CI, 0.83–1.25), respectively. Further analyses did not reveal dose–response for trends in frequency of NSAID use or interactions with sex, UVR, eye and hair color, and skin complexion. In this large nationwide study, NSAID use was not associated with melanoma risk. Prevention Relevance: NSAIDs have been associated with both reduced and increased melanoma risk. However, few studies have examined the role of UVR or personal sun-sensitivity on these associations. Our findings strengthen the evidence that NSAID use is not associated with melanoma risk, even in sun-sensitive subgroups.

Background Given concerns about risks associated with the growing use of mobile phones over recent decades, the authors analyzed temporal trends in incidence rates of nonmalignant meningioma and vestibular schwannoma in the United States. Methods The incidence of nonmalignant meningioma and vestibular schwannoma among adults in the Surveillance, Epidemiology, and End Results 18 registries during 2004 through 2017 was evaluated according to the method of diagnosis: microscopically (MC) or radiographically confirmed (RGC). Annual percent changes (APCs) and 95% CIs were estimated using log-linear models. Results Overall meningioma rates (n = 108,043) increased significantly from 2004 to 2009 (APC, 5.4%; 95% CI, 4.4%-6.4%) but subsequently rose at a slower pace through 2017 (APC, 1.0%; 95% CI, 0.6%-1.5%). Rates for MC meningiomas changed little from 2004 to 2017 (APC, -0.3%; 95% CI, -0.7%, 0.1%) but rose rapidly for RGC meningiomas until 2009 (APC, 9.5%; 95% CI, 7.8%-11.1%) and rose more modestly thereafter (APC, 2.3%; 95% CI, 1.5%-3.0%). Overall vestibular schwannoma rates (n = 17,475) were stable (APC, 0.4%; 95% CI, -0.2%, 1.0%), but MC vestibular schwannoma rates decreased (APC, -1.9%; 95% CI, -2.7%, -1.1%), whereas RGC vestibular schwannoma rates rose (2006-2017: APC, 1.7%; 95% CI, 0.5%-3.0%). For each tumor, the trends by diagnostic method were similar for each sex and each racial/ethnic group, but RGC diagnosis was more likely in older patients and for smaller tumors. Meningioma trends and the proportion of RGC diagnoses varied notably by registry. Conclusions Overall trends obscured differences by diagnostic method in this first large, detailed assessment, but the recent stable rates argue against an association with mobile phone use. Variation among registries requires evaluation to improve the registration of these nonmalignant tumors. Lay summary The etiology of most benign meningiomas and vestibular schwannomas is poorly understood, but concerns have been raised about whether mobile phone use contributes to risk of developing these tumors. Descriptive studies examining temporal trends could provide insight; however, globally, few registries collect these nonmalignant cases. In the United States, reporting benign meningiomas and vestibular schwannomas became required by law in 2004. This was the first large, systematic study to quantify and characterize incidence trends for meningioma and vestibular schwannoma according to whether the tumors were diagnosed microscopically or only radiographically. Differential trends across registries and by diagnostic method suggest that caution should be used when interpreting the patterns.

Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values-8 as genome-wide significant, and p-values-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values5. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.

The average age at menarche declined in European and U.S. populations during the 19th and 20th centuries. The timing of pubertal events may have broad implications for chronic disease risks in aging women. Here we tested for associations of recalled menarcheal age with risks of 19 cancers in 536,450 women [median age, 60 years (range, 31–39 years)] in nine prospective U.S. and European cohorts that enrolled participants from 1981 to 1998. Cox regression estimated multivariable-adjusted HRs and 95% confidence intervals (CI) for associations of the age at menarche with risk of each cancer in each cohort and random-effects meta-analysis was used to generate summary estimates for each cancer. Over a median 10 years of follow-up, 60,968 women were diagnosed with a first primary incident cancer. Inverse linear associations were observed for seven of 19 cancers studied. Each additional year in the age at menarche was associated with reduced risks of endometrial cancer (HR = 0.91; 95% CI, 0.89–0.94), liver cancer (HR = 0.92; 95% CI, 0.85–0.99), melanoma (HR = 0.95; 95% CI, 0.93–0.98), bladder cancer (HR = 0.96; 95% CI, 0.93–0.99), and cancers of the colon (HR = 0.97; 95% CI, 0.96–0.99), lung (HR = 0.98; 95% CI, 0.96–0.99), and breast (HR = 0.98; 95% CI, 0.93–0.99). All but one of these associations remained statistically significant following adjustment for baseline body mass index. Similarities in the observed associations between menarche and seven cancers suggest shared underlying causes rooted early in life. We propose as a testable hypothesis that early exposure to sex hormones increases mid-life cancer risks by altering functional capacities of stem cells with roles in systemic energy balance and tissue homeostasis. Significance: Age at menarche is associated with risk for seven cancers in middle-aged women, and understanding the shared underlying causal pathways across these cancers may suggest new avenues for cancer prevention.

PURPOSE Mortality for patients with classical Hodgkin lymphoma (cHL) treated during an era characterized in the United States by widespread use of doxorubicin, bleomycin, vinblastine, and dacarbazine and diminishing use of radiotherapy is not well understood. PATIENTS AND METHODS We identified 20,007 individuals diagnosed with stage I/II (early) or III/IV (advanced) cHL between age 20 and 74 years treated with initial chemotherapy in US population-based cancer registries during 2000-2015 (follow-up through 2016). We used standardized mortality ratios (SMRs) to compare cause-specific relative mortality risk following cHL to that expected in the general population and estimated excess absolute risks (EARs; per 10,000 patient-years) to quantify disease-specific death burden. RESULTS We identified 3,380 deaths in the cHL cohort, including 1,321 (39%) not attributed to lymphoma. Overall, noncancer SMRs were increased 2.4-fold (95% CI, 2.2 to 2.6; observed, 559; EAR, 61.6) and 1.6-fold (95% CI, 1.4 to 1.7; observed, 473; EAR, 18.2) for advanced- and early-stage cHL, respectively, compared with the general US population. SMRs and EARs differed substantially by cause of death and cHL stage. Among the highest EARs for noncancer causes of death were those for heart disease (EAR, 15.1; SMR, 2.1), infections (EAR, 10.6; SMR, 3.9), interstitial lung disease (ILD; EAR, 9.7; SMR, 22.1), and adverse events (AEs) related to medications/drugs (EAR, 7.4; SMR, 5.0) after advanced-stage cHL and heart disease (EAR, 6.6; SMR, 1.7), ILD (EAR, 3.7; SMR, 13.1), and infections (EAR, 3.1; SMR, 2.2) after early-stage cHL. Strikingly elevated SMRs for ILD, infections, and AEs were observed < 1 year after cHL. Individuals age 60-74 years with advanced-stage cHL experienced a disproportionate excess of deaths as a result of heart disease, ILD, infections, AEs, and solid tumors. CONCLUSION Despite evolving cHL treatment approaches, patients continue to face increased nonlymphoma mortality risks from multiple, potentially preventable causes. Surveillance, early interventions, and cHL treatment refinements may favorably affect patient longevity, particularly among high-risk subgroups.

US physicians in multiple specialties who order or conduct radiological procedures lack formal radiation science education and thus sometimes order procedures of limited benefit or fail to order what is necessary. To this end, a multidisciplinary expert group proposed an introductory broad-based radiation science educational program for U.S. medical schools. Suggested preclinical elements of the curriculum include foundational education on ionizing and nonionizing radiation (eg, definitions, dose metrics, and risk measures) and short- and long-term radiation-related health effects as well as introduction to radiology, radiation therapy, and radiation protection concepts. Recommended clinical elements of the curriculum would impart knowledge and practical experience in radiology, fluoroscopically guided procedures, nuclear medicine, radiation oncology, and identification of patient subgroups requiring special considerations when selecting specific ionizing or nonionizing diagnostic or therapeutic radiation procedures. Critical components of the clinical program would also include educational material and direct experience with patient-centered communication on benefits of, risks of, and shared decision making about ionizing and nonionizing radiation procedures and on health effects and safety requirements for environmental and occupational exposure to ionizing and nonionizing radiation. Overarching is the introduction to evidence-based guidelines for procedures that maximize clinical benefit while limiting unnecessary risk. The content would be further developed, directed, and integrated within the curriculum by local faculties and would address multiple standard elements of the Liaison Committee on Medical Education and Core Entrustable Professional Activities for Entering Residency of the Association of American Medical Colleges.

ObjectivesTo evaluate cumulative occupational radiation dose response and haematopoietic malignancy mortality risks in the US radiologic technologist cohort.MethodsAmong 110 297 radiologic technologists (83 655 women, 26 642 men) who completed a baseline questionnaire sometime during 1983–1998, a retrospective cohort study was undertaken to assess cumulative, low-to-moderate occupational radiation dose and haematopoietic malignancy mortality risks during 1983–2012. Cumulative bone marrow dose (mean 8.5 mGy, range 0–430 mGy) was estimated based on 921 134 badge monitoring measurements during 1960–1997, work histories and historical data; 35.4% of estimated doses were based on badge measurements. Poisson regression was used to estimate excess relative risk of haematopoietic cancers per 100 milligray (ERR/100 mGy) bone-marrow absorbed dose, adjusting for attained age, sex and birth year.ResultsDeaths from baseline questionnaire completion through 2012 included 133 myeloid neoplasms, 381 lymphoid neoplasms and 155 leukaemias excluding chronic lymphocytic leukaemia (CLL). Based on a linear dose-response, no significant ERR/100 mGy occurred for acute myeloid leukaemia (ERR=0.0002, 95% CI 0.5, 85 cases) or leukaemia excluding CLL (ERR=0.05, 95% CI 0.5, 112 cases). Findings did not differ significantly by demographic factors, smoking or specific radiological procedures performed.ConclusionAfter follow-up averaging 22 years, there was little evidence of a relationship between occupational radiation exposure and myeloid or lymphoid haematopoietic neoplasms.

Background A monograph systematically evaluating recent evidence on the dose-response relationship between low-dose ionizing radiation exposure and cancer risk required a critical appraisal of dosimetry methods in 26 potentially informative studies. Methods The relevant literature included studies published in 2006–2017. Studies comprised case-control and cohort designs examining populations predominantly exposed to sparsely ionizing radiation, mostly from external sources, resulting in average doses of no more than 100 mGy. At least two dosimetrists reviewed each study and appraised the strengths and weaknesses of the dosimetry systems used, including assessment of sources and effects of dose estimation error. An overarching concern was whether dose error might cause the spurious appearance of a dose-response where none was present. Results The review included 8 environmental, 4 medical, and 14 occupational studies that varied in properties relative to evaluation criteria. Treatment of dose estimation error also varied among studies, although few conducted a comprehensive evaluation. Six studies appeared to have known or suspected biases in dose estimates. The potential for these biases to cause a spurious dose-response association was constrained to three case-control studies that relied extensively on information gathered in interviews conducted after case ascertainment. Conclusions The potential for spurious dose-response associations from dose information appeared limited to case-control studies vulnerable to recall errors that may be differential by case status. Otherwise, risk estimates appeared reasonably free of a substantial bias from dose estimation error. Future studies would benefit from a comprehensive evaluation of dose estimation errors, including methods accounting for their potential effects on dose-response associations.

Experimental evidence suggests that perinatal light imprinting of circadian clocks and systems may affect downstream physiology and cancer risk in later life. For humans, the predominant circadian stimulus is the daily light-dark cycle. Herein, we explore associations between perinatal photoperiod characteristics (photoperiod: duration of daylight as determined by time-of-year and location) and childhood cancer risk. We use pooled data on 182,856 mothers and babies from prospective birth cohorts in six countries (Australia, Denmark, Israel, Norway, UK, USA) within the International Childhood Cancer Cohort Consortium (I4C). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). In line with predicted differential dose–responses, restricted cubic splines indicate a potential non-linear, non-monotonic relationship between perinatal mean daily photoperiod (0–24 h) and childhood cancer risk. In a restricted analysis of 154,121 individuals who experienced third trimester photoperiods exclusively within the 8–16-h range, the relative risk of developing childhood cancer decreased by 9% with every hour increase in third trimester mean daily photoperiod [HR: 0.91 (95%CIs: 0.84–0.99)]. In conclusion, in this first study of perinatal photoperiod and childhood cancer, we detected an inverse [“protective”] linear association between third trimester mean daily photoperiod and childhood cancer risk in the 8–16-h set of the total study population. Limited statistical power impeded the investigation of risks with individuals exposed to more extreme photoperiods. Future studies are needed to confirm differential photoperiod-associated risks and further investigations into the hypothesized circadian imprinting mechanism are warranted.

Obesity is known to be associated with primary liver cancer (PLC), but the separate effects of excess abdominal and gluteofemoral size are unclear. Thus, we examined the association between waist and hip circumference with risk of PLC overall and by histologic type-hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The Liver Cancer Pooling Project is a consortium of prospective cohort studies that include data from 1,167,244 individuals (PLC n = 2,208, HCC n = 1,154, ICC n = 335). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Waist circumference, per 5 cm increase, was associated with an 11% increased PLC risk (HR = 1.11, 95%CI: 1.09-1.14), including when adjusted for hip circumference (HR = 1.12, 95%CI: 1.08-1.17) and also when restricted to individuals in a normal body mass index (BMI) range (18.5 to

Background Basal cell carcinoma of the skin (BCC) is the most common cancer in populations of European ancestry. Although consistently linked with basal cell carcinoma of the skin in case-control studies, few prospective cohort studies have evaluated the shape of the exposure-response of basal cell carcinoma associated with cumulative radiant solar ultraviolet exposure (UVR). Methods We followed 63,912 white cancer-free US radiologic technologists from entry (1983–1998) to exit (2003–2005) with known ultraviolet irradiance at up to 5 residential locations. Using generalized-additive and relative risk models we analyzed the exposure-response of basal cell carcinomas associated with ambient cumulative ultraviolet radiant exposure using ground-based National Solar Radiation database Average Daily Total Global data and satellite-based National Aeronautics and Space Administration Total Ozone Mapping Spectrometer data. Results There were 2151 technologists with an incident primary basal cell carcinoma. Risk of basal cell carcinoma rose with increasing cumulative ultraviolet radiation exposure using both measures, such that 1 MJ cm− 2 increased basal cell carcinoma risk by 8.48 (95% CI 5.22, 11.09, p p Conclusions We observed increases in risk of basal cell carcinoma and a similar exposure-response for ground-based and satellite ultraviolet radiation measures. Our observations suggest that interventions should concentrate on persons with higher levels of ultraviolet radiation exposure.

PURPOSE To determine whether recommended amounts of leisure-time physical activity (ie, 7.5-15 metabolic equivalent task [MET] hours/week) are associated with lower cancer risk, describe the shape of the dose-response relationship, and explore associations with moderate- and vigorous-intensity physical activity. METHODS Data from 9 prospective cohorts with self-reported leisure-time physical activity and follow-up for cancer incidence were pooled. Multivariable Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% CIs of the relationships between physical activity with incidence of 15 types of cancer. Dose-response relationships were modeled with restricted cubic spline functions that compared 7.5, 15.0, 22.5, and 30.0 MET hours/week to no leisure-time physical activity, and statistically significant associations were determined using tests for trend ( P < .05) and 95% CIs (< 1.0). RESULTS A total of 755,459 participants (median age, 62 years [range, 32-91 years]; 53% female) were followed for 10.1 years, and 50,620 incident cancers accrued. Engagement in recommended amounts of activity (7.5-15 MET hours/week) was associated with a statistically significant lower risk of 7 of the 15 cancer types studied, including colon (8%-14% lower risk in men), breast (6%-10% lower risk), endometrial (10%-18% lower risk), kidney (11%-17% lower risk), myeloma (14%-19% lower risk), liver (18%-27% lower risk), and non-Hodgkin lymphoma (11%-18% lower risk in women). The dose response was linear in shape for half of the associations and nonlinear for the others. Results for moderate- and vigorous-intensity leisure-time physical activity were mixed. Adjustment for body mass index eliminated the association with endometrial cancer but had limited effect on other cancer types. CONCLUSION Health care providers, fitness professionals, and public health practitioners should encourage adults to adopt and maintain physical activity at recommended levels to lower risks of multiple cancers.

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

Background: A previous International Lymphoma Epidemiology (InterLymph) Consortium evaluation of joint associations between five immune gene variants and autoimmune conditions reported interactions between B-cell response-mediated autoimmune conditions and the rs1800629 genotype on risk of B-cell non–Hodgkin lymphoma (NHL) subtypes. Here, we extend that evaluation using NHL subtype-specific polygenic risk scores (PRS) constructed from loci identified in genome-wide association studies of three common B-cell NHL subtypes. Methods: In a pooled analysis of NHL cases and controls of Caucasian descent from 14 participating InterLymph studies, we evaluated joint associations between B-cell–mediated autoimmune conditions and tertile (T) of PRS for risk of diffuse large B-cell lymphoma (DLBCL; n = 1,914), follicular lymphoma (n = 1,733), and marginal zone lymphoma (MZL; n = 407), using unconditional logistic regression. Results: We demonstrated a positive association of DLBCL PRS with DLBCL risk [T2 vs. T1: OR = 1.24; 95% confidence interval (CI), 1.08–1.43; T3 vs. T1: OR = 1.81; 95% CI, 1.59–2.07; P-trend (Ptrend) < 0.0001]. DLBCL risk also increased with increasing PRS tertile among those with an autoimmune condition, being highest for those with a B-cell–mediated autoimmune condition and a T3 PRS [OR = 6.46 vs. no autoimmune condition and a T1 PRS, Ptrend < 0.0001, P-interaction (Pinteraction) = 0.49]. Follicular lymphoma and MZL risk demonstrated no evidence of joint associations or significant Pinteraction. Conclusions: Our results suggest that PRS constructed from currently known subtype-specific loci may not necessarily capture biological pathways shared with autoimmune conditions. Impact: Targeted genetic (PRS) screening among population subsets with autoimmune conditions may offer opportunities for identifying those at highest risk for (and early detection from) DLBCL.

BACKGROUND: Occupational doses to most medical radiation workers have declined substantially since the 1950s because of improvements in radiation protection practices. However, different patterns may have emerged for radiologic technologists working with nuclear medicine because of the higher per-procedure doses and increasing workloads. PURPOSE: To summarize annual occupational doses during a 36-year period for a large cohort of U.S. radiologic technologists and to compare dose between general radiologic technologists and those specializing in nuclear medicine procedures. MATERIALS AND METHODS: Annual personal dose equivalents (referred to as doses) from 1980 to 2015 were summarized for 58 434 (62%) participants in the U.S. Radiologic Technologists (USRT) cohort who responded to the most recent mailed work history survey (years 2012–2014) and reported never regularly performing interventional procedures. Doses were partitioned according to the performance of nuclear medicine (yes or no, frequency, procedure type) by calendar year. Annual dose records were described by using summary statistics (eg, median and 25th and 75th percentiles). RESULTS: Median annual doses related to performance of general radiologic procedures decreased from 0.60 mSv (interquartile range [IQR], 0.10–1.9 mSv) in 1980 to levels below the limits of detection by 2015, whereas annual doses related to performance of nuclear medicine procedures remained relatively high during this period (median, 1.2 mSv; IQR, 0.12–3.0 mSv). Higher median annual doses were associated with more frequent (above vs below the median) performance of diagnostic nuclear medicine procedures (≥35 vs

BackgroundCopy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data.ResultsGene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci.ConclusionsThis is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

Chronic inflammation underlies many autoimmune diseases, including hypothyroidism, hyperthyroidism, and rheumatoid arthritis, also type-2 diabetes and osteoarthritis. Associations have been suggested of high-dose ionising radiation exposure with type-2 diabetes and elevated levels of C-reactive protein, a marker of chronic inflammation. In this analysis we used a proportional hazards model to assess effects of radiotherapy on risks of subsequent inflammatory disease morbidity in 110,368 US radiologic technologists followed from a baseline survey (1983–1989/1994–1998) through 2008. We used a linear model to assess log-transformed C-reactive protein concentration following radiotherapy in 1326 technologists. Relative risk of diabetes increased following radiotherapy (p p = 0.092). For osteoarthritis there was increased relative risk associated with prior radiotherapy on all questionnaires (p = 0.005), and a significant increasing trend per previous treatment (p = 0.024). No consistent increases were observed for other types of inflammatory disease (hypothyroidism, hyperthyroidism, rheumatoid arthritis) associated with radiotherapy. There was a borderline significant (p = 0.059) increasing trend with dose for C-reactive protein with numbers of prior radiotherapy treatments. Our results suggest that radiotherapy is associated with subsequent increased risk of certain inflammatory conditions, which is reinforced by our finding of elevated levels of C-reactive protein.

Background There is international consensus that benzene exposure is causally related to acute myeloid leukemia (AML), and more recent evidence of association with myelodysplastic syndromes (MDS). However, there are uncertainties about the exposure response, particularly risks by time since exposure and age at exposure. Methods In a case–cohort study in 110 631 Chinese workers followed up during 1972–1999 we evaluated combined MDS/AML (n = 44) and chronic myeloid leukemia (n = 18). We estimated benzene exposures using hierarchical modeling of occupational factors calibrated with historical routine measurements, and evaluated exposure response for cumulative exposure and average intensity using Cox regression; P values were two-sided. Results Increased MDS/AML risk with increasing cumulative exposure in our a priori defined time window (2 to Conclusion For myeloid neoplasms, the strongest effects were apparent for MDS/AML arising within 10 years of benzene exposure and for first exposure in the 2 to less than 10-year window before age 30 years.

There is limited evidence that non-leukaemic lymphoid malignancies are radiogenic. As radiation-related cancer risks are generally higher after childhood exposure, we analysed pooled lymphoid neoplasm data in nine cohorts first exposed to external radiation aged 0.4). In six cohorts with estimates of lymphatic tissue dose, borderline significant increased risks (p-trend = 0.02-0.07) were observed for NHL + CLL, NHL, andCLL. Further pooled epidemiological studies are needed with longer follow-up, central outcome review by expert hematopathologists, and assessment of radiation doses to lymphoid tissues.