This is the third analysis of solid cancer incidence among the Life Span Study (LSS) cohort of atomic bomb survivors in Hiroshima and Nagasaki, adding eleven years of follow-up data since the previously reported analysis. For this analysis, several changes and improvements were implemented, including updated dose estimates (DS02R1) and adjustment for smoking. Here, we focus on all solid cancers in aggregate. The eligible cohort included 105,444 subjects who were alive and had no known history of cancer at the start of follow-up. A total of 80,205 subjects had individual dose estimates and 25,239 were not in either city at the time of the bombings. The follow-up period was 1958-2009, providing 3,079,484 person-years of follow-up. Cases were identified by linkage with population-based Hiroshima and Nagasaki Cancer Registries. Poisson regression methods were used to elucidate the nature of the radiation-associated risks per Gy of weighted absorbed colon dose using both excess relative risk (ERR) and excess absolute risk (EAR) models adjusted for smoking. Risk estimates were reported for a person exposed at age 30 years with attained age of 70 years. In this study, 22,538 incident first primary solid cancer cases were identified, of which 992 were associated with radiation exposure. There were 5,918 cases (26%) that occurred in the 11 years (1999-2009) since the previously reported study. For females, the dose response was consistent with linearity with an estimated ERR of 0.64 per Gy (95% CI: 0.52 to 0.77). For males, significant upward curvature over the full dose range as well as restricted dose ranges was observed and therefore, a linear-quadratic model was used, which resulted in an ERR of 0.20 (95% CI: 0.12 to 0.28) at 1 Gy and an ERR of 0.010 (95% CI: -0.0003 to 0.021) at 0.1 Gy. The shape of the ERR dose response was significantly different among males and females (P = 0.02). While there was a significant decrease in the ERR with increasing attained age, this decrease was more rapid in males compared to females. The lowest dose range that showed a statistically significant dose response using the sex-averaged, linear ERR model was 0-100 mGy (P = 0.038). In conclusion, this analysis demonstrates that solid cancer risks remain elevated more than 60 years after exposure. Sex-averaged upward curvature was observed in the dose response independent of adjustment for smoking. Findings from the current analysis regarding the dose-response shape were not fully consistent with those previously reported, raising unresolved questions. At this time, uncertainties in the shape of the dose response preclude definitive conclusions to confidently guide radiation protection policies. Upcoming results from a series of analyses focusing on the radiation risks for specific organs or organ families, as well as continued follow-up are needed to fully understand the nature of radiation-related cancer risk and its public health significance. Data and analysis scripts are available for download at: http://www.rerf.or.jp .

Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene–environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4×10−6) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1×10−4). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01–1.16) in nulliparous women and ranged from 1.03 (0.96–1.10) in parous women with one birth to 1.26 (1.16–1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85–0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14–1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3×10−5), with a per-allele OR of 1.14 (1.11–1.17) in parous women and 0.98 (0.92–1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.

The Life Span Study (LSS) of Japanese atomic bomb survivors is comprised of a large, population-based cohort offering one of the best opportunities to study the relationship between exposure to radiation and incidence of respiratory cancers. Risks of lung, laryngeal and other cancers of the respiratory system were evaluated among 105,444 LSS subjects followed from 1958 to 2009. During this period, we identified 2,446 lung, 180 laryngeal and 115 other respiratory (trachea, mediastinum and other ill-defined sites) first primary incident cancer cases. Ten additional years of follow-up, improved radiation dose estimates, revised smoking data, and updated migration information were used to investigate the joint effects of radiation and smoking using Poisson regression methods. For nonsmokers, the sex-averaged excess relative risk per Gy (ERR/Gy) for lung cancer (at age 70 after radiation exposure at age 30) was estimated as 0.81 (95% CI: 0.51, 1.18) with a female-to-male ratio of 2.83. There was no evidence of curvature in the radiation dose-response relationship overall or by sex. Lung cancer risks increased with pack-years of smoking and decreased with time since quitting smoking at any level of radiation exposure. Similar to the previously reported study, which followed cohort members through 1999, the ERR/Gy for lung cancer was significantly higher for low-to-moderate smokers than for heavy smokers, with little evidence of any radiation-associated excess risk in heavy smokers. Of 2,446 lung cancer cases, 113 (5%) could be attributed to radiation exposure. Of the 1,165 lung cancer cases occurring among smokers, 886 (76%) could be attributed to smoking. While there was little evidence of a radiation effect for laryngeal cancer, a nonsignificantly elevated risk of other respiratory cancers was observed. However, significant smoking effects were observed for both laryngeal (ERR per 50 pack-years = 23.57; 95% CI: 8.44, 71.05) and other respiratory cancers (ERR per 50 pack-years = 1.21; 95% CI: 0.10, 3.25).

Ecologic studies have reported that solar ultraviolet radiation (UVR) exposure is associated with cancer, but little evidence is available from prospective studies. We aimed to assess the association between an objective measure of ambient UVR exposure and risk of total and site-specific cancer in a large, regionally diverse cohort (450,934 white, non-Hispanic subjects (50-71 years old) in the prospective NIH-AARP Diet and Health Study) after accounting for individual-level confounding risk factors. Estimated erythemal UVR exposure from satellite Total Ozone Mapping Spectrometer (TOMS) data from NASA was linked to the U.S. Census Bureau 2000 census tract (centroid) of baseline residence for each subject. We used Cox proportional hazards models adjusted for multiple potential confounders to estimate hazard ratios (HR) and 95% confidence intervals (CI) for quartiles of UVR exposure. Restricted cubic splines examined non-linear relationships. Over 9 years of follow-up, UVR exposure was inversely associated with total cancer risk (N=75,917; highest vs. lowest quartile, HR=0.97 (0.95, 0.99), p-trend<0.001). In site-specific cancer analyses, UVR exposure was associated with increased melanoma risk (highest vs. lowest quartile, HR=1.22 (1.13, 1.32), p-trend<0.001) and decreased risk of Non-Hodgkin’s lymphoma (HR=0.82 (0.74, 0.92)) and colon (HR=0.88 (0.82, 0.96)), squamous cell lung (HR=0.86 (0.75, 0.98)), pleural (HR=0.57 (0.38, 0.84)), prostate (HR=0.91 (0.88, 0.95)), kidney (HR=0.83 (0.73, 0.94)), and bladder (HR=0.88 (0.81, 0.96)) cancers (all p-trend<0.05). We also found non-linear associations for some cancer sites, including the thyroid and pancreas. Our results add to mounting evidence for the influential role of UVR exposure on cancer.

The 1986 Chernobyl nuclear power plant accident increased papillary thyroid carcinoma (PTC) incidence in surrounding regions, particularly for radioactive iodine (131I)–exposed children. We analyzed genomic, transcriptomic, and epigenomic characteristics of 440 PTCs from Ukraine (from 359 individuals with estimated childhood 131I exposure and 81 unexposed children born after 1986). PTCs displayed radiation dose–dependent enrichment of fusion drivers, nearly all in the mitogen-activated protein kinase pathway, and increases in small deletions and simple/balanced structural variants that were clonal and bore hallmarks of nonhomologous end-joining repair. Radiation-related genomic alterations were more pronounced for individuals who were younger at exposure. Transcriptomic and epigenomic features were strongly associated with driver events but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth after environmental radiation exposure.

Circulating 25-hydroxyvitamin D (25(OH)D), a marker for vitamin D status, is associated with bone health and possibly cancers and other diseases; yet, the determinants of 25(OH)D status, particularly ultraviolet radiation (UVR) exposure, are poorly understood. Determinants of 25(OH)D were analyzed in a subcohort of 1,500 participants of the US Radiologic Technologists (USRT) Study that included whites (n = 842), blacks (n = 646), and people of other races/ethnicities (n = 12). Participants were recruited monthly (2008-2009) across age, sex, race, and ambient UVR level groups. Questionnaires addressing UVR and other exposures were generally completed within 9 days of blood collection. The relation between potential determinants and 25(OH)D levels was examined through regression analysis in a random two-thirds sample and validated in the remaining one third. In the regression model for the full study population, age, race, body mass index, some seasons, hours outdoors being physically active, and vitamin D supplement use were associated with 25(OH)D levels. In whites, generally, the same factors were explanatory. In blacks, only age and vitamin D supplement use predicted 25(OH)D concentrations. In the full population, determinants accounted for 25% of circulating 25(OH)D variability, with similar correlations for subgroups. Despite detailed data on UVR and other factors near the time of blood collection, the ability to explain 25(OH)D was modest.

The importance of reproductive history in breast tissue development and etiology of sporadic breast cancer in females is well established. However, there is limited evidence of factors, other than age, that modify risk of radiation-related breast cancer. In this study, we evaluated breast cancer incidence in the Life Span Study cohort of atomic bomb survivors, adding 11 years of follow-up and incorporating reproductive history data. We used Poisson regression models to describe radiation risks and modifying effects of age and reproductive factors. Among 62,534 females, we identified 1,470 breast cancers between 1958 and 2009. Of 397 new cases diagnosed since 1998, 75% were exposed before age 20. We found a strong linear dose response with excess relative risk (ERR) of 1.12 per Gy [95% confidence interval (CI): 0.73 to 1.59] for females at age 70 after exposure at age 30. The ERR decreased with increasing attained age ( P = 0.007) while excess absolute rate (EAR) increased with attained age up to age 70 ( P < 0.001). Age at menarche was a strong modifier of the radiation effect: for a given dose, both the ERR and EAR decreased with increasing age at menarche ( P = 0.007 and P < 0.001). Also, independently, age-at-exposure effects on ERR and EAR differed before and after menarche ( P = 0.043 and P = 0.015, respectively, relative to log-linear trends), with highest risks for exposures around menarche. Despite the small number of male breast cancers (n = 10), the data continue to suggest a dose response (ERR per Gy = 5.7; 95% CI: 0.3 to 30.8; P = 0.018). Persistently increased risk of female breast cancer after radiation exposure and its modification pattern suggests heightened breast sensitivity during puberty.

Due to treatment with immunosuppressive medications, solid organ transplant recipients have elevated risk for Kaposi sarcoma (KS), which is caused by human herpesvirus 8 (HHV8). Other risk factors for KS are poorly understood. We linked the United States solid organ transplant registry with 17 population-based cancer registries to ascertain KS incidence among 244,964 transplant recipients from 1987-2014. To compare incidence rates of KS according to patient and transplant characteristics, we calculated incidence rate ratios (IRRs) using Poisson regression. To compare associations of KS with other skin cancers occurring before or within 12 months of KS diagnosis, we computed odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression. All statistical tests were two-sided. We identified 163 KS cases during follow-up. Among transplant recipients, we found significantly increased risk of KS associated with male sex (IRR = 1.87; 95%CI:1.32,2.71), nonwhite race (IRR = 2.67; 95%CI:1.92,3.72), non-US citizenship (IRR = 2.10; 95%CI:1.19,3.47), lung transplant (IRR = 2.22; 95%CI:1.03,4.24, vs. kidney), and older age at transplant. KS risk decreased significantly with time since transplant and recent calendar year, however, no specific induction or maintenance medication was associated with KS. KS incidence was not significantly associated with ambient ultraviolet radiation (IRR = 1.32 95%CI:0.87,2.02, tertile 3 vs. 1). KS incidence has decreased in recent calendar years. In a cross-sectional sample, we found cutaneous squamous cell carcinoma was associated with KS (OR = 4.83; 95%CI:1.30,14.69). KS risk factors included those potentially associated with HHV8 infection and increased immunosuppression. Our findings suggest that transplant recipients with a non-KS skin cancer may also be at high KS risk.