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Background: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease.Methods: Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided.Results: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4).Conclusions: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations. [ABSTRACT FROM AUTHOR]

Background: Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk.Methods: We tested multiplicative statistical interactions between BMI (per 5 kg/m2) and approximately 2.7 million single nucleotide polymorphisms with colorectal cancer risk among 14 059 colorectal cancer case (53.2% women) and 14 416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included 2-step (ie, Cocktail method) and single-step (ie, case-control logistic regression and a joint 2-degree of freedom test) procedures. All statistical tests were two-sided.Results: Each 5 kg/m2 increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR] = 1.14, 95% confidence intervals [CI] = 1.11 to 1.18; P = 9.75 × 10-17) than for men (OR = 1.26, 95% CI = 1.20 to 1.32; P = 2.13 × 10-24). The 2-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; Pobserved = .0009; Pthreshold = .005). A joint 2-degree of freedom test was consistent with this finding for women (joint P = 2.43 × 10-10). Each 5 kg/m2 increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR = 1.24, 95% CI = 1.16 to 1.32; P = 2.60 × 10-10) than for women with the CT (OR = 1.14, 95% CI = 1.09 to 1.19; P = 1.04 × 10-8) or TT (OR = 1.07, 95% CI = 1.01 to 1.14; P = .02) genotypes.Conclusion: These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women. [ABSTRACT FROM AUTHOR]

Background: Excess body weight is an established cause of postmenopausal breast cancer, but it is unknown if weight loss reduces risk.Methods: Associations between weight change and risk of breast cancer were examined among women aged 50 years and older in the Pooling Project of Prospective Studies of Diet and Cancer. In 10 cohorts, weight assessed on three surveys was used to examine weight change patterns over approximately 10 years (interval 1 median = 5.2 years; interval 2 median = 4.0 years). Sustained weight loss was defined as no less than 2 kg lost in interval 1 that was not regained in interval 2. Among 180 885 women, 6930 invasive breast cancers were identified during follow-up.Results: Compared with women with stable weight (±2 kg), women with sustained weight loss had a lower risk of breast cancer. This risk reduction was linear and specific to women not using postmenopausal hormones (>2-4.5 kg lost: hazard ratio [HR] = 0.82, 95% confidence interval [CI] = 0.70 to 0.96; >4.5-<9 kg lost: HR = 0.75, 95% CI = 0.63 to 0.90; ≥9 kg lost: HR = 0.68, 95% CI = 0.50 to 0.93). Women who lost at least 9 kg and gained back some (but not all) of it were also at a lower risk of breast cancer. Other patterns of weight loss and gain over the two intervals had a similar risk of breast cancer to women with stable weight.Conclusions: These results suggest that sustained weight loss, even modest amounts, is associated with lower breast cancer risk for women aged 50 years and older. Breast cancer prevention may be a strong weight-loss motivator for the two-thirds of American women who are overweight or obese. [ABSTRACT FROM AUTHOR]

Higher body mass index (BMI; weight (kg)/height (m)2) is associated with increased risk of pancreatic cancer in epidemiologic studies. However, BMI has usually been assessed at older ages, potentially underestimating the full impact of excess weight. We examined the association between BMI and pancreatic cancer mortality among 963,317 adults who were aged 30–89 years at their enrollment in Cancer Prevention Study II in 1982. During follow-up through 2014, a total of 8,354 participants died of pancreatic cancer. Hazard ratios per 5 BMI units, calculated using proportional hazards regression, declined steadily with age at BMI assessment, from 1.25 (95% confidence interval: 1.18, 1.33) in persons aged 30–49 years at enrollment to 1.13 (95% confidence interval: 1.02, 1.26) in those aged 70–89 years at enrollment (P for trend = 0.005). On the basis of a hazard ratio of 1.25 per 5 BMI units at age 45 years, we estimated that 28% of US pancreatic cancer deaths among persons born in 1970–1974 will be attributable to BMI ≥25.0—nearly twice the equivalent proportion of those born in the 1930s, a birth cohort with much lower BMI in middle age. These results suggest that BMI before age 50 years is more strongly associated with pancreatic cancer risk than BMI at older ages, and they underscore the importance of avoiding excess weight gain before middle age for preventing this highly fatal cancer. [ABSTRACT FROM AUTHOR]

Background: Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear.Methods: We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided.Results: Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend < .01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers.Conclusions: Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract. [ABSTRACT FROM AUTHOR]

Background: Experimental and epidemiological studies suggest a protective role for vitamin D in colorectal carcinogenesis, but evidence is inconclusive. Circulating 25-hydroxyvitamin D (25(OH)D) concentrations that minimize risk are unknown. Current Institute of Medicine (IOM) vitamin D guidance is based solely on bone health.Methods: We pooled participant-level data from 17 cohorts, comprising 5706 colorectal cancer case participants and 7107 control participants with a wide range of circulating 25(OH)D concentrations. For 30.1% of participants, 25(OH)D was newly measured. Previously measured 25(OH)D was calibrated to the same assay to permit estimating risk by absolute concentrations. Study-specific relative risks (RRs) for prediagnostic season-standardized 25(OH)D concentrations were calculated using conditional logistic regression and pooled using random effects models.Results: Compared with the lower range of sufficiency for bone health (50-<62.5 nmol/L), deficient 25(OH)D (<30 nmol/L) was associated with 31% higher colorectal cancer risk (RR = 1.31, 95% confidence interval [CI] = 1.05 to 1.62); 25(OH)D above sufficiency (75-<87.5 and 87.5-<100 nmol/L) was associated with 19% (RR = 0.81, 95% CI = 0.67 to 0.99) and 27% (RR = 0.73, 95% CI = 0.59 to 0.91) lower risk, respectively. At 25(OH)D of 100 nmol/L or greater, risk did not continue to decline and was not statistically significantly reduced (RR = 0.91, 95% CI = 0.67 to 1.24, 3.5% of control participants). Associations were minimally affected when adjusting for body mass index, physical activity, or other risk factors. For each 25 nmol/L increment in circulating 25(OH)D, colorectal cancer risk was 19% lower in women (RR = 0.81, 95% CI = 0.75 to 0.87) and 7% lower in men (RR = 0.93, 95% CI = 0.86 to 1.00) (two-sided Pheterogeneity by sex = .008). Associations were inverse in all subgroups, including colorectal subsite, geographic region, and season of blood collection.Conclusions: Higher circulating 25(OH)D was related to a statistically significant, substantially lower colorectal cancer risk in women and non-statistically significant lower risk in men. Optimal 25(OH)D concentrations for colorectal cancer risk reduction, 75-100 nmol/L, appear higher than current IOM recommendations. [ABSTRACT FROM AUTHOR]

Background: Esophageal adenocarcinoma (EA) and gastric cardia adenocarcinoma (GCA) are characterized by a strong male predominance. Concentrations of sex steroid hormones have been hypothesized to explain this sex disparity. However, no prospective population-based study has examined sex steroid hormones in relation to EA/GCA risk. Thus, we investigated whether prediagnostic circulating sex steroid hormone concentrations were associated with EA/GCA in a nested case-control study drawn from participants in three prospective cohort studies.Methods: Using gas chromatography-mass spectrometry (GC-MS) and electrochemiluminescence immunoassay, we quantitated sex steroid hormones and sex hormone binding globulin, respectively, in serum from 259 EA/GCA male case participants and 259 matched male control participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and Cancer Prevention Study II Nutrition Cohort. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between circulating hormones and EA/GCA risk. All statistical tests were two-sided.Results: Higher concentrations of dehydroepiandrosterone (DHEA) were associated with a 38% decreased risk of EA/GCA (OR per unit increase in log2 DHEA = 0.62, 95% CI = 0.47 to 0.82, Ptrend = .001). Higher estradiol concentrations were associated with a 34% reduced risk of EA/GCA (OR = 0.66, 95% CI = 0.45 to 0.98, Ptrend = .05), and the association with free estradiol was similar. No other associations between baseline hormone concentrations and future EA/GCA risk were observed.Conclusions: This study provides the first evidence that higher concentrations of circulating DHEA, estradiol, and free estradiol may be associated with lower risks of EA/GCA in men. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The majority of leisure time is spent in sedentary behaviors such as television viewing. Studies have documented that prolonged leisure-time sitting is associated with higher risk of mortality—total, cardiovascular disease, cancer, and "all other causes"—but few have examined the "other" causes of death in detail. To examine associations of leisure-time sitting with risk of specific causes of death, we analyzed data from the Cancer Prevention Study II (CPS-II) Nutrition Cohort, a prospective US cohort including 127,554 men and women who were free of major chronic disease at study entry, and among whom 48,784 died during 21 years of follow-up (1993–2014; median follow-up, 20.3 years, interquartile range, 4.6 years). After multivariable adjustment, prolonged leisure-time sitting (≥6 vs. <3 hours per day) was associated with higher risk of mortality from all causes, cardiovascular disease (including coronary heart disease and stroke-specific mortality), cancer, diabetes, kidney disease, suicide, chronic obstructive pulmonary disease, pneumonitis due to solids and liquids, liver, peptic ulcer and other digestive disease, Parkinson disease, Alzheimer disease, nervous disorders, and musculoskeletal disorders. These findings provide additional evidence for associations between a broad range of mortality outcomes and prolonged sitting time. Given the pervasive nature of sitting in the contemporary lifestyle, this study further supports the recommendation that encouraging individuals to reduce sedentary time may provide health benefits. [ABSTRACT FROM AUTHOR]

Background: Numerous studies have sought to identify genes that influence the ability to quit smoking, but none found any that are consistently associated with smoking cessation.Methods: We developed a novel difficulty of quitting smoking phenotype based on the extremes of the number of quit attempts needed to achieve successful abstinence: Easy quitters were defined as having achieved long-term (>1 year) abstinence after their first quit attempt and difficult quitters as having reported 10 or more quit attempts. We conducted a two-stage study to determine if this phenotype could be useful for identifying single nucleotide polymorphisms (SNPs) that influence smoking cessation. In stage 1, 82 SNPs in 26 genes involved in nicotine signaling and metabolism were genotyped in 1357 easy quitters and 1321 difficult quitters from Cancer Prevention Study 3 (CPS-3). In stage 2, the 11 SNPs associated with difficult quitting in stage 1 (p < .1) were genotyped in an independent sample of 1300 easy quitters and 1299 difficult quitters from CPS-3.Results: Three of 11 SNPs (HTR1B rs6298, NR4A2 rs834829, and CYP2A65 rs8192729) were significantly associated with the difficult quitting phenotype in stage 2 (p < .05). In addition, a polygenic risk score based on the 11 SNPs identified in stage 1 was significantly associated with the difficult quitting phenotype in stage 2 (odds ratio = 1.08, 95% confidence interval: 1.03-1.14 per quintile, p trend = 4.5×10-3).Conclusions: Using a novel difficulty of quitting phenotype, three gene variants and a polygenic risk score based on 11 SNPs were found to be significantly associated with smoking cessation.Implications: Our results provide evidence that a difficulty of quitting smoking phenotype based on the extremes of number of quit attempts could be a useful tool for identifying genetic variants that influence difficulty of smoking cessation. Knowledge of these genetic variants will indicate biological pathways that could be targeted for the development of novel smoking cessation aids and could be used to determine which smokers are most likely to benefit from such smoking cessation aids. [ABSTRACT FROM AUTHOR]

Background: Breast cancer aetiology may differ by estrogen receptor (ER) status. Associations of alcohol and folate intakes with risk of breast cancer defined by ER status were examined in pooled analyses of the primary data from 20 cohorts.Methods: During a maximum of 6-18 years of follow-up of 1 089 273 women, 21 624 ER+ and 5113 ER- breast cancers were identified. Study-specific multivariable relative risks (RRs) were calculated using Cox proportional hazards regression models and then combined using a random-effects model.Results: Alcohol consumption was positively associated with risk of ER+ and ER- breast cancer. The pooled multivariable RRs (95% confidence intervals) comparing ≥ 30 g/d with 0 g/day of alcohol consumption were 1.35 (1.23-1.48) for ER+ and 1.28 (1.10-1.49) for ER- breast cancer (Ptrend ≤ 0.001; Pcommon-effects by ER status: 0.57). Associations were similar for alcohol intake from beer, wine and liquor. The associations with alcohol intake did not vary significantly by total (from foods and supplements) folate intake (Pinteraction ≥ 0.26). Dietary (from foods only) and total folate intakes were not associated with risk of overall, ER+ and ER- breast cancer; pooled multivariable RRs ranged from 0.98 to 1.02 comparing extreme quintiles. Following-up US studies through only the period before mandatory folic acid fortification did not change the results. The alcohol and folate associations did not vary by tumour subtypes defined by progesterone receptor status.Conclusions: Alcohol consumption was positively associated with risk of both ER+ and ER- breast cancer, even among women with high folate intake. Folate intake was not associated with breast cancer risk. [ABSTRACT FROM AUTHOR]

Weight cycling, which consists of repeated cycles of intentional weight loss and regain, is common among individuals who try to lose weight. Some evidence suggests that weight cycling may affect biological processes that could contribute to carcinogenesis, but whether it is associated with cancer risk is unclear. Using 62,792 men and 69,520 women enrolled in the Cancer Prevention Study II Nutrition Cohort in 1992, we examined the association between weight cycling and cancer incidence. Weight cycles were defined by using baseline questions that asked the number of times ≥10 pounds (4.54 kg) was purposely lost and later regained. Multivariable-adjusted hazard ratios and 95% confidence intervals for all cancer and 15 individual cancers were estimated by using Cox proportional hazards regression. During up to 17 years of follow-up, 15,333 men and 9,984 women developed cancer. Weight cycling was not associated with overall risk of cancer in men (hazard ratio = 0.96, 95% confidence interval: 0.83, 1.11 for ≥20 cycles vs. no weight cycles) or women (hazard ratio = 0.96, 95% confidence interval: 0.86, 1.08) in models that adjusted for body mass index and other covariates.Weight cycling was also not associated with any individual cancer investigated. These results suggest that weight cycling, independent of body weight, is unlikely to influence subsequent cancer risk. [ABSTRACT FROM AUTHOR]

The proportion of parents aged ≥35 years at the birth of their child continues to increase, but long-term health consequences for these children are not fully understood. A recent prospective study of 110,999 adult women showed an association between paternal—but not maternal—age at birth and sporadic hematological cancer risk. To further investigate this topic, we examined these associations in women and men in the American Cancer Society Cancer Prevention Study-II Nutrition Cohort. Among 138,003 Cancer Prevention Study-II participants, 2,532 incident hematological cancers were identified between 1992 and 2009. Multivariable-adjusted hazard ratios and 95% confidence intervals were computed by using Cox proportional hazards regression. There was no clear linear trend in the risk of hematological malignancies by either paternal or maternal age. However, there was a strong, positive association with paternal age among participants without siblings. In that group, the hazard ratio for fathers aged ≥35 years compared with <25 years at birth was 1.63 (95% confidence interval: 1.19, 2.23), and a linear dose-response association was suggested (Pspline = 0.002).There were no differences by subtype of hematological cancer. Results of this study support the need for further research to better understand the association between paternal age at birth and hematological malignancies. [ABSTRACT FROM AUTHOR]

The International Agency for Research on Cancer recently classified outdoor air pollution and airborne particulate matter as carcinogenic to humans. However, there are gaps in the epidemiologic literature, including assessment of possible joint effects of cigarette smoking and fine particulate matter (particulate matter less than or equal to 2.5 µm in diameter) on lung cancer risk. We present estimates of interaction on the additive scale between these risk factors from Cancer Prevention Study II, a large prospective US cohort study of nearly 1.2 million participants recruited in 1982. Estimates of the relative excess risk of lung cancer mortality due to interaction, the attributable proportion due to interaction, and the synergy index were 2.19 (95% confidence interval (CI): −0.10, 4.83), 0.14 (95% CI: 0.00, 0.25), and 1.17 (95% CI: 1.00, 1.37), respectively, using the 25th and 75th percentiles as cutpoints for fine particulate matter. This suggests small increases in lung cancer risk among persons with both exposures beyond what would be expected from the sum of the effects of the individual exposures alone. Although reductions in cigarette smoking will achieve the greatest impact on lung cancer rates, these results suggest that attempted reductions in lung cancer risk through both tobacco control and air quality management may exceed expectations based on reducing exposure to either risk factor alone. [ABSTRACT FROM PUBLISHER]

We systematically examined common genetic variants in the 9p21 region and risk of eight cancers, based on GWAS data deposited in dbGaP. A number of SNPs were associated with multiple cancers, which are not confined to the CDKN2/MTAP cluster.The chromosome 9p21 region has been implicated in the pathogenesis of multiple cancers. We analyzed 9p21 single nucleotide polymorphisms (SNPs) from eight genome-wide association studies (GWAS) with data deposited in dbGaP, including studies of esophageal squamous cell carcinoma (ESCC), gastric cancer (GC), pancreatic cancer, renal cell carcinoma (RCC), lung cancer (LC), breast cancer (BrC), bladder cancer (BC) and prostate cancer (PrC). The number of subjects ranged from 2252 (PrC) to 7619 (LC). SNP-level analyses for each cancer were conducted by logistic regression or random-effects meta-analysis. A subset-based statistical approach (ASSET) was performed to combine SNP-level P values across multiple cancers. We calculated gene-level P values using the adaptive rank truncated product method. We identified that rs1063192 and rs2157719 in the CDKN2A/2B region were significantly associated with ESCC and rs2764736 (3′ of TUSC1) was associated with BC (P ≤ 2.59 × 10−6). ASSET analyses identified four SNPs significantly associated with multiple cancers: rs3731239 (CDKN2A intronic) with ESCC, GC and BC (P = 3.96 × 10−4); rs10811474 (3′ of IFNW1) with RCC and BrC (P = 0.001); rs12683422 (LINGO2 intronic) with RCC and BC (P = 5.93 × 10−4) and rs10511729 (3′ of ELAVL2) with LC and BrC (P = 8.63 × 10−4). At gene level, CDKN2B, CDKN2A and CDKN2B-AS1 were significantly associated with ESCC (P ≤ 4.70 × 10−5). Rs10511729 and rs10811474 were associated with cis-expression of 9p21 genes in corresponding cancer tissues in the expression quantitative trait loci analysis. In conclusion, we identified several genetic variants in the 9p21 region associated with the risk of multiple cancers, suggesting that this region may contribute to a shared susceptibility across different cancer types. [ABSTRACT FROM AUTHOR]

To understand how US cancer control plans address alcohol use, an important but frequently overlooked cancer risk factor, and how many US adults are at risk.~Aims~Objective~We reviewed alcohol control efforts in 69 comprehensive cancer control plans in US states, tribes and jurisdictions. Using the 2011 Behavioral Risk Factor Surveillance System, we assessed the prevalence of current alcohol use among US adults and the proportion of these drinkers who exceeded guidelines for moderate drinking.~Methods~Methods~Most comprehensive cancer control plans acknowledged alcohol use as a cancer risk factor but fewer than half included a goal, objective or strategy to address alcohol use. More than half of US adults reported current alcohol use in 2011, and two of three drinkers exceeded moderate drinking guidelines at least once in the past month. Many states that did not address alcohol use in comprehensive cancer control plans also had a high proportion of adults at risk.~Results~Results~Alcohol use is a common cancer risk factor in the USA, but alcohol control strategies are not commonly included in comprehensive cancer control plans. Supporting the implementation of evidence-based strategies to prevent the excessive use of alcohol is one tool the cancer control community can use to reduce the risk of cancer.~Conclusion~Conclusions [ABSTRACT FROM AUTHOR]

Background The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown. Methods Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided. Results The IGF signaling pathway was associated with PCa mortality (P= .03), and IGF2-AS and SSTR2 were the main contributors (both P= .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with Ptrend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r²= 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r² = 0.03).The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; Ptrend = -003) for rs3741211 and 1.44 (95% CI = 1,20 to 1.73; Ptrends < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (Ptrend.corr = -04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0-71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality. Conclusions The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival. [ABSTRACT FROM AUTHOR]

Little is known about the risk of non-Hodgkin lymphoma (NHL) in nonsmokers who are exposed to environmental tobacco smoke (ETS). Previous research on NHL and ETS has not included men or examined doses of ETS exposure during childhood. The Cancer Prevention Study II Nutrition Cohort collected information on smoking habits and exposure to ETS during childhood and adulthood. Among 61,326 never-smoking men and women, 884 incident cases of NHL were identified between 1992 and 2009. Multivariable-adjusted relative risks and 95% confidence intervals were calculated using Cox proportional hazards regression to identify associations between ETS and NHL risk. Compared with no exposure to ETS as a child or an adult, childhood and/or adult ETS exposure was not associated with NHL overall. There was a positive association between the number of smokers in the house as a child (P for trend = 0.05) and exposure to 6 or more hours per week of ETS as an adult (relative risk = 2.37, 95% confidence interval: 1.12, 5.04) with follicular lymphoma risk. Adult ETS exposure was associated with a lower risk of diffuse large B-cell lymphoma (relative risk = 0.68, 95% confidence interval: 0.48, 0.97). This study suggests that adult and childhood ETS exposure may affect the risk of NHL, and that the associations differ by histological subtype. [ABSTRACT FROM PUBLISHER]

Higher dietary intakes of flavonoids and proanthocyanidins have been associated with a lower risk of several cancers. Few prospective epidemiologic studies have examined individual flavonoids and proanthocyanidins in relation to prostate cancer. We examined these associations in a prospective US cohort of 43,268 men with a mean age of 70 years who completed detailed self-administered questionnaires in 1999–2000. During a mean follow-up of 7.8 years, 3,974 total prostate cancers, including 567 high-grade cases and 362 advanced cases, were ascertained. Cox proportional hazards regression models were used to calculate multivariable-adjusted relative risks and 95% confidence intervals. Residual energy-adjusted total flavonoids (for fifth quintile vs. first quintile, relative risk = 1.11, 95% confidence interval: 1.01, 1.23; P for trend = 0.02) and several subclasses were positively associated with overall prostate cancer risk, mostly limited to the top quintile and the first 2 years of follow-up. The associations for total flavonoids, flavan-3-ols, and proanthocyanidins with high-grade prostate cancer risk varied by follow-up time. During follow-up from 2002 to 2009, we observed suggestive inverse trends with higher total flavonoids (P for trend = 0.05) and proanthocyanidins (P for trend = 0.04) with high-grade prostate cancer, but not with advanced prostate cancer. Although evidence is limited, a possible role of total flavonoids and proanthocyanidins in prostate cancer tumor progression deserves further study. [ABSTRACT FROM PUBLISHER]

Background The etiology of male breast cancer is poorly understood, partly because of its relative rarity. Although genetic factors are involved, less is known regarding the role of anthropometric and hormonally related risk factors. Methods In the Male Breast Cancer Pooling Project, a consortium of 11 case-control and 10 cohort investigations involving 2405 case patients (n = 1190 from case-control and n = 1215 from cohort studies) and 52013 control subjects, individual participant data were harmonized and pooled. Unconditional logistic regression generated study design-specific (case-control/cohort) odds ratios (ORs) and 95% confidence intervals (CIs), with exposure estimates combined using fixed effects meta-analysis. All statistical tests were two-sided. Results Risk was statistically significantly associated with weight (highest/lowest tertile: OR = 1.36; 95% CI = 1.18 to 1.57), height (OR = 1.18; 95% CI = 1.01 to 1.38), and body mass index (BMI; OR = 1.30; 95% CI = 1.12 to 1.51 ), with evidence that recent rather than distant BMI was the strongest predictor. Klinefelter syndrome (OR = 24.7; 95% CI = 8.94 to 68.4) and gynecomastia (OR = 9.78; 95% CI = 7.52 to 12.7) were also statistically significantly associated with risk, relations that were independent of BMI. Diabetes also emerged as an independent risk factor (OR = 1.19; 95% CI = 1.04 to 1.37). There were also suggestive relations with cryptorchidism (OR = 2.18; 95% CI = 0.96 to 4.94) and orchitis (OR = 1.43; 95% CI = 1.02 to 1.99). Although age at onset of puberty and histories of infertility were unrelated to risk, never having had children was statistically significantly related (OR = 1.29; 95% CI = 1.01 to 1.66). Among individuals diagnosed at older ages, a history of fractures was statistically significantly related (OR = 1.41; 95% CI = 1.07 to 1.86). Conclusions Consistent findings across case-control and cohort investigations, complemented by pooled analyses, indicated important roles for anthropometric and hormonal risk factors in the etiology of male breast cancer. Further investigation should focus on potential roles of endogenous hormones. [ABSTRACT FROM AUTHOR]

Background The relationship between active cigarette smoking and breast cancer risk remains controversial because of unresolved issues of confounding and dose response. Methods To investigate these issues further, we analyzed data from 73 388 women in the American Cancer Society's Cancer Prevention Study II (CPS-II) Nutrition Cohort. Analyses were based on 3721 invasive breast cancer case patients identified during a median follow-up of 13.8 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from multivariable-adjusted Cox proportional hazard regression models. P values were two-sided. We also conducted meta-analyses of our results with those published from 14 other cohort studies. Results In CPS-II, incidence was higher in current (HR = 1.24, 95% CI = 1.07 to 1.42) and former smokers (HR = 1.13, 95% CI = 1.06 to 1.21) than in never smokers. Women who initiated smoking before menarche (HR = 1.61,95% CI = 1.10 to 2.34) or after menarche but 11 or more years before first birth (HR = 1.45, 95% CI = 1.21 to 1.74) had higher risk (Ptrend = .03). No relationships were observed with other smoking parameters. Alcohol consumption did not confound associations with smoking status, although neither current nor former smoking were associated with risk among never drinkers (Pinteraction = .11). In meta-analyses, current (HR = 1.12, 95% CI = 1.08 to 1.16) and former smoking (HR = 1.09, 95% CI = 1.04 to 1.15) were weakly associated with risk; a stronger association (HR = 1.21, 95% CI = 1.14 to 1.28) was observed in women who initiated smoking before first birth. Conclusions These results support the hypothesis that active smoking is associated with increased breast cancer risk for women who initiate smoking before first birth and suggest that smoking might play a role in breast cancer initiation. [ABSTRACT FROM AUTHOR]

Epidemiologic studies suggest that coffee intake is associated with reduced risk of oral/pharyngeal cancer. The authors examined associations of caffeinated coffee, decaffeinated coffee, and tea intake with fatal oral/pharyngeal cancer in the Cancer Prevention Study II, a prospective US cohort study begun in 1982 by the American Cancer Society. Among 968,432 men and women who were cancer free at enrollment, 868 deaths due to oral/pharyngeal cancer occurred during 26 years of follow-up. Cox proportional hazards regression was used to estimate multivariable-adjusted relative risk. Intake of >4 cups/day of caffeinated coffee was associated with a 49% lower risk of oral/pharyngeal cancer death relative to no/occasional coffee intake (relative risk = 0.51, 95% confidence interval: 0.40, 0.64) (1 cup/day = 237 ml). A dose-related decline in relative risk was observed with each single cup/day consumed (Ptrend < 0.001). The association was not modified by sex, smoking status, or alcohol use. An inverse association for >2 cups/day of decaffeinated coffee intake was suggested (relative risk = 0.61, 95% confidence interval: 0.37, 1.01). No association was found for tea drinking. In this large prospective study, caffeinated coffee intake was inversely associated with oral/pharyngeal cancer mortality. Research is needed to elucidate biologic mechanisms whereby coffee might help to protect against these often fatal cancers. [ABSTRACT FROM PUBLISHER]

Observational studies have found an inverse association between type 2 diabetes (T2D) and prostate cancer (PCa), and genome-wide association studies have found common variants near 3 loci associated with both diseases. The authors examined whether a genetic background that favors T2D is associated with risk of advanced PCa. Data from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium, a genome-wide association study of 2,782 advanced PCa cases and 4,458 controls, were used to evaluate whether individual single nucleotide polymorphisms or aggregations of these 36 T2D susceptibility loci are associated with PCa. Ten T2D markers near 9 loci (NOTCH2, ADCY5, JAZF1, CDKN2A/B, TCF7L2, KCNQ1, MTNRIB, FTO, and HNFIB) were nominally associated with PCa (P< 0.05); the association for single nucleotide polymorphism rs757210 at the HNFIB locus was significant when multiple comparisons were accounted for (adjusted P= 0.001). Genetic risk scores weighted by the T2D log odds ratio and multilocus kernel tests also indicated a significant relation between T2D variants and PCa risk. A mediation analysis of 9,065 PCa cases and 9,526 controls failed to produce evidence that diabetes mediates the association of the HNF1B locus with PCa risk. These data suggest a shared genetic component between T2D and PCa and add to the evidence for an interrelation between these diseases. [ABSTRACT FROM AUTHOR]

Radon is a known cause of human lung cancer. Previously, the authors observed a significant positive association between mean county-level residential radon concentrations and lung cancer mortality in the Cancer Prevention Study II (CPS-II), a large prospective study of nearly 1.2 million participants recruited in 1982 by the American Cancer Society. There was also a significant positive association with mortality from chronic obstructive pulmonary disease. Because it is unclear whether radon is associated with mortality from other malignant or nonmalignant disease, the authors examined the association between radon and nonrespiratory mortality in the CPS-II. Mean county-level residential radon concentrations (mean = 53.5 (standard deviation: 38.0) Bq/m3) were linked to participants by their zip code at enrollment. Cox proportional hazards regression models were used to estimate adjusted hazard ratios and 95% confidence intervals for all-cause (excluding lung cancer and respiratory mortality) and cause-specific mortality associated with radon concentrations. A total of 811,961 participants in 2,754 counties were analyzed, including 265,477 deaths through 2006. There were no clear associations between radon and nonrespiratory mortality in the CPS-II. These findings suggest that residential radon is not associated with any other mortality beyond lung cancer or chronic obstructive pulmonary disease. [ABSTRACT FROM AUTHOR]

Background A recent pooled analysis of randomized trials of daily aspirin for prevention of vascular events found a substantial reduction (relative risk [RR] = 0.63, 95% confidence interval [CI] = 0.49 to 0.82) in overall cancer mortality during follow-up occurring after 5 years on aspirin. However, the magnitude of the effect of daily aspirin use, particularly long-term use, on cancer mortality is uncertain. Methods We examined the association between daily aspirin use and overall cancer mortality among 100 139 men and women with no history of cancer in the Cancer Prevention Study II Nutrition Cohort. Cox proportional hazards regression models were used to estimate multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs). Results Between 1997 and 2008, 5138 participants died from cancer. Compared with no use, daily aspirin use at base-line was associated with slightly lower cancer mortality, regardless of duration of daily use (for <5 years of use, RR = 0.92, 95% CI = 0.85 to 1.01; for >5 years of use, RR = 0.92, 95% CI = 0.83 to 1.02). Associations were slightly stronger in analyses that used updated aspirin information from periodic follow-up questionnaires and included 3373 cancer deaths (for <5 years of use, RR = 0.84, 95% CI = 0.76 to 0.94; for >5 years of use, RR = 0.84, 95% CI = 0.75 to 0.95). Conclusion These results are consistent with an association between recent daily aspirin use and modestly lower cancer mortality but suggest that any reduction in cancer mortality may be smaller than that observed with long-term aspirin use in the pooled trial analysis. [ABSTRACT FROM AUTHOR]

Background Some, but not all, observational studies have suggested that taller stature is associated with a significant increased risk of glioma. In a pooled analysis of observational studies, we investigated the strength and consistency of this association, overall and for major sub-types, and investigated effect modification by genetic susceptibility to the disease.Methods We standardized and combined individual-level data on 1354 cases and 4734 control subjects from 13 prospective and 2 case–control studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for glioma and glioma sub-types were estimated using logistic regression models stratified by sex and adjusted for birth cohort and study. Pooled ORs were additionally estimated after stratifying the models according to seven recently identified glioma-related genetic variants.Results Among men, we found a positive association between height and glioma risk (&geq;190 vs 170–174 cm, pooled OR = 1.70, 95% CI: 1.11–2.61; P-trend = 0.01), which was slightly stronger after restricting to cases with glioblastoma (pooled OR = 1.99, 95% CI: 1.17–3.38; P-trend = 0.02). Among women, these associations were less clear (&geq;175 vs 160–164 cm, pooled OR for glioma = 1.06, 95% CI: 0.70–1.62; P-trend = 0.22; pooled OR for glioblastoma = 1.36, 95% CI: 0.77–2.39; P-trend = 0.04). In general, we did not observe evidence of effect modification by glioma-related genotypes on the association between height and glioma risk.Conclusion An association of taller adult stature with glioma, particularly for men and stronger for glioblastoma, should be investigated further to clarify the role of environmental and genetic determinants of height in the etiology of this disease. [ABSTRACT FROM PUBLISHER]

The obesity epidemic is attributed in part to reduced physical activity. Evidence supports that reducing time spent sitting, regardless of activity, may improve the metabolic consequences of obesity. Analyses were conducted in a large prospective study of US adults enrolled by the American Cancer Society to examine leisure time spent sitting and physical activity in relation to mortality. Time spent sitting and physical activity were queried by questionnaire on 53,440 men and 69,776 women who were disease free at enrollment. The authors identified 11,307 deaths in men and 7,923 deaths in women during the 14-year follow-up. After adjustment for smoking, body mass index, and other factors, time spent sitting (≥6 vs. <3 hours/day) was associated with mortality in both women (relative risk = 1.34, 95% confidence interval (CI): 1.25, 1.44) and men (relative risk = 1.17, 95% CI: 1.11, 1.24). Relative risks for sitting (≥6 hours/day) and physical activity (<24.5 metabolic equivalent (MET)-hours/week) combined were 1.94 (95% CI: 1.70, 2.20) for women and 1.48 (95% CI: 1.33, 1.65) for men, compared with those with the least time sitting and most activity. Associations were strongest for cardiovascular disease mortality. The time spent sitting was independently associated with total mortality, regardless of physical activity level. Public health messages should include both being physically active and reducing time spent sitting. [ABSTRACT FROM PUBLISHER]

Case-control studies generally suggesting an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) have led to speculation that vitamin D may protect against lymphomagenesis. To examine this hypothesis, the authors conducted a pooled investigation of circulating 25-hydroxyvitamin D (25(OH)D) and subsequent NHL risk within 10 cohorts participating in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. The authors analyzed measurements from 1,353 cases and 1,778 controls using conditional logistic regression and other methods to estimate the association of 25(OH)D with NHL. No clear evidence of association between categories of 25(OH)D concentration and NHL was observed overall (Ptrend = 0.68) or by sex (men, Ptrend = 0.50; women, Ptrend = 0.16). Findings for other measures (continuous log(25(OH)D), categories of 25(OH)D using sex-/cohort-/season-specific quartiles as cutpoints, categories of season-adjusted residuals of predicted 25(OH)D using quartiles as cutpoints) were generally null, although some measures of increasing 25(OH)D were suggestive of an increased risk for women. Results from stratified analyses and investigations of histologic subtypes of NHL were also null. These findings do not support the hypothesis that elevated circulating 25(OH)D concentration is associated with a reduced risk of NHL. Future research investigating the biologic basis for the sunlight–NHL association should consider alternative mechanisms, such as immunologic effects. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented in response to a study by L. R. Teras et al where they found positive association between advanced paternal age and the risk of hematological malignancies at 40 years or older among offspring without siblings.

In the sex hormone binding globulin (SHBG) gene, a pentanucleotide-repeat polymorphism [(TAAAA)n] and a single nucleotide polymorphism (D327N) have been associated with circulating SHBG concentrations in women. Only one study, limited to Scandinavians, has examined these associations in men. Using data from the Coronary Artery Risk Development in Young Adults (CARDIA) Male Hormone Study, the authors assessed associations of SHBG polymorphisms with serum SHBG levels in 511 Black men and 698 White men who had SHBG measured in multiple serum samples collected over an 8-year period from 1987 to 1996 and were aged 20–34 years at the time of the first SHBG measurement. Multivariable repeated-measures analyses were used to assess associations of (TAAAA)n and D327N polymorphisms with SHBG concentrations. Results showed statistically significant differences in mean SHBG concentrations for White men with genotypes of (TAAAA) 6/6 (35.1 nmol/liter), 6/x (30.8 nmol/liter), and x/x (29.6 nmol/liter), where x represents a repeat length greater than 6 (p = 0.001). For Black men, the pattern of association was similar, albeit not statistically significant (p = 0.35). There was no relation between D327N genotype and SHBG levels. These results suggest that the (TAAAA)n repeat length in the SHBG gene, but not the D327N variant, might contribute to the interindividual variability in serum SHBG levels. [ABSTRACT FROM PUBLISHER]

Cross-sectional studies have found associations between components of the insulin-like growth factor (IGF) system and hypertension, total cholesterol, and low density lipoprotein cholesterol. Using partial correlation analysis and longitudinal analysis of data collected at the year 2, year 7, and year 10 examinations, the authors assessed the associations of IGF-1 and IGF binding protein-3 (IGFBP-3) with cardiovascular disease risk factors in 544 Black and 747 White male participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Male Hormone Study who were aged 20–34 years at year 2 (1987–1988). There were no consistent independent associations with blood pressure. Cross-sectionally, there were some inverse associations between IGF-1 and lipid levels in White men (strongest r = –0.095 (p = 0.02) for total cholesterol at year 7) and positive associations between IGFBP-3 and lipid levels in Black and White men (for log(triglycerides), r = 0.072–0.136). Longitudinally, a 1,000-ng/ml increase in IGFBP-3 was associated with 3.7-mg/dl and 2.6-mg/dl higher total cholesterol levels and 2.6-mg/dl and 1.7-mg/dl higher low density lipoprotein cholesterol levels in Black men and White men (p < 0.05), respectively. These findings do not support a strong link between IGF-1 and IGFBP-3 and blood pressure, but they do support the possibility of important relations between IGFBP-3 and lipid levels in young adult men. [ABSTRACT FROM AUTHOR]

Background: Data are limited on the efficacy of health-focused interventions for young, low-acculturated Latino women. Because breast cancer is the most commonly diagnosed cancer and the most common cause of cancer mortality in this population, combined interventions that address both early detection and dietary patterns could help reduce both morbidity and mortality associated with breast cancer in this underserved population. Purpose: Mujeres Felices por ser Saludables was a randomized intervention study designed to assess the efficacy of an 8-month combined dietary and breast health intervention to reduce fat and increase fiber intake as well as to increase the frequency and proficiency of breast self-examination (BSE) and reduce anxiety related to BSE among Latinas. Methods: Blocked randomization in blocks of 6 was used to randomize 256 20- to 40-year-old Latinas to the intervention(n = 127) or control group (n = 129). The intervention group attended an 8-month multi-component education program designed specifically for low-acculturated Latinas. The control group received mailed health education material on a schedule comparable to the intervention. A total of 195 women (76.2%) completed both the baseline and 8-month follow-up interviews. Results: The intervention and control groups were similar on baseline sociodemographic characteristics. At the 8-month follow up, the intervention group reported lower dietary fat (p < .001) and higher fiber intake (p = .06); a higher proportion reported practicing BSE at the recommended interval (p < .001) and showed improved BSE proficiency (p < .001) compared to the control group. BSE-related anxiety was low for both groups at baseline, and no difference in reduction was observed. Conclusions: This project provides a successful model for achieving dietary change and improving breast health behavior in young, low-acculturated Latinas. [ABSTRACT FROM AUTHOR]

Gapstur S M (Division of Epidemiology, University of Minnesota, School of Public Health, Suite 300 1300 South Second Street, Minneapolis, MN 55454-1015, USA), Potter J D and Folsom A R. Alcohol consumption and colon and rectal cancer in postmenopausal women. International Journal of Epidemiology 1994; 23: 50–57. The associations between alcohol and colon and rectal cancers were examined in the Iowa Women's Health Study. In January 1986, 41 837 postmenopausal women, aged 55–69, completed a questionnaire including usual alcohol intake and other information. Through December 1990, 237 incident colon and 75 rectal cancer cases occurred. Mantel-Haenszel age-adjusted relative risks (RR) and 95% confidence intervals (CD for consumers of <4.0 and ≥4.0 g of alcohol per day compared to abstainers were 1.07 (0.617ndash;1.89) and 1.27 (0.72–2.24) {P for trend=0.46) for rectal cancer. Alcohol intake was inversely associated with distal colon cancer (RR for <4.0 and ≥4.0 g of alcohol per day were 0.64 and 0.69 respectively, Pfor trend=0.04), which was specific to wine; however, no association was observed with proximal colon cancer (P for trend=0.94). This is the only report of an inverse association between alcohol and colon cancer in women. Because gut physiology and alcohol metabolism differ between men and women, more research on the association between alcohol and colon cancer in women only, is warranted. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented in response to the article "Weight Cycling and Cancer Incidence in a Large Prospective US Cohort" by V. L. and colleagues in the 2015 issue.

Background: The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown.Methods: Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided.Results: The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r 2 = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r 2 = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P trend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P trend.corr = .04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality.Conclusions: The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival. [ABSTRACT FROM AUTHOR]