Cancer Risk in Human Populations

Division Of Cancer Epidemiology And Genetics

Investigators

Linked publications, trials & patents

Abstract

Case-control studies of cancers of the bladder, kidney, prostate, pancreas, esophagus, stomach, lung, brain, and head and neck, as well as non-Hodgkins lymphoma and multiple myeloma, are in progress. Cigarette smoking is an important risk factor for several cancers examined by OEEB investigators. The observation of an increase in smoking-related bladder cancer in New England was confirmed in the NIH-AARP cohort, with a four-fold risk in current cigarette smokers compared to non-smokers. We also observed for the first time that the population attributable risk for ever smoking and bladder cancer in women had reached the same level as that in men (0.52 and 0.50, respectively). In a pooled analysis, current and former cigarette smokers had an elevated risk of pancreatic cancer compared to never smokers, and significant trends were found with increasing numbers of cigarettes and smoking duration. Importantly, risk of pancreatic cancer reached the level of never smokers about 20 years after quitting. Renal cell cancer (RCC) risk increased with increasing duration and pack-years of cigarette smoking in the U.S. Renal Cell Cancer Study. A null association between cigarette smoking and multiple myeloma was reported in a pooled analysis, confirming that smoking is not a risk factor for this cancer. Significant inverse associations were found between alcohol consumption and RCC in the NIH-AARP and PLCO cohorts. Alcohol consumption was also inversely associated with multiple myeloma in a pooled analysis and in a case-spouse study. High BMI was linked to increased risks of several cancers including RCC, colorectal cancer in men, pancreatic cancer in adults with a substantial gain in adiposity after age 50, esophageal cancer, and multiple myeloma. Regarding physical activity, low levels of transportation-related activity and low leisure-time activity were linked with higher risks of RCC in whites, but not blacks, in the U.S. Similarly, in a large prospective study of Chinese women, high occupational activity and high leisure exercise in post-menopausal women were associated with reduced breast cancer risks. To better understand the genetic basis of obesity and other anthropometric traits, large-scale meta-analyses of GWAS for the extremes of BMI and height (upper and lower 5th percentiles) and clinical classes of obesity and BMI were undertaken, yielding four new loci for height, seven new loci for clinical classes of obesity, and 57 new loci for BMI. Further GWAS meta-analyses for waist and hip-related measurements in over 220,000 individuals identified 33 new loci associated with waist-hip ratio and 19 new loci for waist and hip circumference measures. Sex-specific meta-analyses of GWAS for anthropometric traits identified six new loci for waist-hip ratio and one for waist circumference in women, but not men.216 No new loci were identified in a smaller meta-analysis of GWAS for BMI in young adults, but four established loci were found to have significantly stronger effects in adolescence and young adulthood. OEEB investigators have led molecular studies of circulating adipokines to elucidate the potential mechanisms linking obesity to various malignancies. A prospective study of multiple myeloma in PLCO found consistent evidence of an increased risk among those with low circulating levels of adiponectin; preliminary findings from a follow-up study in the NCI Cohort Consortium have confirmed this observation. Low adiponectin levels were also associated with an increased risk of RCC in one prospective study. Consumption of processed meat was associated with an increased risk of bladder cancer. Consumption of barbecued meat and measured PAHs (benzo(a)pyrene) were associated with an increased risk of RCC, with higher risks among African Americans and current smokers. A study of folate intake found a reduced risk of colorectal cancer associated with high compared to low natural folate intake among PLCO participants with the highest global DNA methylation levels. Pre-diagnostic hypomethylation was associated with higher gastric cancer risk, with a stronger association among those with high isoflavone and folic acid intake in the Shanghai Women’s Health Study. RCC was associated with a history of hypertension and chronic kidney disease, with higher risks among blacks than whites. A GWAS of RCC discovered the first susceptibility loci for sporadic disease and contributed to the discovery of two additional loci. Another GWAS of RCC among African Americans identified a variant important for the clear cell subtype. Analyses evaluating gene-environment interactions with obesity, hypertension and other RCC risk factors are underway. Two pooled analyses of pancreatic cancer reported significant 1.8 and 1.9-fold risks associated with diabetes, with elevated risk apparent as much as 20 years prior to cancer diagnosis. Hay fever and animal allergies were linked to reduced risks of pancreatic cancer. Increased esophageal cancer risk was associated with a history of gastro-esophageal reflux,211 and gastric cancer was linked to low levels of plasma pepsinogen 1 and high levels of plasma pepsinogen 2, indicating independent effects of these circulating pepsinogens. Higher risks of kidney cancer were associated with having had a hysterectomy in the NIH-AARP and PLCO cohorts and in a subsequent meta-analysis of seven cohort and six case-control studies. RCC risk was reduced among women ≥ 30 years of age at first birth; the association was significant among white, but not black, women. A reduced risk of bladder cancer was associated with parity, late menarche, and estrogen and progestin use in the NIH-AARP cohort. Use of nonsteroidal anti-inflammatory drugs was associated with a reduced risk of bladder cancer in a case-control study and in a pooled analysis of three cohort studies. It has also been linked to a lower esophageal cancer risk, as well as a 30% lower risk of colorectal cancer, which was modified by two SNPs at chromosomes 12 and 15. Acetaminophen use was associated with an increased risk of RCC.