Prostate Cancer
Prostate Cancer and Novel Infections
Among African American men, prostate cancer risk was reported to be increased with serologic evidence of prior syphilis, but other associations with sexually transmitted infections or activities have been inconsistent. In FY2006, the Branch completed and submitted for publication a case-control study in which prostate cancer was not associated with KSHV seropositivity in either African or European American men. Contemporaneously, in FY2005, the Branch received approval to test prediagnostic sera from 1100 prostate cancer cases and matched controls in the PLCO cohort with a panel of well validated serologic markers of six sexually transmitted infections. Testing and analysis are expected to be completed in FY2006 and FY2007, respectively.
A previously unknown retrovirus, conditionally named xenotropic murine-related retrovirus (XMRV), was detected in the stromal tissue adjacent to prostate cancers from several men with the homozygous QQ variant of the RNASEL gene, which plays a critical role in innate immunity. IIB has proposed to modify the study of sexually transmitted infections by seeking to detect antibodies against two XMRV antigens in RNASEL homozygous QQ and RR (the common allele) prostate cancer cases and matched controls in the PLCO cohort. This would be completed in FY2007. Subsequent work would depend on the results.
Case-Control Study in Shanghai
A population-based multidisciplinary case-control study was conducted in Shanghai, China to investigate the reasons for the extremely low risk of prostate cancer in China and evaluate factors that might explain the recent increase in incidence in this low-risk population. The study included 237 cancer cases, 206 patients with benign prostatic hyperplasia, and 471 healthy controls randomly selected from the population. Results to date suggest that higher levels of education, a high waist-to-hip ratio (an indicator of central obesity), and a higher intake of total calories, red meat, and animal fat and protein are associated with an increased risk, while higher consumption of allium vegetables, peppers, and mushrooms is associated with reduced risk. In addition, a shorter repeat length of CAG in the androgen receptor gene and higher serum levels of insulin and insulin-like growth factor-1 (IGF- 1) are associated with an increased risk. Several genetic polymorphisms found revealed no association with disease. Other genetic, hormonal, and micronutrient factors are also being examined using serum and genomic DNA extracted from buffy coat samples. More information, Ann Hsing.
Ghana Prostate Cancer Study
The ongoing Ghana study is designed to assess the burden of prostate cancer in Ghana in order to evaluate how the impact of prostate cancer among West Africans compares to that among African-Americans, whose reported incidence rates are among the highest in the world. West Africans and African-Americans share genetic ancestry but have very different lifestyles and environmental exposures. This study has two components: a clinical survey to estimate the incidence of clinical prostate cancer in Accra and a population screening survey to estimate the prevalence of prostate cancer in the male Accra population. The clinical component of the study includes the collection of clinical and pathological data for the more than 500 prostate cancer cases diagnosed over the last five years. The population component of the study seeks to screen 1,000 healthy men, using serum prostate specific antigen (PSA) testing and digital rectal examination, followed by biopsy confirmation as required. Interviews will be conducted to elicit information on demographics, diet, smoking, alcohol consumption, body size, medical history, health care utilization, and urinary symptoms. The collected blood samples will be used for PSA testing and for measurements of genetic, hormonal, and nutritional markers. More information, Ann Hsing.
Nested Case-Control Studies within the PLCO Cohort
Our ongoing studies in a nested case-control study of prostate cancer within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (1,400 cases and 1,400 controls) focused on three themes: inflammation, sex steroids, and circadian rhythms. Within each of these three thematic research programs, we have developed studies of serum-based biomarkers (including cytokines and other inflammatory markers, metabolic markers associated with insulin resistance, melatonin as an endogenous indicator of circadian rhythms, and sarcosine, a metabolite recently found to be associated with aggressive prostate cancer), genetic susceptibility markers (such as genes involved in inflammation, insulin signaling, steroid hormone metabolism, and circadian rhythms), and questionnaire data (including existing conditions, such as diabetes, and anthropometric measurements, such as body mass index) in order to evaluate their roles in prostate carcinogenesis. The large sample size of the nested case-control study permits investigation of relatively small effects of biochemical markers and genetic determinants of prostate cancer. Use of the same study population for all studies also provides an opportunity to explore joint effects of the different risk factors on prostate cancer risk. More information, Ann Hsing.
Case-Control Study within the Washington County CLUE Cohort Study
The insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) appear to play an important role in the development of prostate cancer. In collaboration with investigators at the Johns Hopkins School of Public Health, we are conducting a pilot study of IGFs, IGFBPs, and prostate cancer risk in the Washington County Serum Bank, a prospective cohort study. In 1974, over 8,000 male residents of Washington County, Maryland, donated a blood sample and completed a health questionnaire. Using the stored serum samples from 30 men who developed prostate cancer during the 25 years of follow-up and 60 men who have remained prostate cancer-free, investigators are assessing whether IGF levels in 1974 predict subsequent risk of prostate cancer. More information, Ann Hsing.
Prostate Cancer Risk Following Benign Prostatic Hyperplasia in Sweden and Denmark
DCEG investigators are examining population-based record linkage data from Sweden and Denmark to evaluate the risk of prostate and bladder cancer following diagnosis of benign prostatic hyperplasia (BPH). With nationwide records systems encompassing both hospital discharge diagnoses and cancer registries in these two countries, we have identified 86,626 Swedish BPH patients diagnosed during 1964-1983 and 86,683 Danish BPH patients diagnosed during 1977-1993 and are following them over time through medical records for cancer incidence and mortality. More information, Ann Hsing.
Methodologic Study of Tissue Hormones
We are carrying out a multi-racial methodologic study in the U.S. and China to investigate whether serum levels of hormones reflect intraprostatic androgenicity. A total of 600 subjects, including African Americans, Caucasians, Asian Americans, and Chinese men living in China, diagnosed with prostate cancer, benign prostatic hyperplasia, or bladder cancer undergoing prostatectomy will be recruited for tissue and blood collection. Hormone levels in prostatic tissue will be measured and compared with serum levels and polymorphisms of hormone-related genes. Levels of androgen receptor and its associated proteins in prostate tissue will be measured directly. In addition, factors such as age, smoking, and body size that might alter serum-tissue correlations will be examined. Possible racial variation in the serum-tissue correlations will also be assessed. This study is the first of its kind to investigate androgenicity in target tissue directly and will help guide future epidemiologic studies on prostate cancer. More information, Ann Hsing.
Nested Case-Control Study of Serum Androgens within the Prostate Cancer Prevention Trial (PCPT)
The large randomized and placebo-controlled Prostate Cancer Prevention Trial (PCPT; 18,800 male participants) showed that finasteride, a steroid 5a-reductase inhibitor that blocks conversion of testosterone to the more bioactive dihydrotestosterone (DHT), is effective for the primary prevention of prostate cancer. These results provided clinical evidence that intraprostatic androgen action is important in prostate cancer etiology. To validate and provide biological support for this hypothesis, we are conducting a large, nested case-control study in the PCPT (1,800 case-control pairs) to investigate if finasteride treatment alters serum levels of various androgens, including 3a-diol G (a distal metabolite of tissue DHT and a serum marker for intraprostatic DHT), and if the changes in serum androgen levels between pre- and post-finasteride treatment are associated with reductions in prostate cancer risk. More information, Ann Hsing.
Circadian Rhythms and Prostate Cancer Risk
Disruption in circadian rhythms has recently been classified as probably carcinogenic to humans, although no underlying molecular mechanism has been identified. We are investigating the role of circadian rhythms in prostate cancer, using a multidisciplinary approach. On a genetic level, using data from the Shanghai Prostate Cancer Study, we first reported that variants of several core circadian genes were associated with prostate cancer risk. We are extending this finding to larger and more comprehensive validation studies, including PLCO (1,100 cases and 1,100 controls), the Agricultural Health Study (AHS; 776 cases and 1,444 controls), and the Prostate Cancer Prevention Trial (PCPT; 1,800 cases and 1,800 controls), as well as pooling existing data on variants in circadian genes from genome-wide association studies of advanced prostate cancer in the Breast and Prostate Cancer Cohort Consortium (BPC3). On a serum biomarker level, we are investigating the role of serum melatonin, a nocturnal hormonal marker of circadian rhythms, in a large nested case-control study of prostate cancer in PLCO (800 cases and 800 controls). We are also investigating the relationship between sleep duration and prostate cancer risk in the NIH-AARP Diet and Health Study, a cohort of a quarter of a million men with over 17,200 prostate cancer cases. Results from these studies will provide important insights into how circadian rhythms may influence prostate cancer risk. More information, Ann Hsing.
Diabetes, Obesity, and Prostate Cancer Study in the Cohort Consortium
The relationships among prostate cancer, obesity, and diabetes are highly complex and inconclusive. While an inverse association is seen between diabetes and overall prostate cancer, divergent relationships are seen between obesity and high- and low-grade disease. To provide a better understanding of these complex relationships, we are conducting a pooled analysis within the Cohort Consortium (over 735,000 men, including over 43,000 prostate cancer cases) to determine the independent and joint effects of diabetes (including duration of diabetes) and obesity on aggressive prostate cancer risk. Since obesity, diabetes, and prostate cancer are common conditions with rising incidence rates in most populations, a better understanding of their relationships is critical and has considerable potential for cancer prevention and important public health implications. More information, Ann Hsing.
