More than 30 prostate cancer (PCa) risk-associated loci have been identified in populations of European descent by genome-wide association studies (GWAS). We hypothesized that a subset of these loci may be associated with PCa risk in Chinese men. To test this hypothesis, 33 single nucleotide polymorphisms (SNPs), one each from the 33 independent PCa risk-associated loci reported in populations of European descent, were investigated for their associations with PCa risk in a case-control study of Chinese men (1,108 cases and 1,525 controls). We found that 11 of the 33 SNPs were significantly associated with PCa risk in Chinese men (P < 0.05). The reported risk alleles were associated with increased risk for PCa, with allelic odds ratios ranging from 1.12 to 1.44. The most significant locus was located on 8q24 Region 2 (rs16901979, P = 5.14×10−9) with a genome-wide significance (P < 10−8), and three loci reached the Bonferroni correction significance level (P < 1.52×10−3), including 8q24 Region 1 (rs1447295, P = 7.04×10−6), 8q24 Region 5 (rs10086908, P = 9.24×10−4), and 8p21 (rs1512268, P = 9.39×10−4). Our results suggest that a subset of the PCa risk-associated SNPs discovered by GWAS among men of European descent is also associated with PCa risk in Chinese men. This finding provides evidence of ethnic differences and similarity in genetic susceptibility to PCa. GWAS in Chinese men are needed to identify Chinese-specific PCa risk-associated SNPs.

A recent genome-wide association study has identified five new genetic variants for prostate cancer susceptibility in a Japanese population, but it is unknown whether these newly identified variants are associated with prostate cancer risk in other populations, including Chinese men. We genotyped these five variants in a case–control study of 1524 patients diagnosed with prostate cancer and 2169 control subjects from the Chinese Consortium for Prostate Cancer Genetics (ChinaPCa). We found that three of the five genetic variants were associated with prostate cancer risk (P = 4.33 × 10−8 for rs12653946 at 5p15, 4.43 × 10−5 for rs339331 at 6q22 and 8.42 × 10−4 for rs9600079 at 13q22, respectively). A cumulative effect was observed in a dose-dependent manner with increasing numbers of risk variant alleles (Ptrend = 2.58 × 10−13), and men with 5–6 risk alleles had a 2-fold higher risk of prostate cancer than men with 0–2 risk alleles (odds ratio = 2.26, 95% confidence interval = 1.78–2.87). Furthermore, rs339331 T allele was significantly associated with RFX6 and GPRC6A higher messenger RNA expression, compared with the C allele. However, none of the variants was associated with clinical stage, Gleason score or family history. These results provide further evidence that the risk loci identified in Japanese men also contribute to prostate cancer susceptibility in Chinese men.

Background

The prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was undertaken to determine whether there is a reduction in prostate cancer mortality from screening using serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE). Mortality after 7–10 years of follow-up has been reported previously. We report extended follow-up to 13 years after the trial.

Methods

A total of 76 685 men, aged 55–74 years, were enrolled at 10 screening centers between November 1993 and July 2001 and randomly assigned to the intervention (organized screening of annual PSA testing for 6 years and annual DRE for 4 years; 38 340 men) and control (usual care, which sometimes included opportunistic screening; 38 345 men) arms. Screening was completed in October 2006. All incident prostate cancers and deaths from prostate cancer through 13 years of follow-up or through December 31, 2009, were ascertained. Relative risks (RRs) were estimated as the ratio of observed rates in the intervention and control arms, and 95% confidence intervals (CIs) were calculated assuming a Poisson distribution for the number of events. Poisson regression modeling was used to examine the interactions with respect to prostate cancer mortality between trial arm and age, comorbidity status, and pretrial PSA testing. All statistical tests were two-sided.

Results

Approximately 92% of the study participants were followed to 10 years and 57% to 13 years. At 13 years, 4250 participants had been diagnosed with prostate cancer in the intervention arm compared with 3815 in the control arm. Cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10 000 person-years, respectively, resulting in a relative increase of 12% in the intervention arm (RR = 1.12, 95% CI = 1.07 to 1.17). After 13 years of follow-up, the cumulative mortality rates from prostate cancer in the intervention and control arms were 3.7 and 3.4 deaths per 10 000 person-years, respectively, resulting in a non-statistically significant difference between the two arms (RR = 1.09, 95% CI = 0.87 to 1.36). No statistically significant interactions with respect to prostate cancer mortality were observed between trial arm and age (Pinteraction = .81), pretrial PSA testing (Pinteraction = .52), and comorbidity (Pinteraction = .68).

Conclusions

After 13 years of follow-up, there was no evidence of a mortality benefit for organized annual screening in the PLCO trial compared with opportunistic screening, which forms part of usual care, and there was no apparent interaction with age, baseline comorbidity, or pretrial PSA testing.

BACKGROUND

Androgens and inflammation have been implicated in the etiology of several cancers, including prostate cancer. Serum androgens have been shown to correlate with markers of inflammation and expression of inflammation-related genes.

METHODS

In this report, we evaluated associations between 9,932 single nucleotide polymorphisms (SNPs) marking common genetic variants in 774 inflammation-related genes and four serum androgen levels (total testosterone [T], bioavailable T [BioT]; 5α-androstane-3α, 17β-diol glucuronide [3αdiol G], and 4-Androstene-3,17-dione [androstenedione]), in 560 healthy men (median age 64 years) drawn from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Baseline serum androgens were measured by radioimmunoassay. Genotypes were determined as part of the Cancer Genetic Markers of Susceptibility Study genome-wide scan. SNP-hormone associations were evaluated using linear regression of hormones adjusted for age. Gene-based p-values were generated using an adaptive rank truncated product method.

RESULTS

Suggestive associations were observed for two inflammation-related genes and circulating androgen levels (false discovery rate [FDR] q-value<0.1) in both SNP and gene-based tests. Specifically, T was associated with common variants in MMP2 and CD14, with the most significant SNPs being rs893226G>T in MMP2 and rs3822356T>C in CD14 (FDR q-value=0.09 for both SNPs). Other genes implicated in either SNP or gene-based tests were IK with T and BioT, PRG2 with T, and TNFSF9 with androstenedione.

CONCLUSIONS

These results suggest possible cross-talk between androgen levels and inflammation pathways, but larger studies are needed to confirm these findings and to further clarify the interrelationship between inflammation and androgens and their effects on cancer risk.

In a pooled analysis of 4 US epidemiologic studies (1993–2001), the authors evaluated the role of 5 female reproductive factors in 357 women with glioma and 822 controls. The authors further evaluated the independent association between 5 implicated gene variants and glioma risk among the study population, as well as the joint associations of female reproductive factors (ages at menarche and menopause, menopausal status, use of oral contraceptives, and menopausal hormone therapy) and these gene variants on glioma risk. Risk estimates were calculated as odds ratios and 95% confidence intervals that were adjusted for age, race, and study. Three of the gene variants (rs4295627, a variant of CCDC26; rs4977756, a variant of CDKN2A and CDKN2B; and rs6010620, a variant of RTEL1) were statistically significantly associated with glioma risk in the present population. Compared with women who had an early age at menarche (<12 years of age), those who reported menarche at 12–13 years of age or at 14 years of age or older had a 1.7-fold higher risk and a 1.9-fold higher risk of glioma, respectively (P for trend = 0.009). Postmenopausal women and women who reported ever having used oral contraceptives had a decreased risk of glioma. The authors did not observe joint associations between these reproductive characteristics and the implicated glioma gene variants. These results require replication, but if confirmed, they would suggest that the gene variants that have previously been implicated in the development of glioma are unlikely to act through the same hormonal mechanisms in women.

Background

Genetic variants in inflammation-related genes have been associated with biliary stones and biliary tract cancers in previous studies.

Methods

To follow-up on these findings, we examined 35 single nucleotide polymorphism (SNPs) in 5 genes related to inflammation (IL8, NFKBIL, RNASEL, TNF, and VEGFA) in 456 participants with incident biliary tract cancer cases (262 gallbladder, 141 extrahepatic bile duct, 53 ampulla of Vater), 982 participants with biliary stones, and 860 healthy controls in a population–based case–control study in Shanghai, China.

Results

Suggestive associations were observed for SNPs in VEGFA with biliary stones, IL8 with gallbladder and ampulla of Vater cancers, and RNASEL with ampulla of Vater cancer (false discovery rate≤0.2).

Conclusion

These findings provide additional support for the role of inflammation in biliary stones and biliary tract cancer risk and need further validation.

Background

Human papillomavirus (HPV) persistence is the pivotal event in cervical carcinogenesis. We followed a large-scale community-based cohort for 16 years to investigate the role of genotype-specific HPV persistence in predicting cervical cancer including invasive and in situ carcinoma.

Methods

At the baseline examination in 1991–1992, 11 923 participants (aged 30–65 years) consented to HPV testing and cytology; 6923 participants were reexamined in 1993–1995. For HPV testing, we used a polymerase chain reaction–based assay that detected 39 HPV types. Women who developed cervical cancer were identified from cancer and death registries. Cumulative risks for developing cervical cancer among infected and persistently infected women were calculated by the Kaplan–Meier method.

Results

Of 10 123 women who were initially cytologically normal, 68 developed cervical cancer. The 16-year cumulative risks of subsequent cervical cancer for women with HPV16, HPV58 (without HPV16), or other carcinogenic HPV types (without HPV16 or HPV58) were 13.5%, 10.3%, and 4.0%, respectively, compared with 0.26% for HPV-negative women. Women with type-specific persistence of any carcinogenic HPV had greatly increased risk compared with women who were HPV-negative at both visits (hazard ratio = 75.4, 95% confidence interval = 31.8 to 178.9). The cumulative cervical cancer risks following persistent carcinogenic HPV infections increased with age: The risks were 5.5%, 14.4%, and 18.1% for women aged 30–44 years, 45–54 years, and 55 years and older, respectively. However, newly acquired infections were associated with a low risk of cervical cancer regardless of age.

Conclusions

HPV negativity was associated with a very low long-term risk of cervical cancer. Persistent detection of HPV among cytologically normal women greatly increased risk. Thus, it is useful to perform repeated HPV testing following an initial positive test.

African American men have among the highest prostate cancer incidence rates in the world yet rates among their African counterparts are unclear. In this paper, we compared reported rates among black men of Sub-Saharan African descent using data from the International Agency for Research on Cancer (IARC) and the National Cancer Institute Surveillance, Epidemiology, and End Results Program for 1973–2007. Although population-based data in Africa are quite limited, the available data from IARC showed that rates among blacks were highest in the East (10.7–38.1 per 100,000 man-years, age-adjusted world standard) and lowest in the West (4.7–19.8). These rates were considerably lower than those of 80.0–195.3 observed among African Americans. Rates in Africa increased over time (1987–2002) and have been comparable to those for distant stage in African Americans. These patterns are likely due to differences between African and African American men in medical care access, screening, registry quality, genetic diversity, and Westernization. Incidence rates in Africa will likely continue to rise with improving economies and increasing Westernization, warranting the need for more high-quality population-based registration to monitor cancer incidence in Africa.

Background

Chronic inflammation is etiologically-related to several cancers. We evaluated the performance (ability to detect concentrations above the assay’s lower limit of detection, coefficients-of-variation [CVs], and intraclass correlation coefficients [ICCs]) of 116 inflammation, immune, and metabolic markers across two luminex bead-based commercial kits and three specimen types.

Methods

From 100 cancer-free participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Trial, serum, heparin plasma, and EDTA plasma samples were utilized. We measured levels of 67 and 97 markers using Bio-Rad and Millipore kits, respectively. Reproducibility was assessed using 40 blinded duplicates (20 within-batches and 20 across-batches) for each specimen type.

Results

A majority of markers were detectable in >25% of individuals on all specimen types/kits. Of the 67 Bio-Rad markers, 51, 52, and 47 markers in serum, heparin plasma, and EDTA plasma, respectively, had across-batch CVs <20%. Likewise, of 97 Millipore markers, 75, 69, and 78 markers in serum, heparin plasma, and EDTA plasma, respectively, had across-batch CVs <20%. When results were combined across specimen types, 45 Bio-Rad and 71 Millipore markers had acceptable performance (>25% detectability on all 3 specimen types and across-batch CVs <20% on at least 2 of 3 specimen types). Median concentrations and ICCs differed to a small extent across specimen types and to a large extent between Bio-Rad and Millipore.

Conclusions

Inflammation and immune markers can be measured reliably in serum and plasma samples using multiplexed luminex-based methods.

Impact

Multiplexed assays can be utilized for epidemiologic investigations into the role of inflammation in cancer etiology.

Background

Epidemiologic data on serum melatonin, a marker of circadian rhythms, and cancer are sparse due largely to the lack of reliable assays with high sensitivity to detect relatively low melatonin levels in serum collected during daylight, as commonly available in most epidemiologic studies.

Methods

To help expand epidemiologic research on melatonin, we assessed the reproducibility and refined a currently available melatonin radioimmunoassay, and evaluated its application to epidemiologic investigations by characterizing melatonin levels in serum, urine, and/or plasma in 135 men from several ethnic groups.

Results

Reproducibility was high for the standard 1.0 ml serum- (mean coefficient of variation (CV)=6.9%, intraclass correlation coefficient (ICC)=97.4%, n=2 serum pools in triplicate) and urine-based (mean CV=3.5%, ICC=99.9%) assays. Reproducibility for the 0.5 ml refined-serum assay was equally good (mean CV=6.6%%;ICC=99.0%). There was a positive correlation between morning serum melatonin and 6-sulfatoxymelatonin in 24-hour urine(r=0.46, P=0.008; n=49 subjects). Melatonin levels in serum-plasma pairs had a high correlation (r=0.97, P<1 × 10−4; n=20) Morning serum melatonin levels were five times higher than those from the afternoon (before 9 AM mean = 11.0 pg/mL versus after 11 AM mean=2.0 pg/mL). Chinese men had lower melatonin levels (mean=3.4 pg/mL), while Caucasian, African American, and Ghanaian men had similar levels (mean=6.7–8.6 pg/mL).

Conclusions

These results suggest that melatonin can be detected reliably in serum samples collected in epidemiologic studies in various racial groups.

Impact

With improved assays, it may be possible to investigate the role of melatonin and the emerging circadian rhythm hypothesis in cancer etiology in epidemiologic studies.

BACKGROUND

The high incidence of and few identified risk factors for prostate cancer underscore the need to further evaluate markers of prostate carcinogenesis. The aim of this pilot study was to evaluate urinary estrogen metabolites as a biomarker of prostate cancer risk.

METHODS

Using a liquid chromatography-tandem mass spectrometry method, urinary concentrations of 15 estrogen metabolites were determined in 77 prostate cancer cases, 77 healthy controls, and 37 subjects who had no evidence of prostate cancer after a prostate biopsy.

RESULTS

We observed an inverse association between the urinary 16-ketoestradiol (16-KE2) and 17-epiestriol (17-epiE3)- metabolites with high estrogenic activity- and prostate cancer risk. Men in the lowest quartile of 16-KE2, had a 4.6-fold risk of prostate cancer (OR= 4.62, 95% CI =1.34–15.99), compared with those in the highest quartile.

CONCLUSIONS

We observed modest differences in estrogen metabolite concentrations between prostate cancer patients and subjects without cancer. Larger studies with both androgen and estrogen measurements are needed to confirm these results to clarify further whether estrogen metabolites are independent biomarkers for prostate cancer risk and whether androgen/estrogen imbalance influences prostate cancer risk.

Background

Thyroid cancer incidence has risen dramatically in the U.S. 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: hazard ratio [HR] in women, 1.16 [95% confidence interval (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 to 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.

In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study (GWAS), with 1,047,986 single nucleotide polymorphism (SNP) markers examined in 3,425 African American prostate cancer cases and 3,290 African American male controls. The most significant 17 novel associations in stage 1 were followed-up in 1,844 cases and 3,269 controls of African ancestry. We identified a novel risk variant on chromosome 17q21 (rs7210100; odds ratio per allele=1.51; p=3.4×10−13). The frequency of the risk allele is ~5% in men of African descent while it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting GWAS in diverse populations.

Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucleotide polymorphisms associated with circulating retinol levels, which are located near the transthyretin (TTR) and retinol binding protein 4 (RBP4) genes which encode major carrier proteins of retinol: rs1667255 (P =2.30× 10−17) and rs10882272 (P =6.04× 10−12). We replicated the association with rs10882272 in RBP4 in independent samples from the Nurses’ Health Study and the Invecchiare in Chianti Study (InCHIANTI) that included 3792 women and 504 men (P =9.49× 10−5), but found no association for retinol with rs1667255 in TTR among women, thus suggesting evidence for gender dimorphism (P-interaction=1.31× 10−5). Discovery of common genetic variants associated with serum retinol levels may provide further insight into the contribution of retinol and other vitamin A compounds to the development of cancer and other complex diseases.

Background

Genome-wide association studies have identified multiple independent regions on chromosome 8q24 that are associated with cancers of the prostate, breast, colon, and bladder.

Methods

To investigate their biological basis, we examined the possible association between 164 single nucleotide polymorphism (SNPs) in the 8q24 risk regions, spanning 128,101,433–128,828,043 bp, and serum androgen (testosterone, androstenedione, 3αdiol G, and bioavailable testosterone) and sex hormone-binding globulin levels in 563 healthy, non-Hispanic, Caucasian men (55–74 years old) from a prospective cohort study, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Age-adjusted linear regression models were used to determine the association between the SNPs in an additive genetic model and log transformed biomarker levels.

Results

Three adjacent SNPs centromeric to prostate cancer risk-region 2 (rs12334903, rs1456310, and rs980171) were associated with testosterone (P<1.1×10−3) and bioavailable testosterone (P<6.3×10−4). Suggestive associations were seen for a cluster of 9 SNPs in prostate cancer risk region 1 and androstenedione (P<0.05).

Conclusions

These preliminary findings require confirmation in larger studies, but raise the intriguing hypothesis that genetic variations in the 8q24 cancer risk regions may correlate with androgen levels.

Impact

These results may provide some clues for the strong link between 8q24 and prostate cancer risk.

Objective

Finasteride reduces prostate cancer risk by blocking the conversion of testosterone to dihydrotestosterone. However, whether finasteride affects estrogens levels or change in estrogens affects prostate cancer risk is unknown.

Methods

These questions were investigated in a case–control study nested within the prostate cancer prevention trial (PCPT) with 1,798 biopsy-proven prostate cancer cases and 1,798 matched controls.

Results

Among men on placebo, no relationship of serum estrogens with risk of prostate cancer was found. Among those on finasteride, those in the highest quartile of baseline estrogen levels had a moderately increased risk of Gleason score < 7 prostate cancer (for estrone, odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.06–2.15; for estradiol, OR = 1.50, 95% CI = 1.03–2.18). Finasteride treatment increased serum estrogen concentrations; however, these changes were not associated with prostate cancer risk.

Conclusion

Our findings confirm those from previous studies that there are no associations of serum estrogen with prostate cancer risk in untreated men. In addition, finasteride results in a modest increase in serum estrogen levels, which are not related to prostate cancer risk. Whether finasteride is less effective in men with high serum estrogens, or finasteride interacts with estrogen to increase cancer risk, is uncertain and warrants further investigation.

Biliary tract cancer encompasses tumors of the gallbladder, bile duct and ampulla of Vater. Gallbladder cancer is more common in women, whereas bile duct cancer is more common in men, suggesting that sex hormones may play a role in the etiology of these cancers. The intracellular action of estrogens is regulated by the estrogen receptor (ESR); thus, we examined the role of common genetic variants in ESR genes on the risk of biliary tract cancers and stones in a population-based case–control study in Shanghai, China (411 cancer cases, 895 stone cases and 786 controls). We genotyped six single-nucleotide polymorphisms (SNPs), four in ESR1 (rs2234693, rs3841686, rs2228480 and rs1801132) and two in ESR2 (rs1256049 and rs4986938). In all participants, the ESR1 rs1801132 (P325P) G allele was associated with excess risks of bile duct [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.1–2.8] and ampulla of Vater cancers (OR = 2.1, 95% CI 0.9–4.9) compared with the CC genotype. The association with bile duct cancer was apparent among men (OR = 2.8, 95% CI 1.4–5.7) but not among women (P-heterogeneity = 0.01). Also, the ESR2 rs4986938 (38 bp 3′ of STP) GG genotype was associated with a higher risk of bile duct cancer (OR = 3.3, 95% CI 1.3–8.7) compared with the AA genotype, although this estimate was based on a small number of subjects. None of the other SNPs examined was associated with biliary tract cancers or stones. False discovery rate-adjusted P-values were not significant (P > 0.1). No association was found for ESR1 haplotype based on four SNPs. These preliminary results suggest that variants in ESR genes could play a role in the etiology of biliary tract cancers, especially bile duct cancer in men.

Background

Several genome-wide association studies (GWAS) in populations of European descent have identified more than a dozen common genetic variants that are associated with prostate cancer risk.

Methods

To determine whether these variants are also associated with prostate cancer risk in the Chinese population, we evaluated 17 prostate cancer susceptibility loci in a population-based case-control study from Shanghai, including 288 prostate cancer cases and 155 population controls.

Results

After adjusting for age, two of the 17 loci were significantly associated with prostate cancer risk, while the other 15 loci were suggestively associated with prostate cancer risk in this population. The strongest associations were found for chromosome 8q24 Region 2 (rs1016343: OR=2.07, 95% CI: 1.35-3.20, P=9.4×10-4) and 8q24 Region 1 (rs10090154: OR=2.07, 95% CI: 1.31-3.28, P=0.002); additional single nucleotide polymorphisms (SNPs) assessed in these two 8q24 regions were also significant (ORRegion2=1.92-2.05, P=9.4×10-4-0.003, and ORRegion1=1.77-1.81, P=0.01 for all SNPs).

Conclusions

Our study shows that multiple prostate cancer risk loci identified in European populations using GWAS are also associated with prostate cancer risk in Chinese men, a low-risk population with mostly clinically relevant cancers. Larger studies in Chinese and Asian populations are needed to confirm these findings and the role of these risk loci in prostate cancer etiology in Asian men.

To evaluate the role of oxidative stress in prostate cancer risk, we analyzed serum levels of protein carbonyl groups in 1808 prostate cancer cases and 1805 controls, nested in the Prostate Cancer Prevention Trial, a randomized, placebo-control trial that found finasteride decreased prostate cancer risk. There were no significant differences in protein carbonyl levels in baseline samples between those later diagnosed with prostate cancer and those without at the end of study biopsy. Adjusted ORs and 95% CIs for the 4th quartile of protein carbonyl level for the combined, placebo and finasteride arms were 1.03 (95% CI 0.85–1.24), 0.88 (95% CI 0.69–1.12) and 1.27 (95% CI 0.94–1.71), respectively. There were no significant associations between carbonyl level and risk when analyzing high- and low-grade disease separately, nor did finasteride impact protein oxidation levels. The results of this large nested case-control study do not support the hypothesis that oxidative stress, at least as measured by protein carbonyl level, plays a role in prostate cancer.

Analysis of DNA, RNA, and protein extracted from tissue specimens in epidemiologic studies is useful for assessing etiologic heterogeneity, mechanisms of carcinogenesis and biomarkers for prognosis and prediction of treatment responses. Fresh-frozen tissue samples may provide optimal quality nucleic acids, but pose multiple logistical considerations, including rapid access to tissues prior to histopathologic examination and specialized equipment for freezing, transport and storage; in addition, morphology is often compromised. In contrast, formalin-fixed paraffin-embedded (FFPE) tissue samples, including enormous archives of existing specimens, represent a valuable source of retrospective biological material for epidemiologic research, although presenting different limitations compared to frozen samples. Recent efforts have made progress toward enhancing the utility of FFPE specimens for molecular analyses, including DNA studies, and increasingly for RNA and other macromolecules. Here we report the method that we used to simultaneously recover DNA and RNA from FFPE tissue specimens with appreciable quantity and quality, and discuss briefly the application of tumor markers in epidemiologic studies.

Biliary tract cancers, encompassing cancers of the gallbladder, extrahepatic bile ducts, and ampulla of Vater, are rare but highly fatal. Gallstones represent the major risk factor for biliary tract cancer, and share with gallbladder cancer a female predominance and an association with reproductive factors and obesity. While estrogens have been implicated in earlier studies of gallbladder cancer, there are no data on the role of androgens. Since intracellular androgen activity is mediated through the androgen receptor (AR), we examined associations between AR CAG repeat length [(CAG)n] and the risk of biliary tract cancers and stones in a population-based study of 331 incident cancer cases, 837 gallstone cases, and 750 controls from Shanghai, China, where the incidence rates for biliary tract cancer are rising sharply. Men with (CAG)n>24 had a significant 2-fold risk of gallbladder cancer (odds ratio [OR]=2.00; 95% confidence interval [CI] 1.07–3.73), relative to those with (CAG)n≤22. In contrast, women with (CAG)n>24 had reduced gallbladder cancer risk (OR=0.69, 95% CI 0.43–1.09) relative to those with (CAG)n≤22; P-interaction sex=0.01), which was most pronounced for women aged 68–74 (OR=0.48, 95% CI 0.25–0.93; P-interaction age=0.02). No associations were found for bile duct cancer or gallstones. Reasons for the heterogeneity of genetic effects by gender and age are unclear but may reflect an interplay between AR and the levels of androgen as well as estrogen in men and older women. Further studies are needed to confirm these findings and clarify the mechanisms involved.

Since human papillomavirus (HPV) infection was first identified as a risk factor for cervical cancer, several seroepidemiologic and tissue-based studies have investigated HPV in relation to prostate cancer, another common genitourinary malignancy, with mixed results. To further inform this potential association, we conducted a large, prospective investigation of HPV types 16, 18, and 31 in relation to risk of prostate cancer in the Prostate Cancer Prevention Trial (PCPT). Cases were a sample of men diagnosed with prostate cancer after visit 2 or on their end-of-study biopsy (n=616). Controls were men not diagnosed with prostate cancer during the trial or on their end-of-study biopsy (n=616). Controls were frequency-matched to cases by age, treatment arm, and family history of prostate cancer. Sera from visit 2 were tested for IgG antibodies against HPV-16, -18 and -31. No associations were observed for weak or strong HPV-16 (odds ratio (OR) = 0.94, 95% confidence interval (CI): 0.53–1.64, and OR=1.07, 95% CI: 077–1.48, respectively), HPV-18 (OR=0.75, 95% CI: 0.27–2.04, and OR=0.87, 95% CI: 0.47–1.63) or HPV-31 seropositivity (OR=0.76, 95% CI: 0.45–1.28, and OR=1.15, 95% CI: 0.80–1.64) and risk of prostate cancer. Considering this finding in the context of the HPV and prostate cancer literature, HPV does not appear to be associated with risk of prostate cancer, at least by mechanisms proposed to date, and using epidemiologic designs and laboratory techniques currently available.

Background

Cancers of the biliary tract arise from the gallbladder, extrahepatic bile ducts, and ampulla of Vater. Although relatively uncommon, the incidence of biliary tract cancer rose more than 100% in Shanghai, China between 1972 and 1994. Gallstones are the predominant risk factor for biliary tract cancers, with over 60% of the cancer cases having gallstones. Familial tendency to gallstones has been reported and may further elevate the risk of gallbladder cancer. As part of a large population-based case-control study of biliary tract cancers in Shanghai, China, we examined the association between family history of gallstones and biliary tract cancers as well as biliary stones.

Methods

A total of 627 biliary tract cancers (368 gallbladder, 191 bile duct, 68 ampulla of Vater), 1,037 biliary stone cases (774 gallbladder, 263 bile duct), and 959 healthy subjects randomly selected from the population were included in this study. Information on family history of gallstones among first-degree relatives (i.e. parents, siblings, offspring) was obtained through a self-reported history during in-person interviews.

Results

A family history of gallstones was associated with increased risks of biliary stones (odds ratio (OR) =2.8, 95% confidence interval (CI) =2.1-3.8), gallbladder cancer (OR=2.1, 95% CI=1.4-3.3), and bile duct cancer (OR=1.5, 95% CI=0.9-2.5), after adjusting for age, gender, marital status, education, smoking, alcohol drinking, and body mass index. For gallbladder cancer, subjects with gallstones but without a family history of gallstones had a 21-fold risk (95% CI 14.8-30.1), while those with both gallstones and a positive family history had a 57-fold risk (95% CI 32.0-110.5). Significant risks for gallbladder cancer persisted after additional adjustment for gallstones, and when the analysis was restricted to subjects with first-degree relatives whose gallstones were treated with cholecystectomy. The significant associations with a family history of gallstones were seen for all first-degree relatives, including parents, siblings, and offspring, but not spouses.

Conclusions

This large population-based study not only supports the role of gallstones in biliary carcinogenesis but also suggests that the underlying genetic or lifestyle determinants of stones within families contribute to the risk of biliary tract cancer.