Haojie Li

A Prospective Study of Polyunsaturated Fatty Acid Levels in Blood and Prostate Cancer Risk

Background: Animal models suggest that n-3 fatty acids inhibit prostate cancer proliferation, whereas n-6 fatty acids promote it, but epidemiologic studies do not uniformly support these findings. Methods: A nested case-control study was conducted among 14,916 apparently healthy men who provided blood samples in 1982. Blood fatty acid levels were determined for 476 men diagnosed with prostate cancer during a 13-year follow-up and their matched controls. Conditional logistic regression was used to estimate the relative risks (RR) and 95% confidence intervals (95% CI) of total, non-aggressive (stage A/B and Gleason < 7) and aggressive (stage C/D, Gleason ≥ 7, subsequent distant metastasis or death) prostate cancer associated with blood levels of specific fatty acids expressed as percentages of total fatty acids. Results: Whole blood levels of all long-chain n-3 fatty acids examined and of linoleic acid were inversely related to overall prostate cancer risk (RRQ5vs.Q1, 0.59; 95% CI, 0.38-0.93; Ptrend = 0.01 for total long-chain n-3 fatty acids and RRQ5vs.Q1, 0.62; 95% CI, 0.41-0.95; Ptrend = 0.03 for linoleic). Blood levels of γ-linolenic and dihomo-γ-linolenic acids, fatty acids resulting from the metabolism of linoleic acid, were directly associated with prostate cancer (RR, 1.41; 95% CI, 0.94-2.12; Ptrend = 0.05 for γ-linolenic and RR, 1.54; 95% CI, 1.03-2.30; Ptrend = 0.02 for dihomo-γ-linolenic acid). Levels of arachidonic and α-linolenic acids were unrelated to prostate cancer. Conclusions: Higher blood levels of long-chain n-3 fatty acids, mainly found in marine foods, and of linoleic acid, mainly found in non-hydrogenated vegetable oils, are associated with a reduced risk of prostate cancer. The direct associations of linoleic acid metabolites with prostate cancer risk deserve further investigation. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1364–70)

The Role of Metastasis-Associated Protein 1 in Prostate Cancer Progression

Distinguishing aggressive prostate cancer from indolent disease represents an important clinical challenge, as current therapy requires over treating men with prostate cancer to prevent the progression of a few cases. Expression of the metastasis-associated protein 1 (MTA1) has previously been found to be associated with progression to the metastatic state in various cancers. Analyzing DNA microarray data, we found MTA1 to be selectively overexpressed in metastatic prostate cancer compared with clinically localized prostate cancer and benign prostate tissue. These results were validated by demonstrating overexpression of MTA1 in metastatic prostate cancer by immunoblot analysis. MTA1 protein expression was evaluated by immunohistochemistry in a broad spectrum of prostate tumors with tissue microarrays containing 1940 tissue cores from 300 cases. Metastatic prostate cancer demonstrated significantly higher mean MTA1 protein expression intensity (score = 3.4/4) and percentage of tissue cores staining positive for MTA1 (83%) compared with clinically localized prostate cancer (score = 2.8/4, 63% positive cores) or benign prostate tissue (score = 1.5/4, 25% positive cores) with a mean difference of 0.54 and 1.84, respectively (P < 0.00001 for both). Paradoxically, for localized disease, higher MTA1 protein expression was associated with lower rates of prostate specific antigen recurrence after radical prostatectomy for localized disease. In summary, this study identified an association of MTA1 expression and prostate cancer progression.

Circulating prediagnostic interleukin-6 and C-reactive protein and prostate cancer incidence and mortality.

Interleukin‐6 (IL‐6) and C‐reactive protein (CRP) are elevated in prostate cancer patients, but the role of prediagnostic levels of these inflammatory mediators on prostate cancer outcomes is unclear. We undertook a large, prospective case‐control study to evaluate the relation between prediagnostic levels of IL‐6 and CRP and prostate cancer incidence and mortality. We also investigated the role of the IL‐6 (−174 G/C) polymorphism in relation to circulating levels of IL‐6 and CRP, as well as cancer risk and mortality. We used unconditional logistic regression that adjusted for matching factors to analyze prostate cancer risk. For analyses of prostate cancer mortality, we conducted survival analyses in cases. Because of the strong link between inflammatory markers and body mass index (BMI), we assessed interactions between BMI and plasma levels on prostate cancer outcomes. Neither IL‐6 nor CRP plasma levels varied significantly by IL‐6 genotype. Genotype was not associated with prostate cancer risk or survival. Though neither IL‐6 nor CRP was associated with prostate cancer incidence overall, we observed a statistically significant interaction between IL‐6 and BMI on prostate cancer incidence (pinteraction < 0.01). Increasing IL‐6 levels were positively associated with risk in healthy weight men, but inversely associated with risk in overweight men. Further, prediagnostic IL‐6 was associated with time to prostate cancer progression/death among healthy weight prostate cancer cases (ptrend = 0.02). Adjusted hazard ratios were 1.73 (95% CI: 0.86, 3.51) comparing the highest to lowest IL‐6 level. Our study suggests that IL‐6 may potentially be involved in the development or progression of prostate cancer.

Selenoprotein P genetic variants and mrna expression, circulating selenium, and prostate cancer risk and survival.

Low levels of selenium have been associated with increased risk of prostate cancer (PCa). Selenoprotein P is the most abundant selenoprotein in serum and delivers ten selenocysteine residues to tissues. Variation in the selenoprotein P gene (SEPP1) may influence PCa development or modify the effects of selenium. We examined the association of SEPP1 single nucleotide polymorphisms (SNPs) with PCa risk and survival, and tested for interactions.

Abstract A122: Genetic variation in selenoprotein P, selenium levels, and prostate cancer risk and survival

Background: Selenoprotein P (SelP) is the most common selenoprotein in serum and delivers selenium around the body, carrying up to ten selenocysteine residues per polypeptide. Antioxidants such as selenium may decrease the risk of developing prostate cancer (PCa). One study observed that serum SelP levels were lower in PCa cases than in controls while another found the expression of the gene, SEPP1, decreased with progression from normal prostate tissue to carcinoma to metastatic disease. Genetic variation in SEPP1 may also influence PCa risk or progression, or may modify the effects of selenium. We examined the association of single nucleotide polymorphisms (SNPs) in SEPP1 with PCa risk and survival, and tested for interactions with plasma selenium levels. Methods: The Physicians9 Health Study (PHS) is a prospective cohort of 22,071 US physicians, of whom 2,584 were diagnosed with PCa between 1982 and 2005. Blood was collected from 68% of participants at baseline. We used a nested case‐control study of 1,352 PCa cases and 1,382 controls matched on age, smoking status, and follow‐up time; analyses were restricted to Caucasians. Using the HapMap database, we selected 5 SNPs to capture variation with a minor allele frequency >5% within SEPP1 and 5 kb up‐ and downstream. Four SNPs had high genotyping success (92–97%); the other failed genotyping, however, it tagged only itself so did not reduce the coverage. The incidence analysis used unconditional logistic regression, adjusting for matching factors. For survival analysis, individuals were censored at death or the end of follow‐up; PCa deaths or metastases were considered lethal events (n=191). Plasma selenium levels were measured on 805 cases and 549 controls. Results: Two of the four SNPs were significantly associated with risk of incident PCa. For rs11959466, each additional T allele significantly increased the risk of PCa (odds ratio (OR)=1.31; 95% confidence interval (CI): 1.02, 1.69; ptrend=0.03), while for rs13168440, the minor allele homozygote genotype (CC) was associated with a decreased risk compared to the homozygote TT referent (OR=0.56, 95% CI: 0.33, 0.96). Moreover, there was a significant interaction of rs13168440 with quartiles of plasma selenium; increasing levels were associated with a decreased risk of PCa only among men with the minor allele (OR=0.76; 95% CI: 0.62, 0.93; pinteraction=0.02). None of the four SNPs was associated with PCa survival among the cases. Conclusions: Genetic variation within SEPP1 was associated with PCa incidence and may modify the association of selenium. Considering the multiple hypotheses tested, replication of these findings in an independent data set is needed to confirm or refute these results. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A122.

Abstract A109: A prospective study of vitamin D receptor polymorphisms, interaction with vitamin D status, and colorectal cancer risk in men

A109 Growing evidence suggests an elevated risk of colorectal cancer among individuals with low levels of vitamin D, the biological actions of which is mediated by the vitamin D receptor (VDR). We examined the prospective associations between three VDR single nucleotide polymorphisms (SNPs) (BsmI (bb, bB/BB), FokI (FF, Ff/ff), and Cdx2 (G>A)) and colorectal cancer risk and their interactions with plasma vitamin D status in a nested case-control study among men in the Physicians’ Health Study. A total of 249 incident colorectal cancer cases were identified through 2000 among men who provided blood specimens in 1982-1984 and individually matched to controls by age and smoking. We used conditional logistic regression to calculate the relative risk (RR) and 95% confidence interval (95% CI). We found that men with the VDR Cdx2 variant A allele tended to have a lower risk of developing colorectal cancer compared to men with the homozygous GG genotype (RR=0.71; 95% CI = 0.50-1.02; P = 0.06). Moreover, the lower risk of colorectal cancer associated with the VDR Cdx2 A genotype was mainly confined to men with low vitamin D status (plasma 25(OH)D below median level; RR = 0.45; 95% CI = 0.24-0.84; P = 0.03) but not among men with vitamin D levels above the median (P for interaction = 0.04). We found no statistically significant associations for the other two VDR SNPs, FokI or BsmI, or statistically significant interactions between plasma 25(OH)D levels and these two SNPs. Our prospective data suggest the hypothesis that the functional polymorphic Cdx2 A allele variation in the VDR gene, which is linked to a higher transcriptional activity of the VDR, may be protective against colorectal cancer development when vitamin D status is low. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A109.