Very low PSA concentrations and deletions of the KLK3 gene.

BACKGROUND: Prostate-specific antigen (PSA), a widely used biomarker for prostate cancer (PCa), is encoded by a kallikrein gene (KLK3, kallikrein-related peptidase 3). Serum PSA concentrations vary in the population, with PCa patients generally showing higher PSA concentrations than control individuals, although a small proportion of individuals in the population display very low PSA concentrations. We hypothesized that very low PSA concentrations might reflect gene-inactivating mutations in KLK3 that lead to abnormally reduced gene expression. METHODS: We have sequenced all KLK3 exons and the promoter and searched for gross deletions or duplications in KLK3 in the 30 individuals with the lowest observed PSA concentrations in a sample of approximately 85 000 men from the Prostate Testing for Cancer and Treatment (ProtecT) study. The ProtecT study examines a community-based population of men from across the UK with little prior PSA testing. RESULTS: We observed no stop codons or frameshift mutations, but we did find 30 single-base genetic variants, including 3 variants not described previously. These variants included missense variants that could be functionally inactivating and splicing variants. At this stage, however, we cannot confidently conclude whether these variants markedly lower PSA concentration or activity. More importantly, we identified 3 individuals with different large heterozygous deletions that encompass all KLK3 exons. The absence of a functional copy of KLK3 in these individuals is consistent with their reduced serum PSA concentrations. CONCLUSIONS: The clinical interpretation of the PSA test for individuals with KLK3 gene inactivation could lead to false-negative PSA findings used for screening, diagnosis, or monitoring of PCa.

Serum insulin-like growth factors and mortality in localised and advanced clinically detected prostate cancer.

CONTEXT: Many studies have reported associations of insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with prostate cancer development, but none have investigated their association with fatal progression of prostate cancer. OBJECTIVE: We investigated associations of circulating IGF-I, IGF-II, IGFBP-2 and IGFBP-3 with all-cause and prostate cancer mortality in men with clinically identified prostate cancer, stratified by whether localised (stage T1 or T2) or advanced (T3, T4, N1 or M1) at diagnosis. DESIGN, SETTING AND PARTICIPANTS: UK hospital-based cohort study of 396 men with prostate cancer, diagnosed between 1990 and 2008, with mean follow-up of 3.7 years. MAIN OUTCOME MEASURES: All-cause and prostate cancer-specific mortality. RESULTS: In men with advanced cancer, there was some evidence that IGF-I was positively associated (HR 1.20; 95% CI: 0.96, 1.49; p = 0.11) and IGFBP-3 was inversely associated (HR 0.84; 95% CI: 0.70, 1.01; p = 0.07) with all-cause mortality after controlling for age, treatment status, smoking, prostate-specific antigen and Gleason grade at diagnosis. There was some evidence that IGF-I was positively associated with prostate cancer mortality in advanced cases (HR 1.23; 95% CI: 0.94, 1.62; p = 0.13). In advanced cancers, associations of IGF-I with all-cause (HR 1.68; 95% CI: 1.28, 2.23; p < 0.001) and prostate cancer-specific (HR 1.59; 95% CI: 1.11, 2.28; p = 0.01) mortality strengthened (and were conventionally statistically significant) after further controlling for IGFBP-3. CONCLUSIONS: Measures of IGF-I and IGFBP-3 may have potential as prognostic markers in predicting risk of death in men with advanced prostate cancer. Large, prospective studies with repeat IGFs and IGFBPs are now required.

The causal roles of vitamin B(12) and transcobalamin in prostate cancer: can Mendelian randomization analysis provide definitive answers?

Circulating vitamin B(12) (cobalamin/B(12)) and total transcobalamin (tTC) have been associated with increased and reduced risk, respectively, of prostate cancer. Mendelian randomization has the potential to determine whether these are causal associations. We estimated associations of single nucleotide polymorphisms in B(12)-related genes (MTR, MTRR, FUT2, TCN2, TCN1, CUBN, and MUT) with plasma concentrations of B(12), tTC, holo-transcobalamin, holo-haptocorrin, folate, and homocysteine and with prostate cancer risk in a case-control study (913 cases, 895 controls) nested within the UK-wide population-based ProtecT study of prostate cancer in men age 45-69 years. Instrumental variable (IV) analysis was used to estimate odds ratios for effects of B(12) and tTC on prostate cancer. We observed that B(12) was lower in men with FUT2 204G>A (rs492602), CUBN 758C>T (rs1801222) and MUT 1595G>A (rs1141321) alleles (P(trend)<0.001); tTC was lower in men with the TCN2 776C>G (rs1801198) allele (P(trend)<0.001). FUT2 204G>A and CUBN 758C>T were selected as instruments for B(12); TCN2 776C>G for tTC. Conventional and IV estimates for the association of log(e)(B(12)) with prostate cancer were: OR=1.17 (95% CI 0.90-1.51), P=0.2 and OR=0.60 (0.16-2.15), P=0.4, respectively. Conventional and IV estimates for the association of loge(tTC) with prostate cancer were: OR=0.81 (0.54-1.20), P=0.3 and OR=0.41 (0.13-1.32), P=0.1, respectively. Confidence intervals around the IV estimates in our study were too wide to allow robust inference. Sample size estimates based on our data indicated that Mendelian randomization in this context requires much larger studies or multiple genetic variants that explain all of the variance in the intermediate phenotype.

Associations of folate, vitamin B12, homocysteine, and folate-pathway polymorphisms with prostate-specific antigen velocity in men with localized prostate cancer.

BACKGROUND: Vitamin B(12), holo-haptocorrin, and the folate-pathway single-nucleotide polymorphisms MTR 2756A>G and SHMT1 1420C>T have been associated with an increased risk of prostate cancer. We investigated whether these and other elements of folate metabolism were associated with prostate-specific antigen (PSA) velocity (PSAV) as a proxy measure of prostate cancer progression in men with localized prostate cancer. METHODS: We measured plasma folate, B(12), holo-haptocorrin, holo-transcobalamin, total transcobalamin, and total homocysteine at diagnosis in 424 men (ages 45-70 years) with localized prostate cancer in a U.K.-wide population-based cohort. Thirteen folate-pathway single-nucleotide polymorphisms were genotyped for 311 of these men. Postdiagnosis PSAV (continuous measure and with a threshold set a priori at 2 ng/mL/y) was estimated from repeat PSA measurements. RESULTS: Median follow-up time was 2.5 (range, 0.8-5.6) years. Vitamin B(12), holo-haptocorrin, holo-transcobalamin, total transcobalamin, and total homocysteine were not associated with postdiagnosis PSAV. Folate was associated with an increased risk of PSAV >2 ng/mL/y [odds ratio (OR) per unit increase in log(e) concentration, 1.57; 95% confidence interval (95% CI), 0.98-2.51; P = 0.06]. MTRR 66A>G (rs1801394) was associated with a reduced risk (recessive model OR, 0.33; 95% CI, 0.11-0.97; P = 0.04), and SHMT1 1420C>T (rs1979277) with an increased risk (per-allele OR, 1.49; 95% CI, 0.93-2.37; P = 0.09) of PSAV >2 ng/mL/y. CONCLUSIONS: We found weak evidence that higher folate levels may be associated with faster progression of localized prostate cancer. IMPACT: Long-term follow-up is needed to test associations with metastases and mortality, and the observed genetic effects require replication.

The relation between adiposity throughout the life course and variation in IGFs and IGFBPs: evidence from the ProtecT (Prostate testing for cancer and Treatment) study.

OBJECTIVE: Adiposity is positively associated with advanced, metastatic, and fatal prostate cancer. Obesity-related variations in insulin-like growth factors (IGF-I and -II) and their binding proteins (IGFBPs) could underlie these associations. METHODS: We investigated associations of adiposity throughout the life course (determined retrospectively) with serum levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in a population-based study of 1,106 healthy men. RESULTS: IGF-I and IGF-II showed inverted U-shaped associations with adult body mass index (BMI) (p quadratic model = 0.04 and 0.06, respectively), although differences between quartiles with the highest and lowest IGF-I levels were small (no more than 5 ng/ml). IGFBP-2 was strongly inversely related to adult BMI (-22% change per SD increase in BMI; 95% confidence interval (CI) -24% to -19%) and waist circumference (-18% change per SD increase in waist circumference; 95% CI -20% to -15%) (p < 0.001). IGFBP-3 was positively related to BMI (63.5 ng/ml increase per SD increase in BMI; 95% CI -2.69 to 129.8, p = 0.06). IGFBP-2 and IGFBP-3 were strongly related to body shape change from childhood to adulthood, with men who gained the most weight having the lowest IGFBP-2 (9% lower per category body shape change; 95% CI -11% to -7%, p < 0.001) and the highest IGFBP-3 (50 ng/ml increase per category; 95% CI 8 to 92, p = 0.02). CONCLUSIONS: We provide evidence that adiposity and change in body shape through the life course are related to the IGF system, with the largest effect of adiposity being to lower IGFBP-2, a possible marker of insulin resistance. The results suggest that circulating IGF-I levels may not be important mediators of the association of adiposity with aggressive prostate cancer, but the role of IGFBP-2 deserves further investigation.

Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins, and risk of prostate cancer: a case-control study, systematic review, and meta-analysis.

BACKGROUND: Disturbed folate metabolism is associated with an increased risk of some cancers. Our objective was to determine whether blood levels of folate, vitamin B(12), and related metabolites were associated with prostate cancer risk. METHODS: Matched case-control study nested within the U.K. population-based Prostate testing for cancer and Treatment (ProtecT) study of prostate-specific antigen-detected prostate cancer in men ages 50 to 69 years. Plasma concentrations of folate, B(12) (cobalamin), holo-haptocorrin, holo-transcobalamin total transcobalamin, and total homocysteine (tHcy) were measured in 1,461 cases and 1,507 controls. ProtecT study estimates for associations of folate, B(12), and tHcy with prostate cancer risk were included in a meta-analysis, based on a systematic review. RESULTS: In the ProtecT study, increased B(12) and holo-haptocorrin concentrations showed positive associations with prostate cancer risk [highest versus lowest quartile of B(12) odds ratio (OR) = 1.17 (95% confidence interval, 0.95-1.43); P(trend) = 0.06; highest versus lowest quartile of holo-haptocorrin OR = 1.27 (1.04-1.56); P(trend) = 0.01]; folate, holo-transcobalamin, and tHcy were not associated with prostate cancer risk. In the meta-analysis, circulating B(12) levels were associated with an increased prostate cancer risk [pooled OR = 1.10 (1.01-1.19) per 100 pmol/L increase in B(12); P = 0.002]; the pooled OR for the association of folate with prostate cancer was positive [OR = 1.11 (0.96-1.28) per 10 nmol/L; P = 0.2) and conventionally statistically significant if ProtecT (the only case-control study) was excluded [OR = 1.18 (1.00-1.40) per 10 nmol/L; P = 0.02]. CONCLUSION: Vitamin B(12) and (in cohort studies) folate were associated with increased prostate cancer risk. IMPACT: Given current controversies over mandatory fortification, further research is needed to determine whether these are causal associations.