Association of factors in the folate metabolic pathway with prostate cancer incidence and progression

  • Topic: Prostate Cancer
  • Institution: University of Bristol
  • Country: United Kingdom
  • Status: Completed

Scientific abstract

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Background

Disturbed folate metabolism is associated with an increased risk of some cancers, but the evidence for prostate cancer is inconclusive.

Aim

To determine whether serum and genetic variation in levels of folate, vitamin B12, total homocysteine (tHcy) and related metabolites are associated with screen-detected prostate cancer risk and progression.

Methods

We analysed data from a matched case-control study nested within the U.K. population–based Prostate testing for cancer and Treatment (ProtecT) study of PSA detected prostate cancer in men aged 50-69 years (1,461 cases and 1,507 controls). To place the results of our ProtecT study in context, we included the results in a meta-analysis of data from studies identified by a comprehensive systematic review of the worldwide literature. To assess the causality of the observed associations, we undertook novel instrumental variables (IV) analysis based on genetic instruments (Mendelian randomisation).

Results

In the ProtecT study, increased B12 and holo-haptocorrin concentrations were positively associated with screen detected prostate cancer [highest versus lowest quartile of B12 odds ratio (OR) = 1.17 (95% confidence interval, 0.95-1.43); p for trend = 0.06; highest versus lowest quartile of holo-haptocorrin OR = 1.27 (1.04-1.56); p for trend = 0.01]; folate, holo-transcobalamin, and tHcy were not associated with prostate cancer risk. In the meta-analysis, circulating B12 levels were positively associated with prostate cancer [pooled OR = 1.10 (1.01-1.19) per 100 pmol/L increase in B12; 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]. There was little consistent evidence that common folate-pathway single nucleotide polymorphisms (SNPs) were associated with prostate cancer. Amongst 424 men with localized prostate cancer who were followed up by active monitoring for a median of 2.5 years, serum folate was associated with an increased risk of biochemical progression [effect of a unit increase in loge folate on a prostate-specific antigen velocity (PSAV) value >2 ng/mL/y, OR= 1.57 (0.98-2.51); p = 0.06]. MTRR 66A>G (rs1801394) was associated with a reduced risk [recessive model OR, 0.33 (0.11-0.97); p=0.04] and SHMT1 1420C>T (rs1979277) with an increased risk [per-allele OR, 1.49 (0.93-2.37); p=0.09] of PSAV >2 ng/mL/y.

Conclusions

Our study shows that i) vitamin B12 and (in cohort studies) folate were associated with an increased risk of screen-detected prostate cancer; ii) known common folate-pathway SNPs do not have important effects on susceptibility to prostate cancer; iii) higher folate levels may be associated with faster progression of localised prostate cancer. The Mendelian randomisation experiment was inconclusive because confidence intervals were too wide to allow robust inference, but we are developing improved genetic instruments based on genome-wide association studies (GWAS) and are collaborating with large consortia to overcome sample-size issues.

Plain language abstract

Hypothesis

Aberrant folate metabolism, measured by circulating and genetic variation in folate, vitamin B12, homocysteine (tHcy) and related metabolites, is associated with an increased risk of prostate cancer initiation and progression.

Background

Folate, found in green leafy vegetables, nuts and bread, and vitamin B12, found in meat, fish, poultry, eggs and dairy products, are necessary for homocysteine metabolism, DNA synthesis, repair and methylation. Epidemiological studies examining the relationship of folate and related metabolites with prostate cancer reveal mixed results, however, and biological mechanisms exist whereby folate could plausibly decrease or increase risk.

Methods

Matched case-control study nested within the U.K. population–based Prostate testing for cancer and Treatment (ProtecT) study of PSA detected prostate cancer in men aged 50-69 years (1,461 cases and 1,507 controls). To place the results of our ProtecT study in context, we included the results in a meta-analysis of data from studies identified by a comprehensive systematic review of the worldwide literature. To assess the causality of the observed associations, we undertook novel instrumental variables (IV) analysis based on genetic instruments (Mendelian randomization).

Key findings

In the ProtecT study, increased B12 and holo-haptocorrin concentrations were positively associated with screen detected prostate cancer [highest versus lowest quartile of B12 odds ratio (OR) = 1.17 (95% confidence interval, 0.95-1.43); ptrend = 0.06; highest versus lowest quartile of holo-haptocorrin OR = 1.27 (1.04-1.56); ptrend = 0.01]; folate, holo-transcobalamin, and tHcy were not associated with prostate cancer risk. In the meta-analysis, circulating B12 levels were positively associated with prostate cancer [pooled OR = 1.10 (1.01-1.19) per 100 pmol/L increase in B12; 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]. There was little consistent evidence that common folate-pathway single nucleotide polymorphisms were associated with prostate cancer. Amongst 424 men with localised prostate cancer who were followed up by active monitoring for a median of 2.5 years, serum folate was associated with an increased risk of biochemical progression [odds ratio (OR) of a prostate-specific antigen velocity (PSAV) >2 ng/mL/y per unit increase in loge concentration: 1.57; 0.98-2.51; p = 0.06]. MTRR 66A>G (rs1801394) was associated with a reduced risk (recessive model OR, 0.33; 0.11-0.97; p=0.04), and SHMT1 1420C>T (rs1979277) with an increased risk (per-allele OR, 1.49; 0.93-2.37; p=0.09) of PSAV >2 ng/mL/y. Confidence intervals around the IV estimates in our study were too wide to allow robust inference.

Conclusions

We conclude that: i) vitamin B12 and folate were associated with an increased risk of prostate cancer; ii) known common folate-pathway single nucleotide polymorphisms do not have important effects on susceptibility to prostate cancer; and iii) higher folate levels may be associated with faster progression of localised prostate cancer.

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