Red blood cell folate and plasma folate are not associated with risk of incident colorectal cancer in the Women's Health Initiative observational study

Abstract

The relationship between folate and colorectal cancer (CRC) risk is unclear. We investigated the association of two biomarkers of folate status, plasma folate and red blood cell (RBC) folate with CRC risk using a nested case-control design in the Women’s Health Initiative Observational Study (WHI-OS). Postmenopausal women (n=93,676) aged 50–79 years were enrolled in the WHI-OS (1993–1998). A fasting blood draw and extensive health, dietary and lifestyle data were collected upon enrollment. Through 2008, 988 incident CRC cases were reported and confirmed with medical records adjudication. Cases and controls were matched on age (± 3 y), enrollment date (± 1 y), race/ethnicity, blood draw date (± 6 mo) and hysterectomy status. Plasma and RBC folate were determined by radioassay. Folate biomarker values were divided into quartiles and conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CI) for the associations of folate with total CRC, by tumor site and by stage at diagnosis. Additional analyses examined whether risks varied across time periods corresponding to the United States folic acid fortification policy: pre-fortification (1994–95), peri-fortification (1996–97) and post-fortification (1998). ORs for overall CRC risk comparing Q4 vs. Q1 were 0.91 (95% CI 0.67–1.24) and 0.91 (95% CI 0.67–1.23) for RBC and plasma folate, respectively. There were no changes in risk attributable to food supply fortification. These results do not support an overall association of folate with CRC risk and suggest that folic acid fortification of the U.S. food supply did not alter the associations in these postmenopausal women.

Folate‐mediated one‐carbon metabolism genes and interactions with nutritional factors on colorectal cancer risk: Women's Health Initiative Observational Study

“…We identified several novel FOCM gene-nutrient interactions. Although plasma and RBC folate concentrations did not predict CRC risk in our study population, 23 the significant interaction between FOLH1 and plasma folate suggests that the absorption and uptake of folate before the metabolic reactions in the cell may have important implications in colorectal carcinogenesis. Also, our data suggest that the relation between TCN2 R232P, in which the variant allele may result in a lower affinity and Original Article less efficient transport of B12 in comparison with the wildtype allele, 24 and an increased CRC risk 25 may depend on the long-term folate status, which is represented by RBC folate concentrations.…”

Low folate metabolic stress reprograms DNA methylation‐activated sonic hedgehog signaling to mediate cancer stem cell‐like signatures and invasive tumour stage‐specific malignancy of human colorectal cancers

“…Our data, for the first time, localized tumour folate depletion to the T4 malignancy stage when CRCs execute deep invasion from the muscularis propria into pericolorectal tissues, penetrating to the surface of the visceral peritoneum and adherent to other organs before lymphocyte and distant organ metastases proceed . High frequency of LFMS‐embedded CRC was specifically confined to the T3/T4/N0/M0 stage, consistent with the null association of RBC folate with local/regional metastasis of CRC . Such invasive stage‐specific folate depletion may be distinctive with developing tumour malignancy course, which was independent of CRC risk factors such as sex, age, and one‐carbon genetic polymorphisms at MTHFR C677T locus and TS 5'UTR 3 R locus .…”

“…21 High frequency of LFMSembedded CRC was specifically confined to the T3/T4/N0/M0 stage, consistent with the null association of RBC folate with local/regional metastasis of CRC. 27 Such invasive stage-specific folate depletion may be distinctive with developing tumour malignancy course, which was independent of CRC risk factors such as sex, age, and one-carbon genetic polymorphisms at MTHFR C677T locus and TS 5'UTR 3 R locus. 23 In relative to the paired non-CRC counterpart, differentially elevated changes of tumour folate, however, were coined for highly proliferated CRC with increased CEA tumour markers, at the perineural invasive stage, and high alcoholic intake.…”

Tea consumption is not associated with reduced plasma folate concentration among chinese pregnant women

“…The reason is the “cup” varies in shape and size in different areas in China, between rural and urban, so it is hard to collect those information and made it comparable; besides, the frequency of drinking tea is easy to recall. Third, erythrocyte folate (RBC folate) was not detected in the current analysis, which is a longer‐term measure of folate status that reflects intracellular concentrations (Neuhouser et al, ). Fourth, we did not test Hcy concentration.…”