One-carbon metabolism biomarkers and upper gastrointestinal cancer in the Golestan Cohort Study

Abstract

Incidence of esophageal and gastric cancer has been linked to low B-vitamin status. We conducted matched nested case-control studies of incident esophageal squamous cell carcinoma (ESCC; 340 case-control pairs) and gastric cancer (GC; 352 case-control pairs) within the Golestan Cohort Study. The primary exposure was plasma biomarkers: riboflavin and flavin mononucleotide (FMN) (vitamin B2), pyridoxal phosphate (PLP) (B6), cobalamin (B12), para-aminobenzoylglutamate (pABG) (folate), and total homocysteine (tHcy); and indicators for deficiency: 3-hydroxykyurenine-ratio (HK-r for vitamin B6) and methylmalonic acid (MMA for B12). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression adjusting for matching factors and potential confounders. High proportions of participants had low B-vitamin and high tHcy levels. None of the measured vitamin B levels was associated with the risk of ESCC and GC, but elevated level of MMA was marginally associated with ESCC (OR = 1.42, 95% CI = 0.99-2.04) and associated with GC (OR = 1.53, 95% CI = 1.05-2.22). Risk of GC was higher for the highest versus lowest quartile of HK-r (OR = 1.95, 95%CI = 1.19-3.21) and for elevated versus non-elevated HK-r level (OR = 1.59, 95% CI = 1.13-2.25). Risk of ESCC (OR = 2.81, 95% CI = 1.54-5.13) and gastric cancer (OR = 2.09, 95%CI = 1.17-3.73) was higher for the highest versus lowest quartile of tHcy. In conclusion, insufficient vitamin B12 was associated with higher risk of ESCC and GC, and insufficient vitamin B6 status was associated with higher risk of GC in this population with prevalent low plasma B-vitamin status. Higher level of tHcy, a global indicator of OCM function, was associated with higher risk of ESCC and GC.

Keywords: biomarkers; esophageal cancer; gastric cancer; one‐carbon metabolism; vitamin B.

Figure 1.

One-carbon metabolism pathway Footnote: Substrates are in boxes; enzymes are in ovals. Abbreviations: AHCY, S-adnosylhomocysteine hydrolase, BHMT, betaine hydroxymethyltransferase; CBS, cystathionine β-synthase; CHDH, choline dehydrogenase; DHFR, dihydrofolate reductase; DNMT, DNA methyltransferase; GSH, glutathione; Hcy, homocysteine; MAT1A, methionine adenosyltransferase 1A; MAT2A, methionine adenosyltransferase 2A; MAT2B, methionine adenosyltransferase 2B; MTA, methylthioadenosine; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; MTRR, methionine synthase reductase; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; SHMT, serine hydroxymethyltransferase; THF, tetrahydrofolate; TYMS, thymidylate synthase; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate

Figure 2.

Odds ratios for (A) esophageal squamous cell carcinoma (ESCC) and (B) gastric cancer (GC) for the highest versus lowest quartiles of B-vitamins and one-carbon metabolism biomarkers Foot note: Odds ratios (ORs; as dots) and 95% confidence intervals (CIs; as bars). FMN, flavin mononucleotide; PLP, pyridoxal phosphate; pABG, para-aminobenzoylglutamate equivalent; MMA, methylmalonic acid; HK-r, 3-hydroxykynurenine ratio; tHcy, total homocysteine ^a ORs and 95% CIs were adjusted for age (continuous), ethnicity (Turkmen, others), education (none, <=8 years, >8 years), composite wealth score (quartiles), opium use (yes, no), alcohol intake (never, current), tea temperature (<60 C°, 60–64 C°, >=65 C°, no tea intake, missing), tooth brushing (never, nondaily, daily), tooth loss (<= expected, >expected quartiles), total fruit intake (g/day), total vegetable intake (g/day), and processed meat intake (g/day). Analysis of HK-r was limited to 662 participants excluding 18 participants who lacked HK-r data because of high hemolysis in their samples and their matched cases/controls. ^b ORs and 95% CIs were adjusted for age (continuous), ethnicity (Turkemen and others), education (none, <=8 years, and >8 years), composite wealth score (quartiles), tobacco use (never, former, current cigarette or hookah, current nass, and current cigarette or hookah and nass), opium use (yes, no), alcohol intake (never, current), tea temperature (<60C, 60–64C, >=65C, no tea intake, missing), tooth brushing (never, nondaily, daily), tooth loss (<= expected, >expected quartiles), total fruit intake (g/day), total vegetable intake (g/day), and processed meat intake (g/day). Analysis of pABG was limited to 702 participants (351 case-control pairs) excluding 2 participants (1 case whose sample volume was insufficient for the assay and their matched control). Analysis of HK-r was limited to 692 participants (346 case-control pairs) excluding 12 participants (6 subjects who lacked HK-r data because of high hemolysis in their samples and their matched cases or controls).