Relationships between one-carbon factors (folate, B12, homocysteine and MTHFR C677T polymorphism), mitochondrial DNA large deletion, tumor progression, and cancer risk of hepatocellular carcinoma.

• Main Authors: Meng-Ying Wu, 吳孟穎
• Other Authors: Huang Rwei-Fen S.
• Format: Others
• Language: zh-TW
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/79451095616823703399

碩士 === 輔仁大學 === 營養科學系 === 95 === The aims of the study are to investigate the relationships between one-carbon factors (folate, B12, homocysteine and MTHFR C677T polymorphisms) and tumor progression of hepatocellular carcinoma HCC ( I ) and mitochondrial DNA (mtDNA) large deletion (ΔmtDNA4.9kb) in peripheral blood lymphocytes (PBLs) and cancer risk of HCC (Ⅱ). In this case-control study, 90 HCC cases who were first time diagnosed as HCC patients, and 90 age- and sex- paired healthy controls were recruited from Chi-Mei Medcal Center. Blood samples were collected for the analysis of serum folate, B12, homocysteine levels, glutamicoxaloacetic transaminase (GOT), glutamicpyruvic transaminase (GPT), and alpha-fetoprotein (AFP). Total DNA of PBLs was assayed for ΔmtDNA4.9kb, mtDNA copy numbers and MTHFR C677T polymorphism by use of real-time PCR. Results of the part Ⅰstudy revealed that 60% of HCC patients were in marginal folate deficiency (serum folate level < 14 nM), and 19 % of HCC patients were in hyperhomocysteinmia. Serum B12 level of HCC patients was significantly and positively correlated with AFP level (r = 0.2657, P = 0.0119). Serum folate concentration was inversely correlated with HCC tumor size (r = -0.2227, P = 0.0349) and tumor numbers ( r = -0.2742, P = 0.0089). By TNM classification of HCC progression, lower level serum folate and higher concentrations of B12 and GOT levels were associated with higher degree of HCC progression. After the adjustment of multiple factors, odds ratio of large- sized tumor (>5 cm) and multiple tumors were 4.422 (95% CI = 1.272- 15.373) and 6.375 (95% CI = 1.117 -36.391) in HCC patients with low serum folate level (< 14 nM) compared to those in adequate folate level. The odds ratio of tumor aggressiveness (T>2 and stage >Ⅱ) was 6.148 (95%C.I. = 1.105-34.202) and 6.375 (95%C.I. = 1.117-36.391) in HCC patients in low serum folate level (< 14 nM) compared to those in adequate folate level MTHFR C677T polymorphism did not modify risks of tumor progression in HCC patients.Result of part Ⅱ study showed that ΔmtDNA4.9kb of HCC group was siginificantly higher than those of the controls. mtDNA large deletion significantly correlated with serum folate (r = -0.3148, P = 0.0001) and lymphocytic folate (r = -0.1559, P = 0.0411) , serum B12 (r = 0.2287, P = 0.0023) , GOT (r = 0.2059, P = 0.0063) and AFP levels (r = 0.2118, P = 0.0049). The odds ratio of HCC in the group with high ΔmtDNA4.9kb (ΔCt ≧5.32) was 5 compared to those with low ΔmtDNA4.9kb (ΔCt ≧2.535). For those with high mtDNA mutation and low serum folate level , the OR of HCC was 13.62 (95% C.I. = 1.453-122.85) compared to the adequate folate group. Control subjects carrying 677TT genotype had lower level of serum folate and higher level of homocysteine compared with subjects carrying 677CC genotype. HCC patients with 677TT genotype had significantly lower levels of ΔmtDNA4.9kb as compared to those carrying with 677CC genotype. The odds ratio of HCC was 0.016 (95%C.I. = 0.01-0.344) and 0.013 (95%C.I. = 0.001-0.539) in subjects carrying with 677TT compared to those carrying on 677CC in low serum folate status (< 14 nM) or high ΔmtDNA4.9kb (ΔCt ≧5.32) frequency. In summary, we found that the prevalence of folate deficiency was 60% in HCC patient. Low serum folate (< 14 nM) could predict the cancer risk of HCC. Incresed accumulation of ΔmtDNA4.9kb in PBLs was found in HCC patients. The odds ratio of HCC by high ΔmtDNA4.9kb frequency and low serum folate level was 13 (OR = 13.62, 95% C.I. = 1.453-122.85). MTHFR 677TT genotype modulated levels of mtDNA mutation in PBLs of HCC patients. OR of HCC for those with 677TT genotype was significantly reduced, suggesting that 677TT genotype may have a protection against HCC progression. The mechanism is unclear and requires more studies.