Abstract
Although alpha-fetoprotein (AFP) is a widely used tumor marker in hepatocellular carcinoma (HCC), 40% of newly diagnosed patients do not have an elevated AFP level. Research has revealed that mutations in the HNF1A binding site of the AFP gene promoter cause significantly elevated serum AFP levels in patients with hereditary persistence of AFP. This study investigated the relationship between HNF1A genetic variants and serum AFP levels. We examined the association between the HNF1A-rs1169288 (A/C), rs2464196 (G/A), and rs1169310 (C/T) polymorphisms and AFP levels in a healthy Chinese population (n = 1010) and HCC patients (n = 185). Single nucleotide polymorphisms were genotyped by the amplification refractory mutation system combined with TaqMan probe in real-time PCR. The serum AFP concentrations were measured using the Architect i2000 immunochemistry analyzer. In healthy individuals, serum AFP levels were significantly lower with the rs2464196-AA and rs1169310-TT genotypes. Similar significant differences were observed in HCC patients. Moreover, in HCC patients, the distribution frequencies of rs2464196-AA+AG and rs1169310-TT+TC among those with AFP ≤ 20 ng/ml or ≤400 ng/ml were significantly lower than those in patients with AFP > 20 ng/ml or >400 ng/ml. Among all subjects, those carrying the HNF1A-rs2464196-A or rs1169310-T allele tended to have low levels of AFP. However, the HNF1A-rs1169288 polymorphism showed no significant association with the serum AFP level. These findings provide new insight into the genetic determinants of serum AFP level and can aid the differential diagnosis of HCC patients with low serum AFP.
Highlights
Hepatocellular carcinoma (HCC), one of the most frequently occurring cancers worldwide, typically develops on a basis of chronic liver disease and is associated with a short survival time largely due to the limited treatment options [1]
Previous studies have demonstrated that point mutations in the hepatocyte nuclear factor 1 homeobox A (HNF1A) binding sites of the AFP gene promoter can result in elevated serum AFP levels in related patients with hereditary persistence of AFP (HPAFP) without pathological conditions [5,6,7]
By examining the associations between genetic variants in the HNF1A gene and serum AFP levels, we found that the HNF1A rs2464196 and rs1169310 polymorphisms were strongly associated with the serum AFP concentration in both the healthy Chinese Han population and Chinese Han HCC patients
Summary
Hepatocellular carcinoma (HCC), one of the most frequently occurring cancers worldwide, typically develops on a basis of chronic liver disease and is associated with a short survival time largely due to the limited treatment options [1]. Previous studies have demonstrated that point mutations in the hepatocyte nuclear factor 1 homeobox A (HNF1A) binding sites of the AFP gene promoter can result in elevated serum AFP levels in related patients with hereditary persistence of AFP (HPAFP) without pathological conditions [5,6,7]. These mutations could increase the ability of HNF1A to bind to the AFP promoter and enhance AFP transcriptional activity, leading to the increased level of AFP in serum [5, 6]. It has not been reported whether HNF1A gene variants are associated with the serum AFP level in a general population
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