4q13.3

AFPD,FETA,HPAFP

Hepatocellular carcinoma (HCC)

Hepatocellular carcinoma is the most prevalent liver tumor and fifth most frequent cancer worldwide. The major risk factors for development of HCC are chronic infection with hepatitis B or C viruses, prolonged exposure to hepatocarcinogens and cirrhosis (Bosch et al., 1999). HCCs that are often diagnosed at the advanced stages and are highly resistant to conventional chemotherapy have very poor prognosis (about 7% 5-year survival).
Expression and secretion of AFP reversibly repressed in adult liver is dramatically induced in transformed hepatocytes (Abelev et al., 1963; Abelev, 1971). Elevation of serum AFP is widely used as diagnostics marker for HCC. Sensitivity and specificity of the test depends significantly on the cut-off range (typically it varies between 20-50 ng/ml and may depend from age, geographical population and HCC etyology) (Debruyne and Delanghe, 2008). High (>500 ng/ml) serum AFP level is described in >80% of children and about 70% of adults with HCC and distinguishes primary liver cancer from non-malignant liver disease (see below). Small highly differentiated HCCs are often AFP-negative. On the other hand, low AFP levels are also described in highly dedifferentiated anaplastic tumors (probably due to extinction of its tissue-specific transcriptional regulators). Specificity and sensitivity of HCC differentiation diagnosis can be enhanced through detection of LCA-reactive glycoform of AFP (AFP-L3) which is preferably expressed in malignant liver tumors (Debruyne and Delanghe, 2008).

Currently AFP serum test is conventionally used in early diagnostics of HCC especially in high risk groups. Serial measurement of serum AFP level is useful for monitoring the treatment response in HCC patients after surgical resection, chemotherapy or orthotopic liver transplantation. High proportion of LCA-reactive AFP glycoform (AFP-L3 fraction) is associated with more malignant phenotype and poor prognosis of HCC (Debruyne and Delanghe, 2008; Sturgeon et al., 2010).

Hepatoblastoma

The most common type of pediatric liver cancer that phenotypically is highly similar to hepatoblasts - immature parenchimal cells of embryonic liver that give rise to hepatocytes and cholangiocytes. Like hepatoblasts, hepatoblastoma cells produce extremely high levels of AFP. In >80% of affected patients serum AFP level exceeds 1000 ng/ml (Abelev and Eraiser, 1999).

In majority of cases hepatoblastoma is highly sensitive to chemotherapy with cytostatic and cytotoxic drugs. Thus, combination of surgical treatment with neoadjuvant chemotherapy critically improved 5-year survival rate up to 75%.
Increase of serum AFP level in children is a sensitive marker for diagnosis and posttreatment monitoring of hepatoblastoma (Herzog et al., 2000). Correlation of pretreatment AFP level with clinical outcome is not clear.

Germ cell tumors

Germ cell tumors integrate several types of testis and ovary cancers originating from different cell types. Elevation of serum AFP levels is associated with embryonic carcinoma (derived from undifferentiated pluripotent early embryonic cells) and teratocarcinoma (tumors containing both embryonic carcinoma cells and more or less differentiated somatic tissue elements) as well as yolk sac (originating from endodermal component of fetal yolk sac) tumors. Seminoma and dysgerminoma, originating from germinal cells, as well as stromal and surface epithelium derived germ cell tumors are AFP negative (Abelev and Eraiser, 1999).

Due to sensitivity of germ cell tumors to cisplatin-based chemotherapy even metastatic nonseminomatous germ cell tumors are highly curable with overall cure rates >80%. Pretreatment serum concentrations of AFP, human chorionic gonadotropin (HCG, see below), and lactate dehydrogenase are approved to be independent prognostic factors for patients with metastatic nonseminomatous germ cell tumors (International Germ Cell Cancer Collaborative Group, 1997).

Yolk sac is responsible for serum protein production at the outset of embryonic development. Accordingly the forms of germ cell tumors containing embryonic and yolk sac elements (yolk sac tumors, embryonic carcinoma and teratocarcinoma) are characterized by increased AFP levels. Trophoblast elements of embryonic carcinoma and teratocarcinoma also produce elevated levels of HCG. In >80% of yolk sac tumors and embryonic carcinomas serum AFP levels are elevated up to 1000 ng/ml (Abelev and Eraiser, 1999). Combination of AFP and HCG is highly specific for differential diagnosis, choice of treatment strategy and monitoring of different forms of germ cell tumors.

Various cancer

Increase of serum AFP level was also reported in several cases of gastric, biliary tract, pancreatic, lung, breast, renal, colorectal cancer. In majority of cases serum AFP level was

Non-malignant liver diseases

Acute viral hepatitis, alcohol or drug-induced liver damage, cirrhosis, acute liver failure, states associated with liver regeneration. In the majority of hepatitis and cirrhosis cases serum AFP level is lower than 50 ng/ml while about 15% of patients demonstrate moderate AFP levels (>500 ng/ml). AFP produced by nonmalignant hepatocytes can be distinguished from that of HCC origin by its low ability to bind Lens culinaris lectin (AFP-L1 glycoform). Together with AFP elevation level this property is used for differentiation diagnosis of HCC and non-malignant liver diseases (Abelev and Eraiser, 1999).

In patients with acute liver failure high serum AFP concentration does not predict an improved outcome, while post-therapy rise of AFP values is associated with favourable prognosis (Schiodt et al., 2006).

Abnormalities of fetus development and pregnancy disorders

During pregnancy AFP synthesized in the yolk sac of the fetus enters the amniotic fluid through placenta and reaches the maternal circulation. AFP level in maternal serum at second-trimester is used as a diagnostic marker of developmental abnormalities of fetus.

Decreased AFP levels in maternal serum or amniotic fluid signify the chromosomal abnormalities of fetus such as Downs syndrome and trisomy 18. High levels of AFP indicate increased risk for neural tube defects such as spina bifida and anencephalopaty. Abnormal AFP level can also indicate other fetal defects or obstetric complications (Mizejewski, 2007).

Hereditary disoders

Type I hereditary tyrosinemia is autosomal recessive disorder manifested in young infants by severe liver disease, renal tubular dysfunction, growth failure and rickets. Hereditary tyrosinemia results from deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme of tyrosine degradation. Severe liver disease increases the risk of HCC development. In patients newly diagnosed with hereditary tyrosinemia serum AFP levels are very high (up to 100,000 ng/ml), decreasing after treatment with nitisinone. Monitoring of AFP level is used to evaluate the risk of HCC in hereditary tyrosinemia patients.
Ataxia telangiectasia is rare, autosomal recessive disorder of childhood caused by a defect in the ATM gene encoding serine/threonine protein kinase involved in DNA damage response and control of chromosome stability. Ataxia telangiectasia is manifested by cerebellar degeneration, dilation of the blood vessels, immunodeficiency, growth retardation, chromosomal instability, predisposition to cancer. Approximately 95% of patients with ataxia-telangiectasia demonstrate stable elevation of serum AFP in childhood increasing slowly over time. Molecular basis of this correlation is not clear.