ReviewHuman chorionic gonadotropin in cancer
Introduction
Human chorionic gonadotropin (hCG) is a glycoprotein hormone produced at very high concentrations by placental trophoblasts. During pregnancy, the serum concentrations increase rapidly peaking at 7–10 weeks. Placental and other trophoblastic tumors virtually always express hCG, and for these hCG is a very sensitive marker. In addition, serum from many patients with nontrophoblastic tumors contains hCG-immunoreactivity, which with few exceptions consists of the free β subunit of hCG (hCGβ), but expression of intact hCG occasionally occurs in various tumors. Elevated expression of hCGβ in serum, urine, or tumor tissue is a strong indicator of adverse prognosis in many nontrophoblastic tumors. However, hCG and hCGβ are also expressed at low levels by many normal tissues. By using sensitive and specific assays, both hCG and hCGβ can be detected at low concentrations in serum and urine from most men and nonpregnant women. This review will describe the use of various forms of hCG for diagnosis of cancer with emphasis on recent developments in the field.
hCG belongs to the glycoprotein hormone family that also comprises luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH). All members are heterodimers consisting of an α and β subunit. The α subunit, which is common to all glycoprotein hormones, contains 92 amino acids. The β chains determine the biological activity and display extensive homology, that between hCGβ and LHβ being about 80%. LHβ contains 121 and hCGβ 145 amino acids, the difference coming from a 24 amino acid C-terminal extension. The molecular weight of hCG is about 37,500, that of hCGβ is 23,500 and that of hCGα is 14,000 [1], [2]. About one-third of the molecular weight of hCG consists of carbohydrates attached to six glycosylation sites on hCGβ and two on hCGα. The N-linked carbohydrate chains on hCGα are attached to Asn52 and Asn78 and two on hCGβ to Asn13 and Asn30. Four O-linked carbohydrate chains on the C-terminal peptide (CTP) of hCGβ are attached to Ser121, Ser127, Ser132, and Ser138. The carbohydrate chains contain 8–15 terminal sialic acids, and therefore hCG displays extensive charge heterogeneity. In isoelectric focusing, hCG can be separated into components with isoelectric points (pI) between 3 and 7. hCGβ displays pI values in the range 3–5 and hCGα pI values in the range 5–8 [2], [3]. In pregnancy, most of the N-linked carbohydrates on hCGα are mono- and biantennary, and those on hCGβ biantennary and to a lesser extent triantennary. More complex carbohydrates are found in so-called hyperglycosylated hCG produced by choriocarcinoma; triantennary N-linked carbohydrates are common on hCGβ and the O-linked carbohydrates have a biantennary type 2 o-core structure rather than the monoantennary type 1 core in pregnancy hCG. However, in early pregnancy, a large proportion of hCG is also hyperglycosylated [4]. In addition to carbohydrate and charge variants, free subunits and partially degraded forms of hCG occur not only in urine but also in serum of cancer patients [5], [6], [7].
When excreted into urine, much of hCG and hCGβ is degraded to partially cleaved or “nicked“ forms and fragments. In nicked hCG (hCGn) and hCGβ (hCGβn), the peptide chain is cleaved between amino acids 44–45 and 47–48. Much of the hCG-immunoreactivity in urine consists of a fragment of hCGβ [8], [9] comprising amino acids 6–40 and 55–92 linked together by disulfide bridges [7]. This fragment is called the core fragment of hCGβ (hCGβcf) [10]. Methods measuring hCGβcf may also measure other degraded forms of hCG, which collectively have been called urinary gonadotropin fragments (UGF) [11] and urinary gonadotropin peptide (UGP) [12]. Different degraded forms are recognized to a variable extent by different antibodies [13] causing between-assay-variation especially when determining hCG in urine. This is of importance mainly for pregnancy tests [14] because serum assays are used for monitoring of hCG during pregnancy and in cancer patients.
HCGα is encoded by a single gene on chromosome 12q21.1-23 and hCGβ by six nonallelic genes clustered on 19q13.3 together with the gene encoding LHβ. The genes are designated CGβ1-CGβ9. Of these, two pseudogenes, β1 and β2, are not expressed while β4 encodes LH. Of the expressed hCG genes, β7 and β9 are alleles to β6 and β3, respectively. Two structurally different forms of hCG are expressed, genes β6/7, which are called type I genes, encode a protein with alanine at position 117 while type II genes β3/9, β5, and β8 encode a protein with aspartic acid at this position. The expression of type I and II genes is tissue-dependent. Type II genes are predominantly expressed by the placenta, malignant tumors, and testis, while type I genes are preferentially expressed at very low levels by normal nontrophoblastic tissues [15].
LH and hCG mediate their activity through the same receptor. During pregnancy, hCG stimulates steroid hormone production in the ovaries. In early pregnancy, hCG production starts around the time of implantation of the fetus, and elevated serum levels can be detected about 7 days after the LH surge, which is followed by ovulation within 36–48 h. The amount of trophoblast tissue needed to produce detectable concentrations of hCG in serum is extremely low. A trophoblastic tumor containing only 10,000 cells can cause an increase in serum hCG [16].
The subunits lack hCG activity, but hCGβ has been shown to enhance the growth of tumor cells in culture by preventing apoptosis [17]. While this finding needs to be confirmed, it could explain why expression of hCGβ is associated with aggressive cancer.
Section snippets
Standards
Standards issued by WHO are used to calibrate immunoassays for hCG and its subunits. The presently used 3rd (and the identical 4th) international standard (3rd IS) for hCG was assigned values in international units (IU) by comparing its bioactivity to that of the earlier 2nd standard. Because the free subunits lack hCG activity, they were assigned values based on mass, 1 μg corresponding to 1 IU. One microgram of hCG corresponds to 9.3 IU, thus the units for hCG and its subunits are not
Gestational trophoblastic disease
Gestational trophoblastic disease comprises a spectrum of diseases with different propensity for local invasion and metastasis, that is, partial and complete hydatidiform mole, choriocarcinoma, and placental site trophoblastic tumor (PSTT). Persistent trophoblastic disease may develop both from partial and complete moles. All trophoblastic tumors produce hCG, and monitoring of therapy is largely based on the determination of hCG in serum [52]. The more malignant forms also express excessive
HCG in nontrophoblastic cancer
Expression of hCG-immunoreactivity is observed in a variable proportion of many nontrophoblastic tumors. This immunoreactivity mainly consists of hCGβ while hCG expression is rare [37], [39]. However, the first description of a gonadotropin-producing nontrophoblastic tumor was a hepatoblastoma causing precocious puberty in a 2-year-old boy [89]. This is a very rare condition with only 25 cases having been reported by 1985 [90]. Most cases of precocious puberty are idiopathic, one-fifth of those
Detection of tumor cells in blood and urine by RT-PCR of hCGβ mRNA
Determination of hCGβ mRNA in peripheral blood has successfully been used to detect tumor cells in circulation from patients with chorionic cancer [169] and, together with AFP mRNA, in germ cell tumors [169]. Germ cell cancer patients with poor prognosis or relapsed metastatic disease are increasingly treated with high-dose chemotherapy followed by autologous peripheral-blood stem-cell (PBSC) transplantation, and determination of hCGβ and other tumor-associated genes in the PBSC products by
Conclusions
Determination of hCG plays a crucial role in the management of placental trophoblastic disease as well as in testicular tumors. Expression of hCGβ is common in nontrophoblastic cancers and, together with other markers, hCGβ in serum and hCGβcf in urine can be used to improve the diagnostic accuracy for some tumors. At the moment, this use is limited by lack of sensitive commercial assays. Expression of hCGβ is associated with adverse prognosis, and detection of this expression may become
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