For both diagnostic and therapeutic purposes, cancer/tumour markers are being monitored to get an idea about the status of the disease. However, most individual cancer markers are not highly specific, because they are not exclusively expressed and secreted by tumour cells. Therefore, instead of the mere presence of one marker, specificity is often obtained by measuring the levels of a combination of different markers or different forms of the same marker.
For example, prostate cancer-specificity is improved by combining the measurements of total PSA and free-form PSA. Cancer-specificity is also improved by combining CA125 with HE4 levels. The broad-spectrum tumour marker CEA is often combined with CA19-9, and AFP is often used in combination with other markers. Moreover, CA15-3 is used as breast cancer marker, CYFRA21-1 indicates presence of malignancy, faecal Hb is used for colorectal cancer screening, NSE is a marker for neuroendocrine tumours, and finally the PG I/ PG II ratio indicates status of gastric mucosa.
AFP is an albumin-like serum glycoprotein, produced by the foetal liver and yolk sac during embryonic development. AFP concentration gradually decreases after birth and is generally very low but detectable in healthy non-pregnant adults. In addition, AFP was demonstrated to be tumour-associated. Increased levels of serum AFP are detected in majority of hepatocellular carcinomas and in minority of other gastrointestinal cancers. They can be detected in germline cancers, and they can indicate liver disease or damage, such as hepatitis or cirrhosis. An increased AFP concentration in maternal blood or amniotic fluid is often related to neural tube developmental defects or nephrosis. On the other hand, a decreased AFP concentration has been observed in relation to Down syndrome. Because AFP is not specific to a malignancy or disease, it is mostly used in combination with other diagnostic tools.
Cancer Antigen 125 (CA125)
The marker CA125 was identified by the development of a monoclonal antibody developed against ovarian epithelial carcinoma cell lines. The marker is the product of MUC16, and its expression is increased in most of ovarian cancer cases. The heavily glycosylated marker is released from the extracellular membrane by proteolytic cleavage thus becoming a serological marker for anomalies. It’s specificity as a cancer marker is improved by combination with HE4. The combination is often used for detecting late stage and recurrent ovarian cancer and for monitoring its treatment.
Cancer Antigen 15-3 (CA15-3)
CA15-3/MUC1 is a well-established serological breast cancer marker, and it is routinely used for monitoring treatment responses and postoperative recurrence. In addition to breast cancer, elevated CA15-3 levels have also been detected in some other carcinomas.
Carbohydrate Antigen 19-9 (CA19-9)
The sialylated Lewis-a pentasaccharide, also known as sLea antigen or CA19-9, is a carbohydrate epitope found on several glycoproteins, including MUC1. In healthy individuals, the serum concentration of CA19-9 is low, but it increases during gastrointestinal malignancy, including pancreatic cancer, pancreatic or hepatobiliary adenocarcinoma, or colon cancer. To date, CA19-9 is the only FDA-approved biomarker for early detection and establishing a prognosis of pancreatic cancer. Because this marker is not specific for cancer, it is often used in combination with CEA.
Carcinoembryonic Antigen (CEA)
Carcinoembryonic antigen (CEA) is also known as CD66e and CEACAM5, a 180–200 kDa glycoprotein involved in cell adhesion and intracellular signalling. CEA levels are usually very low in normal adult colon and blood. Serum CEA levels are raised by various types of carcinomas, including colorectal, lung, and breast cancer. Although not specific to any cancer type, CEA levels are used to measure therapeutic effects, progression, and prognosis of the several cancers as a broad-spectrum tumour marker
A soluble fragment of Cytokeratin 19, named CYFRA21-1, is an established marker for cancers. Cytokeratin 19 expression is typically increased in malignant epithelial cells and CYFRA21-1 is released into the bloodstream during cell death, especially during necrosis. Thus, increased CYFRA21-1 levels indicate the presence of malignancy in various squamous cell cancers, such as prostate cancer, carcinoma, breast cancer, colorectal cancer, and lung cancer.
Human Epididymis Protein 4 (HE4)
The expression of WFDC2, better known as HE4, is elevated in various tumour cell lines although it was originally described as epididymis-specific, hence its name. Elevated blood levels of HE4 are associated with ovarian and endometrial cancer, thus making HE4 a biomarker for such malignancies. For high specificity and sensitivity this marker is measured in combination with CA125. The “Risk of Ovarian Malignancy Algorithm” (ROMA) which combines measurement of CA125 and HE4, and the woman’s menopausal status, has been approved by the FDA for this purpose.
Haemoglobin is the metalloprotein responsible for the transportation and exchange of O2 and CO2 in the bloodstream through the erythrocytes. The toxicity of carbon monoxide (CO) and nitric oxide (NO) is explained by their influence on Hb’s binding to O2. Detection of Hb in faeces through faecal occult blood (FOB) testing can be used for non-invasive colorectal cancer screening. Hb is also an important biomarker for haemolytic anaemia. Furthermore, the levels of free Hb in serum may serve as a potential biomarker for conditions such as ovarian cancer and acute ischemic stroke.
Neuron-Specific Enolase (NSE)
Under physiological conditions, NSE is mostly present in the brain; it has been linked to neural maturation and it is a commonly used biomarker for identifying neurons and neuroendocrine cells. Increased NSE levels in serum or in cerebrospinal fluid often indicate neuronal damage or malignancies. In clinical diagnostics, NSE is a widely used marker for neuroendocrine tumours (NETs), including neuroblastoma and small-cell lung cancer (SCLC). NSE levels in bodily fluids have been reported to correlate with extent of disease and with response to treatment, allowing the marker to be used as a tool for diagnosis, prognosis, as well as treatment follow-up. But also, non-cancerous conditions, such as brain damage, cerebral accidents, myocardial infarctions, Guillain-Barré syndrome, or Creutzfeldt-Jakob disease, cause elevated NSE levels. Because NSE is also present in erythrocytes, haemolysis will cause false-positives.
Pepsinogen Groups I and II
Pepsinogens are proenzymes for pepsins, digestive enzymes that break down the proteins in food. Pepsinogens are secreted by the chief cells in the stomach wall. Once in the stomach, pepsinogens are cleaved by the acidic environment and converted to active pepsins. Group I (PG I) exists of three genes (PGA3, PGA4 and PGA5), while Group II (PG II) has only one gene: PGC (Pepsinogen C). The levels of serum PG I and PG II serve as commonly accepted biomarkers reflecting functional and morphologic status of gastric mucosa. Conditions leading to alterations in serum pepsinogen concentrations include Helicobacter pylori infections, atrophic gastritis, and gastric cancer. Monitoring the serum levels of PG I and PG II, and their ratio, offers an alternative to invasive endoscopic biopsy.
Prostate-Specific Antigen (PSA)
PSA is a glycoprotein exclusively produced by the epithelial cells of the prostate gland. Because of its tissue-specificity, it serves as a marker for any prostate-related anomaly. Elevated serum PSA levels indicate prostate disorders or cancer. The cancer-specificity of PSA-based screening is improved by measuring the free form PSA (fPSA) and the total PSA (tPSA), which consists of fPSA and complex PSA attached to serum protease inhibitors. Low fPSA/tPSA ratio is associated with cancer, whereas high fPSA/tPSA indicates the presence of non-malignant conditions.