Introduction to Tumour Markers

Georgina Grimsey

Nov 21, 2019

Tumour markers

For both diagnostic and therapeutic purposes, cancer 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.  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.

Alpha1-Fetoprotein (AFP)

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, while a decreased AFP concentration has been observed in
relation to Down syndrome. Because AFP is not specific to a certain 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. Its specificity as a cancer marker is improved by
combination with HE4, especially 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          

CYFRA21-1

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 (Hb)

As commonly
known, 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, and the levels of free Hb
in serum may serve as a potential biomarker for conditions such as ovarian
cancer or 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, as well as 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.

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