Protein Tumor Markers

What are biomarkers

Biomarkers are defined as “any substance, structure, or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease”¹. Certain physiological conditions are characterized by the presence or altered levels of substances specific for that condition. Substances such as proteins and peptides can be readily measured and are therefore often times used as biomarkers.

Biomarkers in tumor diagnostics

Tumor markers represent a subset of biomarkers that are indicative for cancerous growth. Most of these marker are being produced by both normal cells as well as tumor cells. The levels at which they are present in bodily fluids like urine, saliva or blood are however typically significantly higher in patients with various malignancies.

There is a plethora of tumor markers^{2, 3} being used which can be classified base on their function, the way they are detected, or the kind of sample in which they are measured:

• Oncofetal antigens
• Tumor associated antigens
• Hormones and hormone receptors
• Enzymes and isoenzymes
• Serum and tissue proteins
• Cancer stem cells⁴
• other tumor markers such genetic markers and biomolecules.

A perfect tumor marker is highly specific and differentiates reliably between healthy individuals and cancer patients. It can be a universal tumor marker or specific for one particular malignancy. It should permit early detection of early stage tumors and at the same time distinguish tumor stages and have prognostic value for outcome and potential recurrence. Lastly, it should be easily measureable with established techniques to follow any changes during the course of a treatment.

None of the established markers fulfill all the points in the wish list for the perfect tumor marker. Instead, several markers are typically used in conjunction to allow for a reliable diagnosis, prognosis, staging and monitoring of a wide range of different cancer types⁵.

How to measure tumor markers

Presently, the majority of tumor biomarkers are proteins or peptides. Consequently, they can be qualitatively and quantitatively measured using immunological methods such as ELISA, immunohistochemistry, immunofluorescence, flow cytometry, or other methods depending on the nature of the marker and of the sample.

An increasing number of tumor markers are also based on genetic variations⁶. Altered expression patterns and mutations in certain oncogenes do not affect the type of malignancy but are also determinants for the response to treatment.

Protein and Peptid Tumor Markers in different Tissues

The table above compiles a number of protein and peptide markers that are typically used to diagnose and monitor various malignant conditions. The first column classifies the different markers as oncofetal antigens (yellow), tumor associated antigens (green), hormones and hormone receptors (orange), iso-/enzymes (light grey), serum and tissue markers (dark grey), and cancer stem cell markers (blue). The matrix indicates for which cancer types the different markers can be used. Markers for which Independently Validated (IV) products are available are marked in the last column.

Tumor marker related products

Marker class	Marker - click antigen for available products	Gene	Cancer type	IV
Oncofetal antigens	Alpha-fetoprotein	AFP	liver, germ cell tumors, ovarian, testicular
Oncofetal antigens	CEACAM 5	CEACAM5	esophageal, bile duct, colorectal, breast, thyroid
Oncofetal antigens	CEACAM6	CEACAM6	esophageal, bile duct, colorectal, breast, thyroid
Oncofetal antigens	CEACAM1	CEACAM1	esophageal, bile duct, colorectal, breast, thyroid
Oncofetal antigens	CEACAM7	CEACAM7	esophageal, bile duct, colorectal, breast, thyroid
Tumor associated antigens	5-HIAA	-	carcenoid
Tumor associated antigens	CA15-3	MUC1	breast
Tumor associated antigens	CA19-9	-	pancreatic, gallbladder, bile duct, gastric
Tumor associated antigens	CA72-4	-	bile duct, gastric cancer
Tumor associated antigens	CA125	MUC16	ovarian
Hormes and receptors	Chorionic Gonadotropin, beta Polypeptide (CGB)	CGA, CGB	choriocarcinoma, testicular
Hormes and receptors	Calcitonin	CALC1	medullary thyroid cancer
Hormes and receptors	Chromogranin A (CHGA)	CHGA	neuroendocrine tumors
Hormes and receptors	EGFR mutation analysis	EGFR	non-small cell lung cancer
Hormes and receptors	Estrogen receptor (ER)	ESR1	breast
Hormes and receptors	Estrogen receptor (ER)	ESR2	breast
Hormes and receptors	HER2/neu	ERBB2	breast, gastric, esophageal
Hormes and receptors	Osteocalcin	BGLAP	bone
Hormes and receptors	Progesterone receptor (PGR)	PGR	breast
Hormes and receptors	Transferrin Receptor	TFRC	breast
Hormes and receptors	Transthyretin	TTR	ovarian
Enzymes and modulators	Alkaline phosphatase (Bone)	ALPL	bone
Enzymes and modulators	BCR/ABL1	BCR/ABL1	chronic myelogenous leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia
Enzymes and modulators	BRAF V600E	BRAF	Cutaneous melanoma and colorectal cancer
Enzymes and modulators	KIT	KIT	gastrointestinal stromal tumor, mucosal melanoma
Enzymes and modulators	KRAS mutation analysis	KRAS	colorectal, non-small cell lung cancer
Enzymes and modulators	Prostate-specific antigen	PSA	prostate
Enzymes and modulators	Lactate Dehydrogenase A	LDHA	germ cell tumors, gastric
Enzymes and modulators	Lactate Dehydrogenase B	LDHB	germ cell tumors, gastric
Enzymes and modulators	Lactate Dehydrogenase C	LDHC	germ cell tumors, gastric
Enzymes and modulators	Neuron specific enolase (NSE)	ENO2	lung
Enzymes and modulators	Nuclear matrix protein 22 (NMP22)	NUMA1	bladder
Enzymes and modulators	plasminogen activator inhibitor (PAI-1)	SERPINE1	breast
Enzymes and modulators	SCC	SERPINB3	esopahgeal, lung, ovarian, squamous cell carcinoma
Enzymes and modulators	SCC	SERPINB4	esopahgeal, lung, ovarian, squamous cell carcinoma
Enzymes and modulators	Urokinase plasminogen activator (uPA)	PLAU	breast
Serum and tissue proteins	Apolipoprotein A1	APOA1	ovarian
Serum and tissue proteins	Beta-2-microglobulin	B2M	multiple myeloma, chronic lymphocytic leukemia, lymphoma
Serum and tissue proteins	Cytokeratin fragments 21-1 (Cyfra 21-1)	KRT19	breast, lung
Serum and tissue proteins	WAP Four-Disulfide Core Domain 2 (WFDC2)	WAP5	ovarian
Serum and tissue proteins	Ferritin	FTL, FTH1	liver
Serum and tissue proteins	Fibrinogen	-	bladder
Serum and tissue proteins	Fibrin D-Dimer	-	bladder
Serum and tissue proteins	S100	S100A1	malignant melanome
Serum and tissue proteins	Tissue polypeptide antigen (TPA)	-	lung
Serum and tissue proteins	Thyroglobulin	TG	thyroid
Cancer stem cells	Aldehyde dehydrogenase	ALDH1A1	cancer stem cells, breast, colon, lung, melanoma, pancreatic, prostate
Cancer stem cells	CD20	MS4A1	Cancer stem cells, Non-Hodgkin lymphoma, melanoma
Cancer stem cells	CD24	CD24	Cancer stem cells, colon cancer
Cancer stem cells	CD44	CD44	Cancer stem cells, breast, colon, liver, ovarian, pancreatic, prostate
Cancer stem cells	Nestin	NES	Cancer stem cells, glioma, pancreatic

References

• http://www.inchem.org/documents/ehc/ehc/ehc222.htm
• http://www.ncbi.nlm.nih.gov/pubmed/23548926
• http://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet
• http://www.cancersafe.com/screening/index.asp
• http://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet