TUMOUR MARKERS : AN OVERVIEWIndian Journal of Clinical

Biochemistry, 2007 / 22 (2) 17-31

T. MalatiDepartment of Biochemistry, Nizam’s

Institute of Medical Sciences, Punjagutta, Hyderabad- 500 082, India

TUMOUR MARKERS• Synthesized in excess concentration.• Endogenous products or products of

newly switched on genes.• Excellent clinical relevance in

monitoring• Early detection of cancer recurrence

and in prognostication

CLASSIFICATION

1. Oncofetal antigens e.g. AFP, CEA, Pancreatic oncofetal antigen, fetal sulfoglycoprotein.

2. Tumor associated antigens /Cancer Antigens e.g. CA125, CA19-9, CA15-3, CA72-4 CA50 etc.

3. Hormones e.g.β-hCG Calcitonin, Placental lactogen etc.

4. Hormone receptors e.g. estrogen and progesterone receptors5. Enzymes and Isoenzymes -PSA, PAP, NSE, PALP, TDT, Lysozyme, alpha amylase6. Serum and tissue proteins -β-2microglobulin -GFAP, -protein S-100, -ferritin, -fibrinogen degradation products7. Other biomolecules e.g. polyamines

An ideal tumor marker should have the following criteria

1. Highly sensitive2. Highly specific 3. Able to differentiate between

neoplastic and non-neoplastic disease4. Its levels should be preceding the

neoplastic process5. It should be easily assayable

ALPHA FETOPROTEIN (AFP)

• It is expressed either during malignancy or during intra uterine or early postnatal life.

• <15 ng/ml.• The clinical significance of AFP - Prenatal diagnosis of open spina bifida, - Anencephaly, - Atresia of esophagus and - Multiple pregnancy.

THE ROLE OF AFP IN MALIGNANCY

Diagnosis, prognosis and monitoring of-1. Primary hepatocellular carcinoma2. Hepatoblastoma, 3. Non-seminomatous testicular germ cell

tumors4. Germ cell tumors of ovary and extragonadal

germ cell tumors 5. In malignancies of gastrointestinal tract,

pancreas, lungs, kidney, and breast etc

HUMAN CHORIONIC GONADOTROPIN (βHCG)

• A marker of germ cell tumors and trophoblastic disease.

• Peak - 10th & 12th weeks of gestation• Men and non-pregnant women <5 IU /ml and post-

menopausal women <10 IU /ml.• HCG is a marker of first choice for - gonadal choriocarcinoma and extragonadal

choriocarcinoma

CARCINO-EMBYRIONIC ANTIGEN (CEA)

• Adenocarcinoma of the digestive organs.• Primary use in the detection of local and

metastatic cancer recurrence.• A persistently rising CEA value….• A declining CEA value….• Clinical relevance…• Preoperative CEA level has prognostic

significance.

PROSTATE SPECIFIC ANTIGEN (PSA)

• Gammaseminoprotein due to its presence in seminal plasma.

• It is a monomer• Prostate epithelium synthesizes PSA• PSA, a neutral serine protease• The 100 KD PSA-ACT complex• PSA-AT (alpha-1 antitrypsin) • PSA-PCI (protease C inhibitor).

PROSTATE ACID PHOSPHATASE (PAP)

• 200 times more abundant in prostate tissue than in any other tissue.

• Is useful only in staging apparently localized disease i.e., primary prostate cancer before definitive therapy such as radical prostatectomy.

• The enzymatic assay appears superior to the immunoassay

TUMOR ASSOCIATED ANTIGENS CA 125, CA 19.9, CA 15.3, CA 72.4 ETC

CANCER ANTIGEN 125 (CA 125) •Detected by using murine monoclonal antibody OC 125•Epithelial ovarian carcinoma. •In the serum, milk and cervical secretions of pregnant women.

• Levels less than 35 U /ml in serum• Marker of first choice adenocarcinoma ovary.• Higher sensitivity for nonmucinous epithelial

ovarian carcinoma.• 10.4% of benign ovarian tumors.

• Breast (17.6%), Colorectal (15.1%), Gastric (30.9%), Esophagus (10.5%),

Liver (15.1%), Biliary tract(45.8%), Pancreas (52.6%), Lung (29.5%), and Endometrium (31.8%).

CA 19-9 (CANCER ANTIGEN 19-9)• Pancreas and gall bladder cancer. • CA-19-9 are highest for the adenocarcinoma

pancreas. • Acute and chronic Pancreatitis

CA 19-5 AND CA 50• Colon, pancreatic and

hepatocellularcarcinoma• Individually both antigens have low

sensitivity. However use of both together improves sensitivity

CA 15-3-Raised against breast carcinoma cell

CA 549• Associated with breast cancer

CYFRA 21-1NSCLC such as SCC, adenocarcinoma and large cell carcinomas.

• BETA -2 MICROGLOBULIN (β2M)• B-cell leukemia, lymphomas and multiple

Myeloma. Monoclonal gammapathies.

CALCITONIN-Increase in medullary carcinoma of the thyroid, bronchogenic carcinoma, small cell lung cancer, breast, liver, lung, renal cancers and carcinoid tumors

TISSUE POLYPEPTIDE ANTIGEN (TPA)• Moderate elevation in many diseases and in

pregnancy. • The marked elevation in breast, lung,

gastrointestinal, urological, gynecological cancer. • Sensitive but nonspecific tumor marker.

EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)• In SCC, breast cancer, gliomas, lung cancer,

blood cancer, and tumors of female genital tract

ESTROGEN RECEPTOR (ER), PROGESTERON RECEPTOR (PR)

• ER a 70 KD protein is present in nuclei of mammary and uterine tissues

• PR is a more sensitive indicator than ERHYDROXY INDOLE ACETIC ACID (5-HIAA)• Diagnosis of indole secreting tumors. • Carcinoid tumors.

HOMOVANILLIC ACID (HVA) AND VANILYLMANDELIC ACID (VMA)-Detecting and monitoring therapy in patients of pheochromocytoma.-Their measurements are also relevant for neuroblastomas

FERRITIN•In advanced cancers of breast, ovaries, lungs, colon and esophagus.•In acute myelocytic leukemia, teratoblastoma and SCC of head and neck.

INTERLEUKIN-2 RECEPTOR / TAC ANTIGEN (IL-2R)• In some types of lymphoid malignancies.• In adult T-cell leukemia

TUMOR SUPPRESSOR GENE P53• Commonly occurring P53 gene mutations are

reported in primary breast, colon, ovarian, lung, and esophageal carcinomas.

CATECHOLAMINESCHROMOGRANIN ACATHEPSIN D

• LIPID-ASSOCIATED SIALIC ACID IN PLASMA (LASA-P)

• NEURON-SPECIFIC ENOLASE (NSE)

• In breast, GIT, lung Ca, leukemia, lymphoma, Hodgkin’s diseases and melanoma.

• The slight increase of this marker is also observed in several inflammatory diseases.

• In glucagonomas, insulinomas, carcinoid tumor, pheochromocytoma, medullary carcinoma of the thyroid, oat cell carcinomas and small cell lung carcinoma and rarely in other cancers of lung.

ALTERATION OF SERUM BETA 2-MICROGLOBULIN IN ORAL

CARCINOMAIndian Journal of Clinical

Biochemistry, 2002, 17 (2) 104-107C.R.Wilma Delphine Silvia, D.M. Vasudevan

and K. Sudhakar Prabhu.Department of Biochemistry, Kasturba

Medical College, Manipal-576119.

ABSTRACT• Serum β2 –microglobulin (β2–m) levels were

measured in oral carcinoma patients and compared with normal healthy controls.

• It was observed that there was a significant rise in serum β2–microglobulin in oral carcinoma patients.

• Progressively higher values were obtained as the cancer advanced clinically.

INTRODUCTION• It was first described by Berggard and Bearn

in 1968 • β2 –microglobulin is a low molecular weight,

11600 Dalton protein found on the surface of all cells except erythrocytes.

• It was also shown to occur in small quantities in normal human urine, plasma and CSF.

• It exists in two main forms.

MATERIALS AND METHODS

• Patients and controls• Exclusion criteria• Group I: 20 healthy individuals, 8 females

and 12 males. • Group II: 4 oral keratosis, 3 males and 1 female.• Group III: 30 oral carcinoma patients, 17 males and 13 females.

• All patients were clinically staged according to TNM staging system of the International union against cancer (UICC).

• This group of patients were further divided into subgroups.

Group IIIA: 5 patients with stage I oral cancer. Group IIIB: 7 patients with stage II oral cancer. Group IIIC: 10 patients with stage III oral

cancer. Group IIID: 8 patients with stage IV oral

cancer.

β2 –microglobulin assay

• Serum.• frozen at -70° C until assay.• The serum was analyzed by Enzyme

linked immunosorbent assay• 2.4mg/L was used as the upper limit,

when 97% of normal values are below this cut off value.

Statistical analysis• The data were analyzed by using statistical

package for social sciences (SPSS) software. • Cases and controls were tested for statistical

significance with student’s ‘t’ test.• Values of p<0.05 were considered significant.

RESULTS

• The test showed an abnormal result in only 1 out of 20 of healthy controls and thus the

-specificity of 95.2%, - positive predictive value 95%, -negative predictive value of 66.6%, - and efficiency of the test 78%.

DISCUSSION• Synthesized and secreted by lymphocytes• It has a low molecular weight and rapid

turnover• Elevated levels of β2 –m have been observed

in a variety of patients mostly with advanced malignancy and other disease states

• Increased in cases of various non neoplastic disorders

• Serum β2 –m values were increased in oral cancer group, when compared with controls, and this is statistically significant (p<0.05)• The mechanism of increase in β2 –m

levels in malignancies• It lacks specificity for oral carcinoma as

an individual marker because it is elevated in other diseases also.