Tumor Markers Dr/ Ehsan Mohamed Rizk

A substance that is present in or produced by a tumor or by the host in response to tumor’s presence. An ideal tumor marker: specific, sensitive, has short half life, its concentration is correlated with tumor burden and its assay is easy, reliable and cost effective.

Clinical Application of Tumor Markers limitedScreening - limited limitedDiagnosis - limited limitedPrognosis - limited limitedTumor staging - limited limitedTumor localization / radiotherapy - limited importantMonitoring the effectiveness of therapy - important importantDetecting tumor recurrence or remission - important

Telomeres

Without some form of correction the end replication leads to the loss of nucleotides from the newly synthesized lagging strand at each chromosome end in each round of duplication In mammalian (and many other) cells, the solution to this problem is that chromosome ends have a special duplication machinery = Telomerase Telomerase (special type of reverse transcriptase) is a protein-RNA complex that carry an RNA template for synthesizing a repeated G-rich telomere. Telomerase is unique in carrying its own RNA template with it all the time.

Telomerase is composed of both RNA and protein

How Telomerase extends the Telomere

Telomerase and Senescence In most somatic tissues, telomerase is expressed at very low levels or not at all -- as cells divide, telomeres shorten Short telomeres may be a signal for cells to senesce (stop dividing)

Telomerase and Cancer The presence of telomerase in cancer cells allows them to maintain telomere length while they proliferate

Genetic Markers

Types of oncogenes

Type I oncogene: Spleen focus- forming virus (SFFV) is a retrovirus that induces erythroleukemia in mice SFFV encodes a protein, gp55, that activates Epo receptors on erythroid precursor cells

Type II: HER-2/neu 0ncogene

RAS oncogene Mutated N-ras gene is found in neuroblastoma and AML. Mutated K-ras gene is found in pancreatic, colon, lung and bladder cancers.

BCR/ABL oncogene

Tumor suppressor genes 1- p53

2- Retinoblastoma gene

BRCA1 and BRCA2 BRCA 1 gene is located on ch 19 while BRCA 2 gerne is located on ch 13. Screening for familial breast-ovarian cancer syndrome, and breast cancer in early-onset breast cancer families

Oncofetal Antigens Carcinoembryonic antigen: Described by Gold and Freedman in 1965 as a marker of Colorectal Cancer. It also increases in pancreatic, gastric, lung, ovarian, uterine and breast cancers. Molecular mass of approximately 200 kDa. Glycoprotein with carbohydrate composition ranging from 45 – 55 % encoded by a gene located on chromosome 19. CEA levels 5 – 10 times upper limit of normal suggests cancer colon. CEA useful for staging and monitoring treatment but not for screening.

Alpha fetoprotein Glycoprotein, found in fetal liver, yolk sac, GI tract, biochemically related to albumin in adults half-life: 4~6 days Normal serum levels; At birth30 ng/ml >1 years old (adult) <10 ng/ml Increased in 70% HCC, elevated in hepatoblastoma, 20~70% germ cell tumors (yolk sac tumors, embryonal cell carcinoma) of testis and ovary, except dysgerminoma

The absolute AFP level correlates with tumor bulk CSF to plasma ratio of AFP > 1:40 → suggest CNS involvement. AFP-L 3 %: > 10 % suggests presence of HCC. Increase in benign conditions that cause hepatic parenchymal inflammation, hepatic necrosis and hepatic regeneration, ex. hepatitis, pregnancy, primary biliary cirrhosis, extrahepatic biliary obstruction

Enzymes as tumor markers Alkaline phosphatase. Lactate dehyrogenase (LDH). Neurone specific enolase. Prostatic acid phospatase. Prostate specific antigen (PSA). Urokinase plasminogen activator system. Cathepsins. Matrix metalloproteinase.

Hormones as tumor makers Hormone Type of cancer ACTH Small cell lung cancer – Cushing's syndrome – Cancer colon- cancer prostate- cancer ovary Calcitonin Medullary carcinoma of the thyroid HCG Chorio carcinoma – Testicular tumors Human Placental Lactogen Trophoplastic tumors – gonads, lung and breast cancers ADH Small cell lung cancer – tumors of adrenal cortex, pancreas and duodenum. Glucagon Glucagonoma Catecholamines and its metabolites Pheochromocytoma Seritonin and 5HIAA Carcinoid tumors

Cytokeratins Tissue polypeptide antigen (TPA) Proliferation marker useful for monitoring metastasis in breast, colon and ovarian cancers Differentiating choriocacinoma and HCC. Tissue polypeptide specific antigen (TPS) Antigenic site on TPA complex. Associated with proliferative activity of lung tumors Cytokeratin 19 fragments (CYFRA) Used for staging, monitoring treatment and follow up of lung cancer Squamous Cell Carcinoma Antigen (SCCA) Elevated in a variety of squamous cell carcinoma of cervix, lung, head and neck, digestive tract, ovaries and urogenital tract Used as a prognostic marker and detection of recurrence.

Carbohydrate Markers (CA) CA 15-3 monitor treatment and to detect recurrence in cancer breast Normal: <31 U/ml ↑in 20% with localized breast cancer, ~80% with metastatic disease, esp. if with bone involvment Specificity of 86%, sensitivity of 30% Also increased in gastric, pancreatic, cervical and lung cancer CA CA 549 High molecular glycoprotein - Increased in cancer breast CA 125 Cell surface glycoprotein, present during embryonic development of coelomic epithelium and is present in adult structures derived from it Normal : <35 U/ml, t ½ : 4~5 days For follow up of ovarian cancer, an increase may predict recurrent disease, may precede clinical recurrence by months. Correlate with tumor bulk

Blood group antigen- related cancer markers CA 19-9 Elevated in patients with mucin-secreting cancers (colorectal, pancreatic, ovarian and gastric cancers) Diagnosis, monitor, detect relapse in ovarian cancer, 70% specificity and 90% sensitivity Mild ↑in pancreatitis CA 242 A marker of pancreatic and colorectal cancers CA 72-4 A marker for carcinoma of GIT and ovary.

Proteins as tumor markers Β2 microglobulin Multiple myeloma – B -cell lymphoma - CLL- Waldenstrom macroglobulinaemia Correlates with tumor burden, prognosis, response to therapy. Increase with poor renal function C-peptide Insulinoma Ferritin Cancer liver, lung, breast and leukaemias immunoglobulins Multiple myeloma and B-cell lymphoma Tyrosinase Use RT-PCR to detect hematogenous spread of melanoma cells from a solid tumor in peripheral blood S100B protein ↑in 70% with stage IV metastasized melanoma

Proteins as tumor markers Melanoma associated antigen Melanoma Pancreas- associated antigen Pancreas and stomach cancers Pregnancy specific protein-1 Trophoblastic and germ cell tumors Prothrombin precursor Hepatocellular cacinoma Thyroglobulin Tissue-specific, glycoprotein produced by thyroid follicular cells normal: <60 ug/L Increased in cancer thyroid. Also increased in breast and lung cancers Tumor-associated trypsin inhibitor Lung, Gastro intestinal and ovarial tumors

Receptors as tumor markers Estrogen Receptors (ER) 2 isoforms: ER α + ER β ERα → better prognosis, predictor of relapse in cancer breast. Useful when deciding an adjuvant hormone treatment ERβ → distinct biological roles and ligand binding specificity, good prognostic factor, correlate with low grade and negative axillary LN status Progesterone Receptors (PR) Useful prognostic maker in cancer breast with ER assay because PR synthesis is dependent on estrogen action Epidermal growth factor receptors (EGFR) Overexpression of EGFR has prognostic value in many cancers: head and neck, ovarian, cervical bladder and esophgeal cancers