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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. - PowerPoint PPT Presentation
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Tumor MarkersTumor 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
• Screening - limitedlimited
• Diagnosis - limitedlimited
• Prognosis - limitedlimited
• Tumor staging - limitedlimited
• Tumor localization / radiotherapy - limitedlimited
• Monitoring the effectiveness of therapy - importantimportant
• Detecting tumor recurrence or remission - importantimportant
Telomeres
Without some form of correction the end replication leads to the loss of 50-100 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 Telomerase (special type of reverse transcriptase) is a protein-RNA complex that carry an RNA template for protein-RNA complex that carry an RNA template for synthesizing a repeated G-rich telomere. synthesizing a repeated G-rich telomere.
Telomerase is unique in carrying its own RNA template Telomerase is unique in carrying its own RNA template with it all the time.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 verylow 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 N-ras gene is found in neuroblastoma and AML.Mutated K-ras gene is found in pancreatic, colon, lung and bladder Mutated K-ras gene is found in pancreatic, colon, lung and bladder cancers.cancers.
BCR/ABL oncogene
Tumor suppressor genes1- 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: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-L3 %: > 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 cancerACTH Small cell lung cancer – Cushing's syndrome
– Cancer colon- cancer prostate- cancer ovary
Calcitonin Medullary carcinoma of the thyroidHCG Chorio carcinoma – Testicular tumorsHuman Placental Lactogen
Trophoplastic tumors – gonads, lung and breast cancers
ADH Small cell lung cancer – tumors of adrenal cortex, pancreas and duodenum.
Glucagon GlucagonomaCatecholamines 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 breastNormal: <31 U/ml↑in 20% with localized breast cancer, ~80% with metastatic disease, esp. if with bone involvmentSpecificity of 86%, sensitivity of 30%Also increased in gastric, pancreatic, cervical and lung cancer
CA 27.29CA 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 itNormal : <35 U/ml, t ½ : 4~5 daysFor 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 markersMelanoma 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 markersEstrogen 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
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