Dr. Amal S. AhmedAss Prof.Clinical Pathology

Suez Canal University

Historical background of tumor markersHistorical background of tumor markers

The first TM reported was Bence Jones protein. Since The first TM reported was Bence Jones protein. Since its discovery in 1847 by precipitation of a protein in its discovery in 1847 by precipitation of a protein in acidified boiled urine , the measurement of B.J.P has acidified boiled urine , the measurement of B.J.P has been a diagnostic test for Multiple myloma (plasma been a diagnostic test for Multiple myloma (plasma cell tumor).cell tumor).

The general application of TM for monitoring cancer The general application of TM for monitoring cancer patient start with the discovery of AFP in 1963 and patient start with the discovery of AFP in 1963 and CEA in 1965.CEA in 1965.

Definition of TMDefinition of TM A substance produced or induced by tumor cells and A substance produced or induced by tumor cells and

released into blood , body fluids or expressed on cell released into blood , body fluids or expressed on cell surface , that can be used to differentiate a tumor from surface , that can be used to differentiate a tumor from normal tissue or to determine the presence of a tumor.normal tissue or to determine the presence of a tumor.

Few markers are specific for a single individual tumorFew markers are specific for a single individual tumor ( ( tumor-specific markerstumor-specific markers) )

Most are found with different tumors of the same tissue Most are found with different tumors of the same tissue typetype

( ( tumor-associated markerstumor-associated markers) )

Classification of TMClassification of TM

Enzymes & isoenzymes Hormones Oncofetal antigens Carbohydrates markers Proteins Receptors & other markers Genetic markers (Oncogenes & suppressor gene mutations )

Potential uses of TMPotential uses of TM

Screening in general population Clinical staging of cancer Prognostic indicator for disease progress Evaluation of treatment success Detection the recurrence of cancer Monitoring response to therapy Radioimmunolocalization of tumor

Recommended Cancer ScreeningRecommended Cancer ScreeningTestsTests

CancerTechnique

BreastMammography

CRCASigmoidoscopy

CervicalPAP

NeuroblastomaVMA

HCCAFP

ProstatePSA

OvarianCA 125

Predictive MarkersPredictive Markers

ER and PR: For predicting response toER and PR: For predicting response to hormone therapy in breast cancerhormone therapy in breast cancer

HER-2: For predicting response toHER-2: For predicting response to trastuzumab (Herceptin) in breast cancertrastuzumab (Herceptin) in breast cancer

Disease ManagementDisease Management

Most TM are usedMost TM are used  to monitor treatment and to monitor treatment and progression of cancer .progression of cancer .

Single determination does not allow definite Single determination does not allow definite conclusion.conclusion.

Combining different markers can improve the Combining different markers can improve the diagnostic precision.diagnostic precision.

Normal level ( negative result ) does not exclude Normal level ( negative result ) does not exclude malignancy.malignancy.

Enzymes & IsoenzymesTMTMcancercancer

AldolaseAldolaseLiverLiver

AmylaseAmylasePancreaticPancreatic

AlpAlpLiver, Bone, leukemia & lymphomaLiver, Bone, leukemia & lymphoma

CK-BBCK-BBProstate, lung , breast, colon, ovaryProstate, lung , breast, colon, ovary

LDHLDHLiver, leukemia & lymphomaLiver, leukemia & lymphoma

GGTGGTLiverLiver

PSA&PAPPSA&PAPProstateProstate

ElastaseElastasebreastbreast

HormonesTMTMcancercancer

ACTHACTHCushingCushing’’s & Lungs & Lung

ADHADHLung, adrenal cortex, pancreasLung, adrenal cortex, pancreas

PTHPTHLiver, renal, breast, lungLiver, renal, breast, lung

CalcitoninCalcitoninMedullary thyroidMedullary thyroid

GastrinGastrinGlucagonomaGlucagonoma

GHGHPituitary, renal , lungPituitary, renal , lung

hCGhCGchoriocarcinomachoriocarcinoma

ProlactinProlactinPituitary, renal , lungPituitary, renal , lung

Oncofetal Ags :Oncofetal Ags :Normally produced proteins during fetal life, decrease to low levels or disappear after birth and reappear in cancer patients

TMTMcancercancer

AFPAFPHCC, germ cell carcinomaHCC, germ cell carcinoma

CEACEAColorectal, GIT, pancreas, lung, breastColorectal, GIT, pancreas, lung, breast

Carcinofetal Carcinofetal ferritinferritin

LiverLiver

Squamous cell AgSquamous cell AgCervix, lung, skin, head & neckCervix, lung, skin, head & neck

Carbohydrate markers: Carbohydrate markers: Either are antigens on the tumor cell surface or are Either are antigens on the tumor cell surface or are secreted by the tumor cellssecreted by the tumor cellsThey are high molecular weight mucins or blood They are high molecular weight mucins or blood group antigensgroup antigens

TMTMcancercancer

CA 125CA 125Ovarian , endometrialOvarian , endometrial

CA 15-3CA 15-3Breast , ovarianBreast , ovarian

CA 19-9CA 19-9Pancreatic , gastrointestinal , hepaticPancreatic , gastrointestinal , hepatic

CA 19-5CA 19-5Gastrointestinal , Pancreatic , ovarianGastrointestinal , Pancreatic , ovarian

CA 50CA 50Pancreatic , gastrointestinal , colonPancreatic , gastrointestinal , colon

Proteins TMProteins TM

TMTMcancercancerBB2-microglobulin2-microglobulinMM ,B-cell lymphoma ,CLLMM ,B-cell lymphoma ,CLL

C-peptideC-peptideInsulinomaInsulinoma

FerritinFerritinLiver, lung, breast, leukemiaLiver, lung, breast, leukemia

immunoglobulinimmunoglobulinMM , lymphomasMM , lymphomas

Other tumor markersOther tumor markers

TMTMNatureNatureCancerCancer

Estrogen & Estrogen & progesterone receptorsprogesterone receptors

TissueTissueBreastBreast

CatecholamineCatecholamine metabolitesmetabolites

Urine ( VMA , HVA )Urine ( VMA , HVA )Nuroblastoma , Nuroblastoma , phyochromocytomaphyochromocytoma

HydroxypolineHydroxypolineUrineUrineBone metastasis Bone metastasis (breast) , MM(breast) , MM

Genetic MarkersGenetic Markers

Two classes of genes are involved in the development of Two classes of genes are involved in the development of cancer :cancer :

1.1. Oncogens :Oncogens : cell activation genes that code for products involved in cell activation genes that code for products involved in

normal cellular processes such as growth factor signaling normal cellular processes such as growth factor signaling pathways.pathways.

over expression ( activation ) of oncogens will lead to over expression ( activation ) of oncogens will lead to abnormal cell growth , resulting in malignancy (mostly abnormal cell growth , resulting in malignancy (mostly hematological malignancy ).hematological malignancy ).

Some oncogens found in human tumorsSome oncogens found in human tumors

oncogenoncogenfunctionfunctioncancercancer

N-ras mutationN-ras mutationSignal transductionSignal transductionAML, nuroblastomaAML, nuroblastoma

K-ras mutationK-ras mutationSignal transductionSignal transductionLeukemia, Leukemia, lymphomalymphoma

bcl-2bcl-2Blocks apoptosisBlocks apoptosisLeukemia, Leukemia, lymphomalymphoma

22 . .Suppressor genesSuppressor genes

Genes involved in the recognition and repair of damaged DNAGenes involved in the recognition and repair of damaged DNA..The loss of function of this genes cause inability of DNA repair The loss of function of this genes cause inability of DNA repair

and lead to tumor formation ( mostly solid tumors )and lead to tumor formation ( mostly solid tumors ). . The oncogenicity is derived from the loss of the gene rather than The oncogenicity is derived from the loss of the gene rather than

activationactivation. .

Some S. genes found in human tumorsSome S. genes found in human tumors

genegenecancercancer

P53 P53 MUTATIONMUTATION

Breast , colorectal , lung , liver , renalBreast , colorectal , lung , liver , renal

BRCA1 BRCA1 MUTATIONMUTATION

Breast , melanomaBreast , melanoma

BRCA2 BRCA2 MUTATIONMUTATION

BreastBreast

RETMedullary thyroid cancer

Genetic Testing for CancerGenetic Testing for CancerSusceptibilitySusceptibility

Genetic testing should be carried outGenetic testing should be carried out:: # # If the individual has personal or family historyIf the individual has personal or family history

suggestive of cancer susceptibilitysuggestive of cancer susceptibility # # If the test can be adequately interpretedIf the test can be adequately interpreted

# # If the test will aid the diagnosis or influence If the test will aid the diagnosis or influence the medical or surgical management of the patient the medical or surgical management of the patient or family membersor family members

J Clin Oncol 2003;21:1J Clin Oncol 2003;21:1

How to identify tumor markerHow to identify tumor marker? ? On cellOn cellCytochemistry, Flow cytometryCytochemistry, Flow cytometry

On tissueOn tissueHistochemistry, Cytosol assaysHistochemistry, Cytosol assays

In body fluidsIn body fluidsBlood, urine, CSF, Amniotic fluidBlood, urine, CSF, Amniotic fluid