Historical background of tumor markersHistorical background of tumor markers

• The first TM reported was Bence Jones protein. Since its The first TM reported was Bence Jones protein. Since its discovery in 1847 by precipitation of a protein in acidified discovery in 1847 by precipitation of a protein in acidified boiled urine , the measurement of B.J.P has been a boiled urine , the measurement of B.J.P has been a diagnostic test for Multiple myloma (plasma cell tumor).diagnostic test for Multiple myloma (plasma 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 CEA patient start with the discovery of AFP in 1963 and CEA in 1965.in 1965.

Definition of TMDefinition of TM

• A substance produced or induced by tumor cells A substance produced or induced by tumor cells and released into blood , body fluids or expressed and released into blood , body fluids or expressed on cell surface , that can be used to differentiate a on cell surface , that can be used to differentiate a tumor from normal tissue or to determine the tumor from normal tissue or to determine the presence of a tumor.presence of a tumor.

• Few markers are specific for a single individual Few markers are specific for a single individual tumortumor

) ) tumor-specific markerstumor-specific markers( ( • Most are found with different tumors of the same Most are found with different tumors of the same

tissue typetissue type

) ) 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 used to monitor treatment and Most TM are used 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 & Isoenzymes

TMTMcancercancer

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

Hormones

TMTMcancercancer

ACTHACTHCushing’s & LungCushing’s & 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 Squamous cell AgAg

Cervix, 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 group They are high molecular weight mucins or blood group antigensantigens

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

TMTMcancercancer

BB2-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 progesterone receptorsreceptors

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 Two classes of genes are involved in the development of cancer :of 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 normal cellular processes such as growth factor signaling pathways.signaling 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 Signal transductiontransduction

AML, AML, nuroblastomanuroblastoma

K-ras mutationK-ras mutationSignal Signal transductiontransduction

Leukemia, Leukemia, lymphomalymphoma

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

22 . .Suppressor genesSuppressor genes

Genes involved in the recognition and repair of damaged Genes involved in the recognition and repair of damaged DNADNA..

The loss of function of this genes cause inability of DNA The loss of function of this genes cause inability of DNA repair and lead to tumor formation ( mostly solid tumors )repair and lead to tumor formation ( mostly solid tumors ) ..

The oncogenicity is derived from the loss of the gene rather The oncogenicity is derived from the loss of the gene rather than activationthan activation. .

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 the If the test will aid the diagnosis or influence the medical or surgical management of the patient medical or surgical management of the patient or family or family membersmembers

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

How to identify tumor markerHow to identify tumor marker? ? On cellOn cell

Cytochemistry, Flow cytometryCytochemistry, Flow cytometry

On tissueOn tissue

Histochemistry, Cytosol assaysHistochemistry, Cytosol assays

In body fluidsIn body fluids

Blood, urine, CSF, Amniotic fluidBlood, urine, CSF, Amniotic fluid