Tumor Markers Tumor Markers

OverviewOverview

Cancer remains the second leading cause of death in the USA, behind Cancer remains the second leading cause of death in the USA, behind

heart disease, with an estimated 1,437,180 new cases & 565,650 heart disease, with an estimated 1,437,180 new cases & 565,650

deaths in 2008 alone.deaths in 2008 alone.

It is expected that malignancies of prostate & breast origin will be It is expected that malignancies of prostate & breast origin will be

the most common causes of new diagnoses in men & women, the most common causes of new diagnoses in men & women,

respectively, with tumors of the lung & bronchus the leading cause respectively, with tumors of the lung & bronchus the leading cause

of cancer-related death in both genders of cancer-related death in both genders

A simple definition of cancer is: A simple definition of cancer is: A relatively autonomous growth of tissue, that can develop into a solid

mass or tumor & spread to other areas of the body

Cancer cells :Cancer cells :• Are not subject to regulatory system of cell growth

• Infiltrate adjacent tissue (in contrast to benign tumours)

• Form metastases due to lymphogenic or haematogenic spread

The proliferation of normal cells is thought to be regulated by growth promoting

proto-oncogenesproto-oncogenes & counterbalanced by tumor-suppressor genestumor-suppressor genes.

CancerCancer

ApoptosisApoptosis

Development of new blood Development of new blood vessels to supply oxygen vessels to supply oxygen

& nutrients to cells& nutrients to cells

ProgrammedProgrammed cell death cell death

Cell cycle

Phases of cell activity divided into G, S & M (Growth, DNA synthesis & Mitosis respectively)

Proto-oncogenesProto-oncogenes

• Proto-oncogenesProto-oncogenes are genes present in normal human cells & their products (proteins) may play important roles in normal cellular processes (as normal promotion of growth)

• These proto-oncogenesproto-oncogenes may be activatedactivated to oncogenes oncogenes • OncogenesOncogenes can convert normal cells into tumor cancer cells. can convert normal cells into tumor cancer cells.

• In cancer cells, oncogenes may beIn cancer cells, oncogenes may be:: Identical to normal genes but regulation of their expression in cancer cells Identical to normal genes but regulation of their expression in cancer cells

is abnormal is abnormal

Or: Or: Show very small structural differences from their counterparts in normal Show very small structural differences from their counterparts in normal

cells. cells. These differences will produce agents that leads to transformation of These differences will produce agents that leads to transformation of normal cells to cancer cells.normal cells to cancer cells.

Tumour Suppressor GenesTumour Suppressor Genes

Tumour suppressor genes are genes that encode for proteins (product)Tumour suppressor genes are genes that encode for proteins (product)

that are involved in protecting cells from unregulated growththat are involved in protecting cells from unregulated growth

Mutation in tumor suppressor genes may lead to cancerMutation in tumor suppressor genes may lead to cancer

• A golden dream of an oncologist is to diagnose cancer at an A golden dream of an oncologist is to diagnose cancer at an early stageearly stage..

• Diagnosis of carcinoma in the early stages Diagnosis of carcinoma in the early stages is a is a difficultdifficult task due to: task due to:

- Lack of - Lack of symptomssymptoms at early stages. at early stages.

- Diagnostic - Diagnostic proceduresprocedures (X ray, CT, MRI..) are (X ray, CT, MRI..) are notnot suitable for early diagnosis. suitable for early diagnosis.

Methods only detect tumors of at least 1-2 cm in size (1x10Methods only detect tumors of at least 1-2 cm in size (1x1099 cells) or more. cells) or more.

• Tumor markers Tumor markers are considered as one of the highly valuable tools for are considered as one of the highly valuable tools for detection & follow up of malignant tumors & their secondariesdetection & follow up of malignant tumors & their secondaries ..

How to Diagnose Cancer?How to Diagnose Cancer?

Tumor MarkersTumor Markers

Tumor Markers Tumor Markers

Substances present in or produced by a tumor itself

OR Produced by host in response to a tumor

Can be used to Can be used to

Determine the presence of a tumor

OR Differentiate a tumor from normal tissue

Based on Based on

Measurements in blood or secretions

Tumor markers include a variety of substances likeTumor markers include a variety of substances like::

Oncofetal proteinsOncofetal proteins Cell surface antigensCell surface antigens Cytoplasmic proteinsCytoplasmic proteins HormonesHormones Enzymes Enzymes ReceptorsReceptors Oncogenes & their products (proteins)Oncogenes & their products (proteins)

Tumor MarkersTumor Markers

Characteristics of an Characteristics of an IdealIdeal Tumor Marker Tumor Marker

• Should be highly specific highly specific (negative in all negative cases(negative in all negative cases)…. Diagnosis & Screening)…. Diagnosis & Screening

• Should be highly sensitive highly sensitive (positive in all positive cases)….(positive in all positive cases)….Diagnosis & ScreeningDiagnosis & Screening

• Should provide a lead-time over clinical diagnosis lead-time over clinical diagnosis ….….ScreeningScreening

• The levels of the marker should correlate with the tumor burden .. correlate with the tumor burden .. PrognosisPrognosis

• It is accurately reflecting any tumor progression or regressionreflecting any tumor progression or regression….….MonitoringMonitoring

• Procedure of estimation of the marker should be reliablereliable

• The test used for detection should be relatively cheapcheap

Applications of Tumor MarkersApplications of Tumor Markers

1- Diagnosis1- Diagnosis (D)(D): : to help to establish the to help to establish the diagnosis diagnosis

2- Screening2- Screening (S)(S): : to identifyto identify patients with patients with earlyearly cancer (before cancer (before

appearance of clinical manifestations) appearance of clinical manifestations)

3- Prognosis3- Prognosis (P)(P): to assess the : to assess the aggressivenessaggressiveness

4- Monitoring 4- Monitoring (M): (M): followfollow up of regression or progression up of regression or progression

Evaluate the Response to Treatment Evaluate the Response to Treatment (RT)(RT)

Detection of Recurrence Detection of Recurrence (R)(R) 5- Determination of Risk: 5- Determination of Risk: i.e. in i.e. in geneticallygenetically predisposed individ. predisposed individ.

1- Screening1- Screening

Screening asymptomatic individuals (in very early cases of cancer)Screening asymptomatic individuals (in very early cases of cancer)Use of tumor markers, to date, has generally notnot been an effective strategy been an effective strategy due to:

• Most of the clinically used tumor markers are found in normal cells & benign conditions in addition to cancer cells.

• The relatively low prevalence of individual cancer types.

• The screening role is generally very The screening role is generally very usefuluseful if restricted to groups if restricted to groups with risk factors as: with risk factors as:

- Family history - Family history

- Environmental exposure- Environmental exposure

- Geographic prevalence - Geographic prevalence

- Clinical profile - Clinical profile

1- Screening 1- Screening cont.

High risk groups: are individuals at increased risks for malignancyHigh risk groups: are individuals at increased risks for malignancy

Tumor markers used for screening of high risk individuals:Tumor markers used for screening of high risk individuals:

Alpha fetoprotein (AFP)Alpha fetoprotein (AFP) For patients with liver cirrhosis or chronic hepatitis who are at risk for

development of hepatocelluar carcinomahepatocelluar carcinoma

Prostate-specific antigen (PSA)Prostate-specific antigen (PSA) For men older than 50 years in conjunction with a physical examination

(clinical profile) for early detection of cancer prostatecancer prostate

CalcitoninCalcitonin For first degree relatives of a patient (family history) with

medullary carcinomamedullary carcinoma

1- Screening 1- Screening cont.

Sensitivity & Specificity of Screening Tumor Markers:Sensitivity & Specificity of Screening Tumor Markers:Ideal tumor marker for screening asymptomatic population should be:Ideal tumor marker for screening asymptomatic population should be:

100% sensitive100% sensitive: Always : Always positivepositive in patients with the disease in patients with the disease

100% specific100% specific: Always : Always negativenegative in individuals who do not have the disease in individuals who do not have the disease

For examples:For examples: If a test gives If a test gives positivepositive results in 99 results in 99 patientspatients out of 100 out of 100 patientspatients: :

Its sensitivity is 99%Its sensitivity is 99% If a test gives If a test gives negativenegative results in 90 results in 90 normalnormal individuals out of 100 individuals out of 100 normal individ.normal individ.

Its specificity is 90%Its specificity is 90%

In reality, an ideal tumor marker which gives 100% specificity & 100 % In reality, an ideal tumor marker which gives 100% specificity & 100 %

sensitivity does sensitivity does notnot exist. exist.

To increase sensitivity & specificity of a tumor markerTo increase sensitivity & specificity of a tumor marker

Combination of Combination of multiplemultiple tumor markers tumor markers Combination of tumor markers with Combination of tumor markers with other procedures other procedures

e.g. combination of Carbohydrate Antigen 125 (CA 125) with e.g. combination of Carbohydrate Antigen 125 (CA 125) with

ultrasonography for early detection of ovarian malignancyultrasonography for early detection of ovarian malignancy

1- Screening 1- Screening cont.

2- Prognosis2- Prognosis

• For cancer patients, determination of prognosisprognosis is based on determination of

aggressiveness of tumoraggressiveness of tumor, which , in turn determines how a patient should which , in turn determines how a patient should

be treated (surgery, chemotherapy, radiotherapy, etc)be treated (surgery, chemotherapy, radiotherapy, etc)

• As the serum concentrations of tumor markers increases with progression and usually

reaches the highest levels when tumors become metastasized, the serum levels at diagnosis

are likely to reflect the aggressiveness of the tumor and predict the outcome.

• High levels of serum tumor marker measured during diagnosis would indicate High levels of serum tumor marker measured during diagnosis would indicate

the presence of a malignant or metastatic tumor associated with poor prognosis.the presence of a malignant or metastatic tumor associated with poor prognosis.

4- Monitoring of Disease, Response of Treatment 4- Monitoring of Disease, Response of Treatment & Detection of Recurrence& Detection of Recurrence

• Constitutes the Constitutes the most common clinical use of serum tumor markers.most common clinical use of serum tumor markers.

• Markers usually increase with progressive disease, decrease with remission & do not Markers usually increase with progressive disease, decrease with remission & do not change significantly with stable disease. change significantly with stable disease.

• After treatment After treatment (surgical resection(surgical resection, radiation or chemotherapyradiation or chemotherapy), tumor markers are routinely followed serially (to monitor the response to treatment & recurrence).

• It is desirable to monitor the patient using It is desirable to monitor the patient using a highly sensitive tumor marker test a highly sensitive tumor marker test to to detect detect recurrencerecurrence as early as possible as early as possible

The appearance of most of the circulating tumor markers have a lead time of several lead time of several

month (3-6 months) month (3-6 months) prior to the stage at which many of the physical procedures can

be used for detection of the cancer So, rising tumor marker levels may detect So, rising tumor marker levels may detect recurrencerecurrence of disease before any clinical of disease before any clinical

or radiological evidence of disease is apparent (biochemical recurrence) or radiological evidence of disease is apparent (biochemical recurrence)

5- Determination of Risk5- Determination of Risk

• Usually involves genetic probes that evaluate any specific genetic abnormality or mutation noted to indicate an increased risk of a particular malignancy.

• Examples of such abnormalities would include:

- Carriers of Philadelphia chromosome Carriers of Philadelphia chromosome for hematological malignancies

- Carriers of BRCA 1 or 2 genesCarriers of BRCA 1 or 2 genes, which confer a higher risk of breast or

ovarian malignancies

False positive results False positive results occur with:occur with:

Inflammatory conditionsInflammatory conditions Benign conditionsBenign conditions

• Presence of liver diseasesPresence of liver diseases: Causes disturbances in metabolism and excretion of : Causes disturbances in metabolism and excretion of some tumor markers some tumor markers

• Disturbances of renal functionDisturbances of renal function: affects levels of some tumor markers : affects levels of some tumor markers

• Consequences of diagnostic and therapeutic proceduresConsequences of diagnostic and therapeutic procedures: digito-rectal : digito-rectal examination, mamography, surgery, radio and chemotherapyexamination, mamography, surgery, radio and chemotherapy

• As a consequence of different physiological conditionsAs a consequence of different physiological conditions: as in pregnancy may : as in pregnancy may affect ßHCG, AFP…..).affect ßHCG, AFP…..).

Factors that affect serum concentrations of tumor markersFactors that affect serum concentrations of tumor markers

AFP: alpha fetoproteinB-hCG: beta human chorionc gonadotrpinCEA: carcinembrionic antigenCA 125: carbohydrate antigen 125

False negative results False negative results occur with:occur with:

Insufficient expression of the marker Insufficient expression of the marker

or production of the marker in some of the tumor cells only or production of the marker in some of the tumor cells only Insufficient blood circulation in the tumorInsufficient blood circulation in the tumor Production of autoantibodies against the markerProduction of autoantibodies against the marker Rapid degradation & clearance of the markerRapid degradation & clearance of the marker

Factors that affect serum concentrations of tumor markersFactors that affect serum concentrations of tumor markers

Frequency of Ordering of MarkersFrequency of Ordering of Markers

• As a general guidelineAs a general guideline, the time interval between serial determinations should be 3 months3 months.

• But in case of an abnormal valueBut in case of an abnormal value, a repeat estimate can be ordered within 2 to 4 within 2 to 4 weeks weeks irrespective of the initial reading.

Checking the effectiveness (success ) of treatment:Checking the effectiveness (success ) of treatment:

• Confirming of the success of Confirming of the success of surgical removal surgical removal of a tumor is checked of a tumor is checked by measuring the marker concentrations ideally after a period not less than 5-6 after a period not less than 5-6 half-liveshalf-lives (to allow tumor marker levels to fall to normal).

• In case of treatment with In case of treatment with chemotherapy or radiotherapychemotherapy or radiotherapy the period should be longer longer

GUIDELINES FOR GUIDELINES FOR ORDERING/ INTERPRETING TUMOR MARKER TESTSORDERING/ INTERPRETING TUMOR MARKER TESTS

• Never rely on the result of a single testNever rely on the result of a single test

• Order every test from the same laboratoryOrder every test from the same laboratory

• Consider half-life of the tumor when interpreting the resultConsider half-life of the tumor when interpreting the result

• Consider how the Tumor Marker is removed or metabolizedConsider how the Tumor Marker is removed or metabolized

Examples of Frequently Ordered Tumor Examples of Frequently Ordered Tumor MarkersMarkers

• Alpha-fetoproteinAlpha-fetoprotein• CA-125CA-125• CEACEA• hCGhCG• PSAPSA• Her-2/neuHer-2/neu• p53p53• BrCa1BrCa1• BrAa2BrAa2• CA-15.3CA-15.3• CS-19.9CS-19.9• Estrogen & progesterone receptorEstrogen & progesterone receptor• VMAVMA

Suggested Recommended Markers for Suggested Recommended Markers for diagnosis/prognosisdiagnosis/prognosis

TumorTumor Tumor markersTumor markers

1.1. Hepatoma Hepatoma (HCC)(HCC)

AFPAFP

2.2. Cancer Cancer ovaryovary

CA-125CA-125 Inherited ovarian cancer: Inherited ovarian cancer: BrCa1(on chromosome 17, which is the same BrCa1(on chromosome 17, which is the same

chromosome having the p53 & Her-2/Neu)chromosome having the p53 & Her-2/Neu)

3.3. Breast Breast CancerCancer

CA15-3CA15-3 CEACEA Her-2/neuHer-2/neu Estrogen and progesterone receptorsEstrogen and progesterone receptors If inherited: BrCa1, and BrCa2 (on chromosome 13)If inherited: BrCa1, and BrCa2 (on chromosome 13)

Suggested Recommended Markers for Suggested Recommended Markers for diagnosis/prognosisdiagnosis/prognosis

TumorTumor Tumor markersTumor markers

4.4. Cancer head of the pancreasCancer head of the pancreasCA 19-9CA 19-9CEACEA

5.5. Colorectal carcinomaColorectal carcinomaCA 19-9CA 19-9CEACEA

6.6. Pheochromocytoma Pheochromocytoma Vanillylmandelic Vanillylmandelic

Acid (VMA) in urineAcid (VMA) in urine

7.7. Nonseminomatous testicular cancerNonseminomatous testicular cancer

AFPAFP-hCG-hCGCEACEA

8.8. Vesicular mole & ChoriocarcinomaVesicular mole & Choriocarcinoma -hCG-hCG

9.9. Prostate cancerProstate cancer PSAPSA

Oncofetal ProteinsOncofetal Proteins

Oncofetal ProteinsOncofetal Proteins

These are proteins produced during fetal life. They are present in high concentrations in the sera of fetuses &

decrease to low levels or disappear after birth. They reappear in individuals with cancer. This demonstrates that certain genes are reactivated as a result of the

malignant transformation of cells. There are several oncofetal antigens as AFP & CEA

Alfa-feto Protein (AFP)Alfa-feto Protein (AFP)

AFP is a glycoprotein. It is one of the major proteins in the fetal circulation The fetalfetal AFP reaches the peak at 14 weeks of gestation & declines at term.

• The maternalmaternal AFP level increase from 12 weeks to peak during the third trimester

• It is a marker of hepatocellular carcinoma hepatocellular carcinoma & nonseminomatous carcinoma of testisnonseminomatous carcinoma of testis

• Other causes of increased AFP due to non-malignant causesOther causes of increased AFP due to non-malignant causes:

- Pregnancy

- Non- cancerous liver diseases : hepatitis & cirrhosis

• Except in pregnancy , AFP level greater than 1000ug/L indicates cancer

Alfa-fetoprotein (AFP) Alfa-fetoprotein (AFP) cont.cont.

Clinical Application of AFP:Clinical Application of AFP:

Screening, diagnosis, prognosis & monitoring Screening, diagnosis, prognosis & monitoring of hepatocellular hepatocellular carcinoma carcinoma

(i.e. hepatoma).(i.e. hepatoma). Used with ultrasound imaging every 6 months in patients at high risk patients at high risk of

developing HCC e.g. patients with hepatitis B virus & hepatitis C virus-induced liver cirrhosis

AFP is used for early detection (in the lead periodearly detection (in the lead period) which is ~ 3 - 6 months before clinical manifestations of the cancer appear.

AFP is AFP is notnot completely specific for HCC completely specific for HCC AFP may be increased in pregnancypregnancy & benign liver diseasebenign liver disease. AFP is used as a tumor marker for nonseminomatous testicular nonseminomatous testicular

cancer cancer ((in combination with -hCG)

Carcinoembryonic Antigen (CEA)Carcinoembryonic Antigen (CEA)

• It is the most widely used tumor marker for colorectal cancercolorectal cancer.• The main clinical use of CEA is as a tumor marker for colorectalcolorectal

cancercancer for: PrognosisPrognosis Post-surgery surveillance Post-surgery surveillance MonitorMonitor response to chemotherapyresponse to chemotherapy

Hormones as Tumor markerHormones as Tumor marker

The production of hormone in cancer involves 2 separate routes:The production of hormone in cancer involves 2 separate routes:

1. The endocrine tissue that normally produces the hormone endocrine tissue that normally produces the hormone can produce excessive amounts (e.g. Vinylmandilic acid, VMA is a tumor marer for pheochrmocytoma, tumor of the adrenal medulla)

2. A hormone can be produced by nonendocrine tissue A hormone can be produced by nonendocrine tissue that normally does not

produce the hormone (e.g. ectopic production of ACTH & PTH)

Human Chorionic Gonadotropin (hCG)Human Chorionic Gonadotropin (hCG)

• hCG is a hormone hCG is a hormone normallynormally secreted by trophoblasts in the placenta during secreted by trophoblasts in the placenta during pregnancy.pregnancy.

It is a glycoprotein consisting of and subunits.

It is the most useful marker for detection of gestational trophoblastic gestational trophoblastic diseasesdiseases (GTDs) that include:

Hydatiform mole (vesicular mole)Hydatiform mole (vesicular mole) ChoriocarcinomaChoriocarcinoma

• It is alsoalso elevated in nonseminomatous tumors of the testis nonseminomatous tumors of the testis (with AFP).(with AFP).

Enzymes as Tumor MarkersEnzymes as Tumor Markers

Generally, an increase in enzymes is not specific or sensitive to identify type of cancer. PSA is an exception

Prostate Specific Antigen (PSA)Prostate Specific Antigen (PSA)

• PSA is a glycoprotein produced onlyonly in the epithelial cells of the acini & ducts of the prostate.

There are 2 major forms of PSA that are found in the blood: FreeFree & ComplexedComplexed: to 1-antichymotrypsin or 2-macroglobulin.

• Total PSA Total PSA is used in screeningscreening & in monitoringmonitoring of prostate cancerprostate cancer

• Free PSA Free PSA can help to differentiate levels of PSA that are in the grey zonethe grey zone: i.e. not high enough to diagnose cancer prostate, but not low enough to rule out the diagnosis of cancer prostate:

Patient with cancer prostate have a lower % of free PSA.

Prostate Specific Antigen (PSA)Prostate Specific Antigen (PSA)

• Annual PSA testing for Annual PSA testing for screening of prostate cancer screening of prostate cancer is indicated for:is indicated for:– In men over 50 years old– In younger men at high risk: e.g. with a family history of prostate cancer.

• To increase the accuracy of the PSA testing, it is essential to use age-adjusted age-adjusted cutoff values of PSAcutoff values of PSA

• The best clinical use & first clinical applications of PSA testing was to monitormonitor for for the progression of prostate cancer after therapy the progression of prostate cancer after therapy (e.g. radical prostatectomy)

• Causes Causes other than other than prostate cancer that can prostate cancer that can elevated PSA elevated PSA: Prostate infectionProstate infection Prostate irritationProstate irritation Benign prostatic hyperplasia (enlargement)Benign prostatic hyperplasia (enlargement)

Carbohydrate MarkersCarbohydrate Markers

Carbohydrate relate tumor markers: Carbohydrate relate tumor markers:

are either:

Antigens on tumor cells

- Or: Secreted by the tumor cells

( CA = carbohydrate antigensCA = carbohydrate antigens)

Carbohydrate Antigen-125 (CA-125)Carbohydrate Antigen-125 (CA-125)

• CA-125 may be useful for detecting ovarian tumorsovarian tumors:: OnlyOnly clinically accepted serologic marker of ovarian cancer DiagnoseDiagnose ovarian tumors at earlyearly stages DistinguishDistinguish benign masses from ovarian cancer MonitoringMonitoring treatments

• CA-125 is notnot considered specific enough for ovarian cancerconsidered specific enough for ovarian cancer, as it may be elevated in patients with

Endometriosis During the first trimester of pregnancy During menstruation.

Receptors as Tumor MarkersReceptors as Tumor Markers

Estrogen/Progesterone Receptors (ER/PREstrogen/Progesterone Receptors (ER/PR))

These receptors can play a role in breast carcinogenesis breast carcinogenesis assessment of ER/PR status is crucial for optimal treatment planning (similar to HER-2)

Decreased recurrence rates & disease-related mortality have been demonstrated with tamoxifentamoxifen for ER+ cancers, which are not seen when the tumors are ER–

Receptor status also has significant prognostic implicationsprognostic implications, with best (ER+/PR+ ) to poorest (ER−/PR–.)

Genetic MarkersGenetic Markers

Two classes are involved in the development of cancerTwo classes are involved in the development of cancer

OncogenesOncogenes: as HER-2/neuSuppressor genesSuppressor genes: as p53, BRCA1 , BRCA2…

Human Epidermal Growth Factor Receptor 2 Human Epidermal Growth Factor Receptor 2 (Her-2/neu)(Her-2/neu)

• HER-2 gene productHER-2 gene product is a transmembrane protein normallynormally involved in

cell growth & differentiation through its interaction with circulating growth

factors

It is identified as an proto-oncogeneproto-oncogene as its amplification results in protein

over expression that supports rapid cellular proliferation (i.e. becomes oncogene).

Her-2/neu is a marker for breast & ovarian cancersbreast & ovarian cancers

In In breast cancer breast cancer to determine the type of therapyto determine the type of therapy:– Breast cancer positivepositive for Her-2/neu is responsiveresponsive to treatment (Herceptin)– Breast cancer negativenegative for Her-2/neu is NOTNOT responsive responsive to treatment

Tumor suppressor genes Tumor suppressor genes

Tumour suppressor genes Tumour suppressor genes are genes that encode for are genes that encode for proteins that are:proteins that are: Involved in normal protection of cells from unregulated Involved in normal protection of cells from unregulated growthgrowth If mutated If mutated may lead to cancermay lead to cancer

Examples of tumor suppressor genes:Examples of tumor suppressor genes: P53P53 BRCA1 & BRCA2BRCA1 & BRCA2

p53p53

• p53 p53 ((an example of tumor suppressor genes)an example of tumor suppressor genes)

P53 gene P53 gene is located on ch.17 (together with genes of BRCA1 & Her-2/neu)

Gene product (protein) normally Gene product (protein) normally result in cell cycle arrest & induces apoptosis

Upon mutation: loss of function mutation Upon mutation: loss of function mutation cancer cancer::

Cancer colon, Brain cancer, Cancer lung & Cancer liverCancer colon, Brain cancer, Cancer lung & Cancer liver

Carcinogens causing mutations in p53:Carcinogens causing mutations in p53:

• Aflatoxin BAflatoxin B Potent hepatocarcinogen (common in China & Africa)

Causes mutations of p53 gene leading to cancer liver cancer liver • SmokingSmoking::

Causes mutations in p53 gene leading to lung cancerlung cancer

BRCA1 & BRCA2BRCA1 & BRCA2

They are genes that are inheritedinherited as autosomal dominant trait.

Two genetic loci : BRCA1 on chromosome 17 & BRAC2 on

chromosome 13

If these genes are mutated, cancer occur (mutation is inherited to offspring)

Carriers of BRCA1 gene mutationCarriers of BRCA1 gene mutation: :

have an 85%85% risk of developing breast cancer breast cancer

& 45%45% risk of developing ovarian cancerovarian cancer