Pakistan Society Of Chemical Pathologists - PowerPoint Presentation

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Pakistan Society Of Chemical PathologistsDistance Learning Programme In Chemical Pathology(DLP-2)Lesson No 19Tumour MarkersBy Col Naveed AsifConsultant Chemical Pathologist / Section Head Endocrinology and Tumour MarkersDepartment of Chemical Pathology and EndocrinologyAFIP Rawalpindi& Brig Aamir IjazMCPS, FCPS, FRCP (Edin), MCPS-HPEHOD and Professor of Pathology / AFIP Rawalpindi

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Part I

MCQs (One Best Type)

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Q.1: Tumor markers that are to be put to clinical use should have certain characteristics that are applicable in all situations. An ideal marker has a number of characteristics. All the following are characteristics of an Ideal tumor marker EXCEPT:a. Have 100% accuracy in differentiating between healthy individuals and tumor patients b. Have a normal plasma level, urine level or both in the presence of micro metastasisc. Have high positive and negative predictive valued. Precede and predict recurrences before they are clinically detectablee. Provide a lead-time over clinical diagnosis

b. Have a normal plasma level, urine level or both in the presence of micro metastasis

Slide4

Tumor Marker

Substances present in, or produced by a tumor itself or produced by host in response to a tumor that can be used to differentiate a tumor from normal tissue or to determine the presence of a tumor based on measurements in blood or secretions

Such substances are found in cells, tissues or body fluids

Measured qualitatively or quantitatively by chemical, immunological or molecular biological methods

Some tumor markers represent re-expression of substances produced normally by embryonically closely related tissue e.g. CEA in Colon, stomach, liver, and pancreas

Slide5

Q 2. Tumor markers are substances present in, or produced by, a tumor itself or by host. It can be detected in plasma or other body fluids including urine by different techniques. Which of the following markers is estimated in urine?a. Human kallikerin 2b. Intercellular adhesion molecule-1 c. Lysophosphatidic acidd. Nuclear matrix proteinse. Urokinase-Plasminogen activator inhibitor

d. Nuclear

matrix proteins

Slide6

Human Kallikerin 2

Human glandular

kallikrein

2 (hK2) is a prostate-specific

kallikrein

produced by the prostatic epithelium with approximately 80% DNA sequence homology with PSA

hK2 is a potent protease, with more than 20,000 times the activity of the relatively weak protease PSA

While PSA production is often decreased in poorly differentiated prostate cancers, hK2 production appears to be increased

In

p

rostatism

patients the ratio of hK2 to free PSA improves the discrimination between Prostate Cancer and Benign Hyperplasia within the diagnostic “Gray Zone” of total PSA 4 to 10 ng/ml

Monoclonal antibodies have been produced to detect hK2

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Intercellular Adhesion Molecule-1

ICAM-1 (Intercellular Adhesion Molecule 1) also known as CD54 (Cluster of Differentiation 54)

A member of the immunoglobulin superfamily Ig-like cell adhesion molecule expressed by several cell types including leukocytes and endothelial cells

Derangement of ICAM-1 expression contributes to the clinical manifestations of a variety of diseases, predominantly by interfering with normal immune function.

Among these are malignancies (e.g., melanoma and lymphomas), many inflammatory disorders (e.g., asthma and autoimmune disorders), atherosclerosis, ischemia, certain neurological disorders, and allogeneic organ transplantation.

Slide8

Lysophosphatidic Acid

LPA is a phospholipid derivative, identical in structure to

phosphatidic

acid (PA)

Bulk of LPA production occurs in bodily fluids, outside the cell. From there, it can bind to, and activate, upwards of six different cell surface receptors, initiating a diverse range of signaling cascades resulting in cell proliferation

Dysregulation of LPA receptors can lead to

hyperproliferation

, which may contribute to

oncogenesis

and metastasis

Alongwith

CA 125, plasma LPA level can be a useful marker for ovarian cancer, particularly in the early stages of disease

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Nuclear Matrix Proteins

The nuclear matrix (NM) is a structure resulting from the aggregation of proteins and RNA in the nucleus of cells

Nuclear matrix proteins (NMPs) make up the internal structure of nucleus. They are associated with key reactions in nucleus like DNA replication and RNA synthesis

Expression pattern of NMP has become an important early indicator for numerous cancers/tumors

NMPs released by cancer cell are different from those in normal cell

Particular importance in bladder cancer patient, owing its excretion in urine

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Urokinase Plasminogen Activator System

Urokinase

plasminogen activator (

uPA

) is a serine protease with an important role in cancer invasion and metastases

.

When

bound to its receptor (

uPAR

),

uPA

converts plasminogen into plasmin and mediates degradation of the extracellular matrix during tumor cell invasion.

High

levels of

uPA

and

uPAR

, as well as the plasminogen activator

inhibitor -1 (PAI-1),

have been associated with shorter survival in women with breast cancer; in contrast, high levels of PAI-2 appear to be associated with better outcomes

.

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Urokinase Plasminogen Activator System (cont)

One explanation is that tumor may be overproducing

uPA

, allowing cancer cells to spread beyond the tumor. High levels of PAI-1 may not be able to inhibit the growth of the tumor

uPA

and PAI-1 can be measured by ELISAs on a minimum of 300 mg of fresh or frozen breast cancer tissue

Both are used for the determination of prognosis in patients with newly diagnosed, node-negative breast cancer

Overexpression of

uPA

and/or PAI-1 have been consistently related to poor prognosis

If a patient has high levels of

uPA

and PAI-1, risk of recurrence of disease is very high

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Q. 3: Changes in concentration of tumor markers is used to describe the true status of a tumor. Different criteria/definitions have been devised based on various scientific facts. “A linear increase in the concentration of tumor marker in three consecutive samples on log scale provided no therapy is given”. This statement truly describes:a. Confirmation of diagnosisb. Partial remission of tumorc. Recurrence of tumord. Relapse of tumore. Screening of tumour

c. Recurrence of tumor

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Q.4: A 59 years male is a known patient of chronic liver disease. His recent result of Alpha Fetoprotein (AFP) is 197ng/ml. Now the major challenge for a Chemical Pathologist is to offer another biochemical test to rule out hepatocellular carcinoma in this patient. Many new candidate tumour markers have been suggested to be used alone or in combination with AFP. Which of the following biomarkers has the strongest evidence to be used in such patients?a. Alpha-L-fucosidase activityb. Human carboxylesterase 1c. Lens culinaris agglutinin-reactive AFP d. Transforming growth factor-beta-1e. Tumor-associated isoenzymes of gamma-glutamyl transpeptidase

c. Lens

culinaris

agglutinin-reactive

AFP

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Lens Culinaris Agglutinin-reactive AFP(AFP-L3)

Lens

culinaris

agglutinin-reactive AFP (AFP-L3) is a

fucosylated

fraction of AFP that may be a helpful diagnostic and prognostic maker of

hepatocellular carcinoma (HCC),

particularly in patients with low serum AFP

levels.

The

sensitivity and specificity of

AFP-L3

assay (using a cut-off of ≥5 percent) for HCC were

found to be 42

and 85 percent,

respectively.

In

addition, patients with high AFP-L3 levels using the highly sensitive assay had lower survival rates than patients with AFP-L3 levels of less than 5 percent.

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Alpha-L-Fucosidase Activity

The

lysosomal

hydrolase, alpha-L-

fucosidase

(alpha-L-

fucoside

fucohydrolase

; (AFU), is present in many mammalian tissues including humans where it degrades

fucose

-containing

glycoconjugates

.

Deficiency of AFU results in a rare neurovisceral storage disease known as

fucosidosis

Women with low serum activity of the enzyme may be prone to ovarian carcinoma.

Raised serum concentrations of AFU have been described in patients with a variety of benign diseases, including diabetes, hyperthyroidism and cirrhosis, alcoholic hepatitis and acute viral hepatitis.

Increased AFU activity has been found in patients with carcinoma of the lung, breast, stomach, ovary, uterus and hepatocellular carcinoma

AFU is both less sensitive and less specific than alpha-fetoprotein as a serum marker of hepatocellular carcinoma.

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Human Carboxylesterase 1

Liver

carboxylesterase

1 (CES1, hCE-1 or CES1A1) is an enzyme, also historically known as serine esterase 1 (SES1), monocyte esterase and cholesterol ester hydrolase (CEH)

It is involved in both drug metabolism and activation, as well as other biological processes including

Detoxification of

xenobiotics

Involvement in cholesterol metabolism

Catalyses

the hydrolysis of heroin and cocaine

A

ctivation of many

prodrugs

such as angiotensin-converting enzyme (ACE) inhibitors,

Carboxylesterase

1 deficiency may be associated with non-Hodgkin lymphoma or B-cell lymphocytic leukemia

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Transforming Growth Factor-beta-1

T

ransforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines

It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation and apoptosis

Heterozygous mutations in TGFB1 gene result in a rare-

Camurati

-Engelmann disease type I (CED) with characteristic anomalies in the skeleton. It is a form of dysplasia

Some TGFB1 gene mutations are acquired. The TGFβ-1 overexpression occurs in certain types of prostate cancers, breast, colon, lung, and bladder cancers

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Tumor-associated Isoenzymes Of Gamma-glutamyl Transpeptidase

γ-

glutamyl

transpeptidase

is a membrane-bound enzyme which hydrolyzes

γ-

glutamyl

y-GT

activity is high in

foetal

liver, in hepatocellular carcinoma (HCC) and in the

preneoplastic

lesions which precede these

tumours

, but is low in adult liver tissue

In damaged hepatocytes, particularly in

hepatocarcinogenesis

, GGT is significantly released into the blood from hepatic tissues

However the total activity of GGT has a significant overlap with various liver diseases which limits its value in diagnosis

However sensitivity and specificity of GGT is increased in HCC when combined with AFP

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Q: 5. A 35 years old lady presented with five years history of pelvic mass. On laparotomy it turned out to be of ovarian origin. Histopathology revealed carcinoma ovary. Blood sample was sent for CA 125 level and result was 20 IU/ml. What could be the most likely cause of normal CA 125 level?a. Endometrial carcinoma alongwith carcinoma ovary b. Haemolysed sample c. Mucinous type of carcinoma ovary d. Multi-loculated cysts in ovariese. Photometric method of analysis

c. Mucinous type of carcinoma ovary

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CA 125

Cancer Antigen (CA) 125 is a high molecular weight glycoprotein expressed by epithelial ovarian

t

umors and other pathologic and normal tissues of

mullerian

duct origin

CA 125 is a most promising marker for ovarian cancer

About 80% of non-mucinous epithelial ovarian cancers have raised CA 125 levels, while normal levels are seen in 75% of mucinous tumors like Brenner, sex cord and germ cell tumors

CA 125 is used for monitoring response to therapy, for detecting residual disease following initial therapy and for detection of recurrent metastasis in ovarian cancer.

However it has limitations in early detection of ovarian cancer due to its low sensitivity and low specificity

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Benign conditions with raised CA 125 levels

NON -GYNECOLOGICAL

GYNECOLOGICAL

Liver failure

Chronic active hepatitis

Cirrhosis with ascites

Acute and chronic pancreatitis

Peritonitis

Pleuritis

Pericarditis

Peritoneal dialysis

Pneumonia

Peritoneal sarcoidosis

Meig’s

syndrome

Menstruation

Early pregnancy

Endometriosis

Pelvic inflammatory disease

Uterine fibroids

Adenomyosis

Ovarian cyst

Abruptio

placenta

Salpingitis

Hydatiform

mole

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Malignant conditions with raised CA 125levels

Epithelial ovarian cancer

Endometrial cancer

Endocervical

cancer

Fallopian tube cancer

Gastrointestinal malignancy

Breast cancer

Liver cancer

Lung cancer

Carcinoma of kidney

Lymphoma

Malignant mesotheliomas

Immature

teratoma

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Q. 6: Hyperglycosylated hCG (hCG-H) is a glycoprotein with the same polypeptide structure as hCG with higher molecular weight and much larger N- and O-linked oligosaccharides. It has some important clinical applications. hCG–H is useful in all these conditions EXCEPT:a. Detecting non-seminomatous testicular tumors b. Monitoring placental implantation in pregnancyc. Predicting down syndrome pregnanciesd. Predicting eclampsia during pregnancye. Predicting pregnancy outcome after in-vitro fertilization

a. Detecting non-

seminomatous

testicular tumors

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Hyperglycosylated hCG (hCG-H)

Hyperglycosylated

hCG

(

hCG

-H

) is a

major glycosylation variant of

hCG

which has a different 3dimensional structure, is also produced by

placenta

It is

made by

extravillous

cytotrophoblast

cells of placenta

It

promotes

trophoblast invasion

during

choriocarcinoma

, growth of

cytotrophoblast

cells and placental implantation in

pregnancy

hCG

-H

is the principal form of total

hCG

made

in early pregnancy. In serum it accounts for 90

+/-

11% of total

hCG

in the 3rd complete week of gestation and 54

+/- 7

% of

total

hCG

during the 4th complete week of gestation.

Its level decreases in remaining pregnancy

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Clinical Applications of HCG-H

Gestational trophoblastic diseases are governed and

regulated by

the presence of

hCG

-H

Management

of quiescent

gestational trophoblastic diseases

P

redicting

down syndrome

pregnancies-

Triple test (

hCG

/

hCG

-H, a-fetoprotein

,

unconjugated

estriol

,

inhibin

)

Predicting

hypertensive

disorders

To

differentiate pregnancies that will miscarry and pregnancies that will go to

term

T

o

test for early pregnancy in in-vitro fertilized and

infertility clinic cases

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Q. 7: A new tumour marker is being evaluated in a Chemical Pathology lab for the diagnosis of a tumour. At a serum cut off level of 2.5 ng/ml, the sensitivity and specificity of the tumour marker is 94% and 56%, respectively. Increasing the level to 8.0 ng/ml the sensitivity and specificity become 51% and 93%, respectively. The Chemical Pathologist is in search of a cut-off value with optimum sensitivity and specificity. The most appropriate statistical procedure for this purpose would be:a. Chi-square testb. Kaplan–Meier survival estimatorc. Pearson` correlation coefficient d. Receiver operating curvee. Student`s t test

d. Receiver operating curve

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Q. 8. A 62 year man has Serum PSA level of 6.9 ng/ml. According to the available evidence, the most promising method of PSA testing to avoid unnecessary prostatic biopsy in this patient is:a. Free to total PSA percentage b. PSA assay with age related cut-off valuesc. PSA Densityd. PSA velocitye. Serum isoform [-2]proPSA

e. Serum isoform [-2]

proPSA

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Improving the Accuracy of PSA

Numerous strategies have been proposed to improve the diagnostic performance of PSA when levels are less than 10.0 ng/ml

These strategies include

Measuring PSA velocity

PSA density

Free PSA

Complexed

PSA

Using age- and race-specific reference ranges

Serum

isoform

[-2]

proPSA

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Free to total PSA percentage 

The ratio of free-to-total PSA is reduced in men with prostate cancer

Biopsies should be performed only in men with lower ratios.

An optimal cutoff selected for

biposy

is 25 %

Men with a normal free-to-total PSA ratio still had an 8% probability of having cancer

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PSA density: PSA concentration / prostatic volume  

It is determined by trans-rectal ultrasonography

PSA density measurements better discriminates between cancer and non-cancer groups than PSA levels alone

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PSA velocity

It is the rate of PSA increase as a function of time

A baseline concentration of PSA in each patient is established, the rate of increase of PSA is then calculated

Men with a PSA velocity > 0.75 ng/ml/year are at increased risk of being diagnosed with prostate cancer

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PSA assay with age related cut-off values

 

AGE (in years) CUTOFF

40 to 49 0

to

2.5 ng/ml

50 to 59

0 to 3.5

ng

/ml

60 to 69 0 to 4.5ng/ml

70 to 79 0

to 6.5

ng

/ml

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Serum isoform [-2]proPSA

 It is also known as P2PSA

Is a specific isoform of the PSA

proenzyme

proPSA

Increases the detection of prostate cancer for men with PSA values between 2.0 to 10.0

ng

/ml

Reduces the number of unnecessary biopsies by 7.6 % with sensitivity of 95 % for detecting prostate cancer

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Q. 9: In the last a few decades cancer research has resulted in discovery of many new tumour markers e.g. Osteopontin and human epididymis protein 4 (HE4). Which of the following laboratory techniques is most helpful in the discovery of these tumour markers through their genetic over-expression : a. Chemiluminescenceb. DNA sequencingc. Mass spectrometryd. Microarraye. PCR

d. Microarray

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Q. 10: A 32 y male has a unilateral swelling of his left testis and symptoms of hyperthyroidism. His thyroid profile was as following:• Serum Free T3 4.12 ng/ml (1.60-4.20)• Serum T4 2.18 pg/ml (0.70-1.68)• Serum TSH 0.14 mIU/L (0.30-4.0)His physician has sought your advice regarding the diagnosis of testicular swelling in this patient. The most probable testicular tumour you would like to exclude is: a. Embryonal carcinomab. Granulosa cell tumourc. Leydig cell tumourd. Sertoli cell tumoure. Unclassified tumour

a.

Embryonal

carcinoma

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Hyperthyroidism Associated with Testicular Tumor

Germ

cell tumors are divided

into

seminomatous

or non-

seminomatous

types

Ninety

percent of

non-

seminomatous

tumors express

either

alphafetoprotein

or

hCG

Intact

hCG

consists of two

subunits

. The α subunit is identical to the

α subunit

of the pituitary

gonadotrophins

and thyroid-stimulating

hormone (TSH).

Β

subunit

is unique to

hCG

hCG

can activate

the TSH receptor when present

in excess

and induce thyrotoxicosis.

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Part

II

Short Answer Questions:

Slide38

Q.11:

A

32 years old lady presented in surgical OPD with lump in her left breast for last six months. On examination there was thickness, swelling and redness of skin with nipple retraction and bloody discharge. Later on her mastectomy was done and specimen was sent for histopathology. Her laboratory tests revealed following results:

•

CEA : 52

ng

/ml (< 2.5)

• CA 15-3

: 86 U/ml (30)

• Estrogen receptor (ER) : Negative in breast tissue by IHC*

• Progesterone receptor (PR)

:

Negative in breast tissue by IHC

•

HER2/

neu

: Negative in breast tissue

by IHC

Please answer following questions  

What

is name of breast cancer she is suffering from?

Can

ER, PR and HER2/

neu

be assayed in serum? If yes, please write

name(s

) of assay which can be used for analyses in serum.

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Q.11:

a. What

is name of breast cancer she is suffering from

?

Triple-negative breast

cancer

b. Can

ER, PR and HER2/

neu

be assayed in serum? If yes, please write

name(s

) of assay which can be used for analyses in serum

.

No serum assay is available for ER and PR.

Only Her2/

neu

can be assayed in serum by following technique

Enzyme immunoassay

Chemiluminescent

assay

 

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Q.12:

A 40 years old female has five years history of iron deficiency anaemia and constipation off and on for same duration. She never consulted doctor for these complaints. Later on she developed severe pain in right iliac fossa and was operated upon for Acute Appendicitis. During closing of abdomen surgeon found abnormal small nodular growth on

omentum

. On further exploration likewise growth was found in both ovaries. Tissue was taken and sent for histopathology. IHC was done on tumor tissue which revealed CK7 negative and CK20 positive in tumor cells. Other laboratory tests were also advised. Their results revealed

:

CEA: 25 U/l (less than 2.5)

CA 19.9: 111 U/ml (less than 37)

CA 242: 55 U/ml (less than 20)

Stool for occult blood is

equivocal

Please

answer following questions  

What type of cancer she is having

?

 

Name a single tumor marker emerging as a reliable screening test for 

this tumor

. What is the most suitable sample for its detection? Comment in not more than one line about its sensitivity and specificity in this cancer.

Slide41

Q.12:

What

type of cancer she is having

?

 

Colorectal adenocarcinoma with ovarian metastasis

b. Name

a single tumor marker emerging as a reliable screening test for 

this tumor

. What is the most suitable sample for its detection? Comment in not more than one line about its sensitivity and specificity in this cancer

.

(1) Increased

stool (fecal) levels of Tumor

M2-Pyruvate Kinase (TM2-PK) an excellent

method of screening for colorectal tumors.

Sample required for its detection is

stool.

It is a tumor marker with high sensitivity and high specificity with no false negative, but false positive may be occurring. When measured in feces with a cutoff value of 4 U/ml, its sensitivity has been estimated to be 85% for colon cancer and 56% for rectal cancer. Its specificity is 95%.

(2) Fecal

DNA testing for which stool sample (collection of one entire bowel movement) is required.

Its

sensitivity for detection of adenocarcinoma is 72-77% and Specificity is 95.2%.

Slide42

Q.13:

A 39 years old lady reported to a private

Gynae

clinic with full term pregnancy. She gave birth to a baby boy through normal vaginal, but obstructed delivery. After about one month same lady ended up in the emergency in critical condition with abdominal pain, vaginal bleeding, cough, difficulty in breathing and fits.

Please

answer following questions

a

. What is most likely diagnosis

?

b. Name TWO biochemical tests which can be helpful to confirm the diagnosis. Write in not more than TWO lines importance and interpretation of the test

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Q.13:

a. What

is most likely diagnosis

?

Choriocarcinoma

or gestational trophoblastic neoplasm

b. Name TWO biochemical tests which can be helpful to confirm the diagnosis. Write in not more than TWO lines importance and interpretation of the test

1. Serum

β-

hCG

level – it becomes normal within 2-4

weeks

after a normal delivery. So persistent elevation

after

a

nonmolar

pregnancy is indicative of GTD.

2. Serum

Hyperglycosylated

hCG

(

hCG

-H)- it is a very

sensitive

marker to differentiate active from quiescent

GTD

. If

hCG

-H is >40% of total

hCG

or > 3000 IU/L, it is indicative of active GTD and interventions such

as hysterectomy

or chemotherapy should be done

3. CSF (cerebrospinal fluid) to serum

hGC

ratio: Normal

CSF (cerebrospinal fluid) to serum

hGC

ratio is 1:60, levels greater than 1:60 indicate cerebral

metastases

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Q.14:

Currently

a number of tumor markers are available for ovarian cancer. CA125 is the only marker that can be recommended for use. New ovarian cancer markers offer promise, however, their contribution to the current standard of care is unknown and further clinical trials are needed. CA 125 lacks sensitivity and specificity particularly in early diagnosis of ovarian cancer. Many strategies have been proposed to improve the diagnostic accuracy of CA 125 for ovarian cancer, though there is no consensus about acceptance of these modifications.

Please

answer following questions (One mark each):

a

. Name FOUR strategies proposed for improvement of diagnostic performance of CA 125.

b. Write brief description of THREE of these strategies (not more than 3-4 lines for each).

Slide45

Q.14:

a

. Name FOUR strategies proposed for improvement of diagnostic performance of CA 125.

Risk

of malignancy index (RMI)

Risk of ovarian malignancy algorithm. (ROMA)

OVA1 test

OVASure

test

b

. Write brief description of THREE of these strategies

(Please see next a few slides).

Slide46

Risk of malignancy index (RMI)

RMI

combines

three pre-surgical features: serum CA125 (CA125), menopausal status (M) and ultrasound score (U). The RMI is a product of the ultrasound scan score, the menopausal status and the serum CA125 level (IU/ml).

RMI = U x M x CA125

The

ultrasound result is scored 1 point for each of the following characteristics:

multilocular

cysts, solid areas, metastases, ascites and bilateral lesions. U = 0 (for an ultrasound score of 0), U = 1 (for an ultrasound score of 1), U = 3 (for an ultrasound score of 2–5).

The

menopausal status is scored as 1 = pre-menopausal and 3 = post-menopausal

The

classification of 'post-menopausal' is a woman who has had no period for more than 1 year or a woman over 50 who has had a hysterectomy.

Serum

CA125 is measured in IU/ml and can vary between 0 and hundreds or even thousands of units.

Slide47

Risk of ovarian malignancy algorithm. (ROMA)

Risk

of ovarian malignancy algorithm is a qualitative serum test that combines results of HE4, CA 125 and menopausal status into a numerical score

ROMA

is intended to aid in assessing whether a premenopausal or postmenopausal woman who presents with an ovarian adnexal mass is at high or low likelihood of finding malignancy on surgery.

ROMA

must be interpreted in conjunction with an independent clinical and radiological assessment. The test is not intended as a screening or stand-alone diagnostic assay.

ROMA

(HE4 + CA125) should not be used without an independent clinical/radiological evaluation

ROMA

is determined using the following equation:

ROMA

(%) =

exp

(PI)/[1 –

exp

(PI)]*100.

13.1% and 27.7% as the cutoff points for pre- and postmenopausal patients,

respectively, and predictive

index =

(

PI)

Slide48

OVA1 Test

OVA1

test is a qualitative serum test that

combines the

result of

five immunoassays

into a single

numeric score

. Five markers are; CA 125

,

Prealbumin

(

transthyretin

),

apolipoprotein

A1, transferrin

and

beta 2

microglobulin

Its a

proprietary

algorithm (i.e

.,

OvaCalc

) to determine the likelihood

of malignancy in women with pelvic mass for whom surgery is planned

It is indicated for women who meet the following

criteria i.e.

age over 18, ovarian adnexal mass present for which

surgery is

planned, and not yet referred to an oncologist.

OVA1

score has values between 0 and 10.

Slide49

Q.15:

Cancer

is caused by the accumulation of genetic and epigenetic mutations that normally play a role in the regulation of cell proliferation, thus leading to uncontrolled cell growth. Depending on how they affect each process, these genes can be grouped into two general categories: tumor suppressor genes (growth inhibitory) and proto-oncogenes (

growth promoting).

Mutant alleles of proto-oncogenes are called oncogenes.

Below

is a list of different body tumors. You are required to write ONE oncogene and ONE tumor suppressor gene associated with each tumor

:

a

. Colorectal cancer:

b

. Renal cancer

c

. Medullary thyroid carcinoma

d

. Lung cancer:

Slide50

Q.15: a. Colorectal cancer:

K-

ras

mutation

APC

mutation

 

The protein product of the normal KRAS gene is a

GTPase

and is an early player in many signal transduction pathways necessary for the propagation of growth

 

Adenomatous

polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the APC gene.

The APC protein is a negative regulator that controls Beta-catenin concentrations and interacts with E-cadherin, which are involved in normal cell adhesion

Slide51

Q.15: b. Renal cancer

VHL mutation

WTI

mutation

The VHL gene provides instructions for making a protein that functions as part of a complex (a group of proteins that work together) called the VCB-CUL2 complex. One of the targets of the VCB-CUL2 complex is a protein called hypoxia-inducible factor 2-alpha (HIF-2α). HIF-2α is one part (subunit) of a larger protein complex called HIF. HIF controls several genes involved in cell division, the formation of new blood vessels, and the production of red blood cells. It is the major regulator of a hormone called erythropoietin, which controls red blood cell production.

The WTI gene encodes a transcription factor that contains four zinc finger motifs at the C-terminus and a

proline

/ glutamine-rich DNA-binding domain at the N-terminus. It has an essential role in the normal development of the urogenital system

Slide52

Q.15: c. Medullary thyroid carcinoma

RET mutation

Sprouty

1

RET

is an abbreviation for "rearranged during transfection." The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived

neurotrophic

factor (GDNF) family of extracellular

signalling

molecules.

Sprouty

1 (SPRY1) functions as a regulator of fundamental signaling pathways. It is a key regulator of proper organ and tissue development.

Slide53

Q.15: d. Lung cancer:

MAX mutation

LHX6 LIM

homeobox

6 mutation

Protein

max also known as

myc

-associated factor X is a protein

that in humans is encoded by the MAX gene.

yc

is an

oncoprotein

implicated in cell proliferation, differentiation and apoptosis.

 

LIM/

homeobox

protein Lhx6 is a protein that in humans is encoded by the LHX6 gene. This gene encodes a member of a large protein family that contains the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein may function as a transcriptional regulator and

Slide54

Thank You and Best Of Luck