growth promoting protooncogenes

Things invovled in cell to divide: Growth factors eg, Epidermal derived growth factor.

Protoncogenes: these are cancer genes. But normally, when not activated, they are actually serving normal function in the normal growth process. Thats why called as protoncogenes. When they become oncogenes it means that they are bad, they are cancer producing genes.

So we have certain protoncogenes that are "Co-"??? to growth factors, eg Sis-protoncogenes whose only function is to make growth factors. All factors have to hook into receptors just like all hormones have to hook into receptors like insulin hooks in to tyrosine kinase receptor on adipose in muscle.

We have certain protoncogenes whose main job is to make receptors.

Erb-2 protoncogene, a classic one from breast cancer who calls for receptors; Ret-protocogene, of MENI and MenII.

Therefore protoncogenes are involved in receptors not the growth hormones, thats their speciality. We have to send the message to the nucleus.

We have another whole set of protoncogenes whose job is to send the message like telegraph system.

Some of them are located in the cell membrane ---> Ras protoncogenes, its messanger is GTP, who sends a phosphorylated protein message. So its a cell membrane located messanger system.

Abl-protoncogene: Lives in the cytosol very close to the membrane also involved in messages as well.

So we have to have some messanger system. The message is sent to group of protoncogenes located in the nucleus. Once that message is sent to them, then they stimulate nuclear transcription of that message, in other words cell divides and makes what ever it is suppose to make.

The classic protoncogenes are Myc-protoncogene. We have N-Myc (for neuroblastoma ) and C-Myc (for burkitts lymphoma n L-myc for Small cell carcinoma of lungs ).

The protoncogenes are involved in the normal cell process, make receptors for growth factors ---> those that send messages, lots of those messages are phosphorylated proteins like tyrosine kinase which is often attached to the receptors. Eg, Insulin hooks in to receptors on adipose, it activates tyrosine kinase, right there forms phosphorylated product which goes into the nucleus, to divide and goes to the Golgi appratus ---> Glut4 (glucose transport unit like...guards) ---> Glut4 goes into the cell membrane of adipose and add receptors for glucose.

So the message goes to the nuclear transcribers (myc-oncogenes) in the nucleus

Added from robbins: about 5 types n total 16 subtypes

i) Growth factors: sis, TGF-alpha(transforming), HGF(hepatocyte), HST1-INT2

ii) GF Receptors: ERB B1&B2, FMS, RET, PDGF-R, KIT

iii) Signal transduction proteins: RAS, ABL, BRAF, beta-catenin

iv) Nuclear regulatory proteins: MYC

v) Cell cycle regulators: cyclins D, E and CDK4

2. growth inhibiting tumor suppressor genes

3. apoptotic genes

4. DNA repair genes

.

Whose controlling these dudes? Ans - the suppressor genes (Rb and P53) ---> keeping the cell cycle in G1 phase, so that everything can be cleaned up a little bit before it goes into S-Phase and gets initiated.

Point mutations: like trinucleotides, that could be substituting adenine for thymine.

The 2 most important genes involved in cancers are both involved in point mutation ---> P53 suppressor genes and Ras-Oncogenes are point mutations.

All suppressor genes are point mutations.

Amplifications: its kind of like PCR-reaction which makes multiple copies of something. The Erb-2 in breast cancer is the amplification type of system.

Translocation: Take something and put it in some other place. In translocation things translocated cannot go back.

Classic translocation:
CML: Tranlocation of the Abl (9;22), it has non-receptor tyrosine kinase activity. Abl gene translocated from chromosome 9 to 22 and where it fuses with the great cluster region forms its fusion gene (philadelphia chromosome), and all of a sudden because of its tyrosine activity ---> it sends a message and those stem cells just keeps on dividing.

Neoplasia

Post 32: (Dated: Feb 21 - 2009)

EBV: Cancer ---> translocation of Myc nuclear transcriber gene from chromosome 8 and it sticks around the chromosome 14 ---> Burkitts lymphoma(8;14); There is a receptor for EBV in all of our B-Cells (CD 21) ---> when it hooks into CD 21 ---> B-Cells becomes plasma cells and make antibodies; Because of the fact that it stimulates the B-Cells to become plasma cells,lots of divisions occurs ---> the more cells divides ---> more something can happen to it.

t(14:18): B-Cell lymphoma involving the inactivation of suppressor gene.
t(15:17): Acute progranulocytic leukemia ---> Rx Retinoic acid (Vit A) ---> Matures the blasts, so the malignant cells becomes benign.

Suppressor Gene: Use to suppress; We knock them off ---> what ever they were suppressing keeps on going.

Familial Adenomatosis polyposis coli:
Suppressor gene - Neurofibramatosis & Wilms tumor - suppressor gene ---> BRCA-1 (Ch. 13) & BRCA2 (Ch. 17)---> DNA repair.

BRCA-2 totally associated with breast cancer.
BRCA-1 can be breast cancer or ovarian cancer.

Only 15% have genetic relationship and most of the time they are not genetic.

Suppressor genes and protoncogenes are inhibited by: Chemical, viruses and radiations. The most common is chemicals (80%)---> smoking ---> polycyclic hydrocarbons are the carcinogens of smoke ---> not just lungs cancer also of mouth, larynx, pancreas, bladder, cervical, colon, leukemias.

Pappilary tumor in bladder: most common cause of transitional cancers is smoking. In dye industry it would be Amylin.

Qs: If you have Wegeners granulamatosis, you are put on a drug and ended up with hematuria; you did a cytology which showed some abnormal cells. Which drug ---> Ans - Cyclophosphamide.

Cyclophosphamide: Causes hemorrhagic cystitis ---> Rx Mesna; Carcinogen for transitional cell carcinoma.

Lungs: Cancers that are most often associated with smoking are squamous and small cell.

Non-pruritic raised red lession ---> kaposi's sarcoma (HPV-8)

Burkitt's lymphoma ---> EBV

Nasopharyngeal carcinoma ---> EBV (commonly in Chinese)

Hepatocellular carcinoma ---> HBV (Asians); Combination of HBV + Cirrhosis + Aflatoxin B (in food) ---> Most common cancer in far-east; HCV can also produce liver cancers.

Primary senile Lymphoma ---> HIV; Qs - rapidly increasing incidence of prim. CNS lymphoma in USA. are directly attributable to? Ans - HIV.

Sq. Cancers ---> HPV (cervix, Vagina, vulva, Anus in homosexuals, unprotected intercourse); E6, E7 protein products ---> E6 knocks off the P53, and E7 knocks of Retinoblastoma.

Most common cancer associated with Radiations is Leukemia; Most common leukemia associated with radiation is Chronic Myelogenous Leukemia ---> t(9;22) of Abl-protoncogene.

Qs: History of radiation in the head and neck area, they have non-tender nodular mass in the cervical region - Ans, Metastatic Papillary carcinoma of thyroid related to ionizing radiation; Another one is Osteogenic sarcoma.

Qs: Which medical proffesion is most likely to get Acute leukemia - Ans, Radiologist.

Qs:???? Disease with radiation, what would you be? Ans- Neuropathologists as they are dealing with brains and the prions.

Basal cell carcinoma:??? Multifocal; Non ionizing radiation (ionizing is the bad stuff of radiation); UV-B light (B = Bad).

UV-A: Superficial dermatophytes, shagreen patches in tuberous sclerosis ---> Rx Black Light (UV-A).

UV-B: Protects from skin cancers like Basal cell Ca. most common, Sq cell Ca 2nd most common, malignant melonoma; by mechanism of Thymine dimers.

Precursor lession for certain cancers that are commonly seen in sun exposed area, which you can scrape it off and it comes black ---> Actinic keratosis (solar keratosis) ---> predisposes to Sq. cancer ---> Pearly grayish white and looks like somebody just scraped it off.

Actinic keratosis: Only 3-4% of Actinic keratosis becomes squamous cancers; which Heavy metal predispose it? - Arsenic; Country - Bangladesh (probably water supply which is contaiminated with Arsenic related cancers are increasing).

Arsenic related cancers: Skin cancers, lung cancers, and angiosarcoma of the liver.

Kid with white eye reflex ---> retinoblastoma, chromosome 13.

Qs - How many mutations that it takes for sporadic to become retinoblastoma? Ans; 2 separate ones ---> You have to knock one from One chromosome 13 and from another one.

Qs - How many mutations in autosomal dominant genetic inheritance? Ans- 1; You are born with one already and activated, so you need one more mutation on the other chromosome only.

White eye reflex is most commonly caused by congenital cataracts (congenital infections like CMV or Rubella etc.) ---> shinning a light on newborn eye ---> its white ---> retinoblastoma.

Qs - Why would a patient with Cushings have cataracts? Ans- Corticosteroids.

Neoplasia

Post 33: (Dated: Feb 23 - 2009)

The sun exposed area would be predisposed to all the skin cancers (basal cells, Sq Cells and melanomas).

Xeroderma pigmentosa: Autosomal recessive disease. Defect in the DNA repair enzymes.

Group of diseases which are also DNA repair enzyme defects ---> BRCA1, BRCA2, P-53.

Chromosomal Instabillity syndrome: wiskott aldrich syndrome, bloom syndrome, Ataxia telangiectasia, fanconi's syndrome ---> All of them have problems with DNA repair.

Upper Lip: Basal cell.
Lower Lip: Sq cell.

Sq Cell Ca: keloids after burns, develops in the draining sinus, also does't heals with antibiotics, constant irritation in the division of cells ---> greater risk of cancer because you are dealing with squamous epithelium not glandular epithelium

Lungs: Scar-cancers related to Old TB scar are adenocarcinoma not squamous (related mostly to skin)

Only bacteria associated with the cancer ---> H.Pylori ---> Adenocarcinoma and Low Grade Malignant lymphoma.

Grade of the cancer ---> whats it looks like.

If you can identify what it is because it is doing something like making keratin, glands and is well differentiated ---> Low Grade.

Its anplastic and high grade, not well differenciated ---> you cant tell by looking at it Under Microscope what it is.

Slide: Sq cancer ---> Keratin pearls (you can identify it ---> low grade)

Slide: Gland like spaces ---> Adenocarcinoma ---> (you can identify it ---> low grade)

Stages of tumor:

T - Toy ---> Size of the Tumor (<2 sonometers it generally has the chance to metastasize)
N - Nancy ---> Nodes
M - Machine ---> Metastasis outside the nodes.

Most common staging system which goes from least important to most important.

Scenario: Breast Cancer ---> Low axillary nodes are involved ---> You think that its the worst part but instead it the end part of TNM ---> Worst part when it is out side the lymph nodes likes bones, lungs, or liver.

In staging the most imortant thing is Metastasis.

Qs: Which is the worst prognosis in prostate cancer?
a Limited to prostate
b Went into seminal vesicles
c Went into wall of the bladder
d went into lymph nodes
e went into the bones (Correct)

Slide: Colon Cancer ---> Lymph nodes. Which one is important size of the tumor or lymph node involvement? Ans- Lymph nodes; Simillar focus of cancer in the liver ---> then liver is the most important prognostic factor.

Host Defences: The most important is Cytotoxic CD8-T cells (No 1 most imp. host defence sys. wehave got); We have other things ---> Macrophages, NK cells, Antibodies (Type2 HSN).

Cyt-CD8 T cells: They rounds every day looking for altered class I antigens ---> when ever neoplastic cells those class 1 antigens ---> Cyt CD8 T cells they get interested in that cell to kill that cell ---> put perforin which is the signal to Caspases (proteases ---> start breaking down the nucleus, screwing up the mitochondria) to start apoptosis.

Cachaxia: Cause is TNF ---> irreversible. Once you see the pt with dessiminated cancer just begining to go into the catabolic state, you can get them total parenteral nutrition ---> they will not get their muscle mass due to TNF-alpha.

Hematologic causes of anemia are present in malignancy. Most common anemia in malignancy is the anemia of chronic disease.

Colon cancer: Left side obstructs and the right side bleed ---> if you have the right sided colon cancer ---> then iron defeciency will be more common; Metastasis to bones and replaced all the bone marrow ---> anemia.

Chemotherapy drugs that are cell cycle specific or non specific ---> you wipe out the marrow.

Autoimmune mechanisms with certain types of cancers; But overall is the anemia of chronic disease.

Most patients that have the dessiminated cancers are hypercoagulable (tendency of forming clots)

Qs: Pt that has the painless jaundice, left supraclavicular nodes, light colored stools, he has this peculiar lession in the vein which jumps from one part of the body to the next? Ans- trousseau sign, superficial migratory thrombophelibits of the patient with carcinoma of the head of the pancrease.

Pancreatic cancers also likes to go to left supraclavicular nodes.

Dessiminated cancers - Thrombocytosis: An elevated platelet count.

Labs: We need to work up the cause of thrombocytosis ---> hematology slip; Iron defeciency, scar over here (left abd ---> spleenectomy), if TB; No obvious cause of thrombocytosis that rule out the Myeloproliferative dissease or stuff like that.

40% of all dessiminated cancers have thrombocytosis.

Most of the time Colon cancer is missed due to presence of black stool.

Fever: Most common cause of fever in malignancy is gram (-) infection. Usually gram (-) is hospital acquired.

E.COli - Indwelling catheter
Pseudomonas Aeruginosa - Respirator
Staph Aureus (gram +) - Indwelling catheter in vein.

Most common cause of death in cancer is infections.

Paraneoplatic syndromes: These are the signs which shows that there may be some underlying cancer. They are kind of clues, tells that something going on in the patient, so you can actually find that cancer before it get metastasized.

Most common Paraneoplastic syndrome is hypercalcemia.

Qs:There are 2 mechanisms behind hepercalcemia in malignancy.

1) It has metastasized to bones ---> produce some kind of chemical like IL1, PGE2 that activates osteoclasts ---> produces lytic lessions in bones ---> Hypercalcemia.

2) It can be secretory tumours like a renal adenocarcinoma or sq. carcinoma of main bronchus which makes paratharmone like peptide and cause hypercalcemia.

Which one is the paraneoplastic? Ans- 2nd one.

Slide: Two lessions that are black here. Both of these are phenotypic markers for same cancer, the gastric adenocarcinoma. The black lession under the arm is acanthosis nigricans; This is called as seborrheic keratosis (beningn). If they develope all of a sudden, called Lesser-Trélat sign, you get multiple outcropping of these things ---> phenotypic marker of gastric adenocarcinoma.

Acanthosis Nigricans: Also associated with other things like Insulin receptor defeciency related to DM, also with MEN syndromes. So its phenotypic marker for lots of things but most commonly adenocarcinoma.

Clubbing: Hypertrophic osteoarthritis ---> Inflammation underlying bone, thats stimulates increase in soft tissues developement producing clubbing; Clubbing also associated with bronchiectasis, inflamatory bowl disease, but in case of malignancy it would be mostly associated with primary lung cancer.

Dermatomyositis: Least common collagen vascular disease which is most commonly associated with underlying cancer, and with elevation of serum CK, raccoon eyes (heliotrope eyes ), inflammation of skin and muscles. High association with Leukemias, lung cancers, lymphomas etc, and Goltran’s patches over the knuckles.

Marantic endocarditis: sterile Vegetations on mitral valves, sterile which are associated with mucous producing cancers like colon cancer. Its a paraneoplastic syndrome, not infected, can embolize (pretty big and can chip off); Looks similar to Rheumatic fever, looks like right along the margins of the valve, except the history tells that its related to colon cancer then rheumatic fever.

In infective-endocarditis: Huge vegetations.

Libman sack endocarditis: Vegetations are all over the place.

Qs: Hyponatremia or cushings?; Lung; cancer - Small cell carcinoma; Harmones - ADH and ACTH.

Small cell cancers are APUD tumors, S100 antigen positive, neuralcrest origin and neurosecretory granules on EM.

Qs: Hypercalcemia or Secondary polycythemia?;

Renal adenocarcinoma, can make paratharmone like peptide and they can also make erythropoietin (EPO).

Qs: Hypoglycemia or Secondary polycythemia?;

Hepatocellular carcinoma, can make EPO producing polycythemia, can produce insulin like factor producing hypoglycemia.

Qs: Hypocalcemia or cushings;

Autosomal dominant, rare tumors where the tumor markers can be

converted to amyloid?; Medulary carcinoma of thyroid; Tumor marker = Calcitonin.

2 tumor markers always get incase of Testicular cancer: AFP and HCG.

AFP: A marker for yolk sac tumor (endodermal sinus tumor). AFP Sounds young, its the albumin of fetus. So tumors in kids like the ovaries in girl are most commonly yold sac tumors. Also associated with hepatocellular carcinoma, increased In open neural tube defects (have to be on folate before pregnancy to prevent neural tube defects), and decreased in down syndrome.

BJ proteins: Marker for a malignancy of bone that is associated with mono-clonal spike ---> MM.

BJ protein is the light chain of I-Globulin.

PSA: tumor marker for Prostate cancer. It can be increased in hyperplasia. It is sensitive but not specific.

Neoplasia

Post 34: (Dated: Feb 25 - 2009)

PSA: Its not increased during DRE ---> its not an enzyme, but an antigen and actually with in the cell and cannot increase anyways.

Breast Cancer: CA 15-3
Ovarian Cancer: Surface derived CA-125
Colon Cancer : carcinoembryonic antigen (CEA) ---> also in small cell and breast; CEA can be part of immune complex ---> CEA - Anti-CEA-complex, immune complex which is depostited in kidney and can produce nephrotic syndrome ( diffuse membranous glomerulonephritis ).

Over all good percentage of nephrotic syndrome in adults is diffuse membranous glomerulonephritis, and most of them are related to malignancy. One of the common malignancy is colon cancer because CEA could be antigen part of immune complex and end up depositing into glomeruli.

Women with a trophoblastic tumor or mole: Tumor marker - Beta HCG.

Most common Primary tumor of the brain in kids: Cerebellar cystic astrocytoma (benign) of astrocytes;

Most common primary cancer in kids: medulloblastoma,

Most common childhood cancer: Leukemia (specifically Acute Lymphoblastic Leukemia ); 2nd group is CNS tumors; after that neuroblastomas, very common in renal medulla; Burkitts lymphoma also B-Cells; Ewings sarcoma, tumor of the bone with "Onion skin" type of calcification; Embroyonal rhabdomyosarcoma.

Incidence of cancers in man and women:

Womens:
No 1 Cancer: Breast
No 2 Cancer: Lungs

No 3 Cancer: Colon

Man:
No 1 Cancer: Prostate
No 2 Cancer: Lungs

No 3 Cancer: Colon

???

2nd most Common cancer and cancer killer in man and women combined: Colon cancer.

After Age 50 onwards: Should have rectal exam and stool black, men get a flexible sig, endo, or colonoscopy, depending on the risk.

After 50 the most common cause of stool black is colon cancer.

Gyn Cancer: Most common is endometrial; 2nd Ovarian; 3rd Cervix, because of pap-smear.

Why is that’s incidence of cervix cancer decreased due to pap smear?? Shouldn’t it increase??

Cervical Papsmear: If you pick up the sq. cell dysplasia which is not the cancer ---> you treat the patient.

Initially mammography the incidence of breast cancer increase.

Same thing with prostate cancer and PSA, they got leveled off. Which means we need more sensitive techniques to pick them up.

Gyn Cancer killers:
1 - Ovarian
2 - Cervical
3 - Endometrial

The most common has the best prognosis: Endometrial.

Only known existing tumor vaccine: Hepatitis-B

Most common infection in hospital by accidental needle stick: Hepatitis-B ---> the viral burden of Hep-B is more then any infection.

Once you got vaccinated you will not get: Hepatitis-B, Hepatitis-D because it need surface antigen, and also HCC related to Hepatitis-B related cirrhosis.

You can irridicate HCC which is most common cancer in far east by simple vaccination.

A 25-year-old man presents with a chief complaint of persistent,high-pitched ringing noises in his ears. Questioning reveals that he has also been losing his balance lately. CT of the head demonstrates bilateral tumors involving the vestibulocochlear nerve. Which of the following chromosomes contains the tumor suppressor gene most likely to be involved in this case?

A. 5q

B. 13q

C. 17q

D. 18q

E. 22q

Answer

17>The correct answer is E. The patient has bilateral acoustic neuromas, probably due to neurofibromatosis type II (over 90% of patients with NF-2 develop bilateral acoustic neuromas). This condition is a associated with the NF-2, gene, located on 22q (note all the 2's). Patients often develop meningiomas, gliomas, and schwannomas of cranial and spinal nerves.

5q (choice A) contains the APC tumor suppressor gene, which is associated with familial and sporadic colorectal cancers.

13q (choice B) contains the Rb tumor suppressor gene, which is associated with retinoblastoma and osteosarcoma.

17q (choice C) contains both the NF-1 tumor suppressor gene, which is associated with neurofibromatosis type I, and the p53 tumor suppressor gene, associated with many human cancers.

18q (choice D) contains both the DCC gene, which is associated with colon and gastric carcinomas and the DPC gene, associated with pancreatic cancer.
----------End Neoplasia -----------

Added from robbins:

Some protooncogene info

❶ RET

it encodes protein which serves as TYROSINE KINASE RECEPTOR for glial cell derived neurotrophic factors(promoting cell survival during neural development).

Ret is normally present in neuroendocrine cells eq. parafollicular C cells of thyroid, adrenal medulla, parathyroid cell precursors..

POINT MUTATION in RET leads to 1. MEN 2A,2B

2. familial medullary thyroid carcinoma

MEN 2A(mutation causes constant dimerization n activation of Rc): ---> tumors of thyroid, parathyroid n adrenal medulla

MEN 2B(mutation alters substrate specificity for tyrosine kianse): ---> thyroid and adrenal tumors but NO PARATHYROID TUMOR

COMPLETE LOSS OF FUCTION OF RET: ---> causes lack of development of intestinal nerve plexuses(MEISSNER SUBMUCOSAL N AUERBACH’S MYENTRIC PLEXUS) leading to HIRSCHSPRUNG DISEASE(congenital aganglionic megacolon)(char. STERCHORAL ulcers seen in proximal dilated intestinal mucosa, delay in the initial passage of meconium, which is followed by vomiting in 48 to 72 hours)

---> sometimes hirschsprung’s disease is also due to mutation in ENDOTHELIN 3 OR ENDOTHELIN Rc!!

❷

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