They won the Noble Prize in 1989 for proving that viruses contain a cancercausing gene derived from

the genome of the organism they infect. Specifically, they showed that chicken Rous Sarcoma Virus (RSV) carried an oncogene called vsrc and this gene was an intronless version of a normal chicken gene called c-src.

Cellular functions related to growth and proliferation. The proteins encoded by them function as
Growth factor/ receptor Signal transducers Transcription factors Cell cycle component

Mutation converts them into constitutively active oncogene/oncoprotein.

Myc gene

Ras gene

Myc-IgH Fusion

Bcr-Abl Fusion

Oncogene causes cancer by affecting:

1. Cell Proliferation: (example; Ras, Raf, EGF) 2. Cell differentiation (example, PML/RAR that inhibits the differentiation of promyelocyte to granulocyte which will maintain the cell in its active proliferate state) 3. Cell Survival (example; Pl-3/AKT which will activate BCL-2 inhibit Apoptosis & Maintain cell survival.)

1. 2. 3. 4.

Growth Factor (example, Epithelium growth factor EGF , and platelet derived growth factor PDGF) Growth Factor Receptor (Example; PDGFR) Signal transudation (example; Ras, Raf, & MEK) Transcription Factor (example; Jun, Fos, Elk-1 & myc)

Growth factor e.g. SIS oncogene (PDGF)- low-grade astrocytomas and osteosarcomas

Growth factor receptor

RET is a receptor for GCDNF mutation causes MEN 2A

and 2B FLT3 AML PDGFR in CMML ERB B1- 80% of squamous cell carcinomas of the lung, in 50% or more of high-grade astrocytomas called glioblastomas, in 80% to100% of head and neck tumors, and less commonly, in carcinomas of the urinary bladder and the gastrointestinal tract. the ERB B2 gene ( HER 2/Neu) is amplified in approximately 25% of breast cancers and in human adenocarcinomas arising within the ovary, lung, stomach, and salivary glands. a mutation in c-KIT, (also known as steel factor) in GIST

G proteins (signal transduction) - RAS Point mutation of RAS family genes is the single most common abnormality of dominant oncogenes in human tumors reduce the GTPase activity of the RAS proteins. The mutations generally involve codons 12, 59, or 61 of HRAS, KRAS, and NRAS. Colon and pancreatic tumors - KRAS, bladder tumors have HRAS mutations, and hematopoietic tumors - NRAS mutations. RAS is also involved in regulation of the cell cycle RAS proteins can indirectly regulate the levels of cyclins by activating the MAP kinase pathway and the AP-1 transcription factor.

RAF and MAP Kinase are also involved in oncogenesis. BRAF, a member of RAF - 60% of melanomas and in more than 80% of benign nevi

CHROMOSOMAL TRANSLOCATION/ REARRANGEMENT

POINT MUTATION OF NEGATIVE REGULATORY DOMAIN

C-ABL TK

JAK 2

BCR-ABL IN CML

STAT IN PCV/ET/PMF

Nuclear transcription factors implicated as oncogenes e.g. MYC,MYB,JUN,FOS and REL. MYC
transcription factor that can act in concert to reprogram somatic cell into pleuripotent cell. C-MYC in burkitts, some cases of breast, colon and lung ca N-MYC Neuroblastoma L-MYC-Small cell ca of lung

Cyclins
Cyclin D in mantle cell lymphoma t(11;14). Cyclin E in BRCA 1 mutated breast ca

CDK
Amplification CDK4 gene melanoma,

sarcoma and GBM

Tumor suppressor genes apply brakes to cell proliferation. These gene helps in regulating the cell growth and differentiation at various stages of cell cycle.

Two main cell cycle checkpoints - G1/S transition and G2/M transition. To function properly, cell cycle checkpoints require sensors of DNA damage, signal transducers, and effector molecules.

The sensors and transducers of DNA damage seem to be similar

for the G1/S and G2/M checkpoints. They include, as sensors, proteins of the RAD family and ataxia telangiectasia mutated (ATM) and as transducers, the CHK kinase families. In the G1/S checkpoint, cell cycle arrest is mostly mediated through p53, which induces the cell cycle inhibitor p21. Arrest of the cell cycle by the G2/M checkpoint involves both p53-dependent and p53-independent mechanisms. Defects in cell cycle checkpoint components are a major cause of genetic instability in cancer cells.

CIP/KIP family: p21, p27 (CDKN2A-C)

Block the cell cycle by binding to cyclin-CDK complexes; p21 is induced by the tumor suppressor p53; p27 responds to growth suppressors such as TGF.

INK4/ARF family (CDKN1A-D)

p16/INK4a binds to cyclin DCDK4 and promotes the inhibitory effects of RB; p14/ARF increases p53 levels by inhibiting MDM2 activity Mutations causes pancreatic ca, familial melanoma and sq cc of esophagus.

The genes normal function is to regulate cell division. Both alleles need to be mutated or removed in order to lose the gene activity. The first mutation may be inherited or somatic. The second mutation will often be a gross event leading to loss of heterozygosity in the surrounding area.

RB, the first, and prototypic, tumor suppressor gene discovered. Approximately 60% of retinoblastomas are sporadic, and the remaining are familial, with the predisposition to develop the tumor being transmitted as an autosomal dominant trait. Patients with familial retinoblastoma are also at greatly increased risk of developing osteosarcoma and other soft-tissue sarcomas.

A child carrying an inherited mutant RB allele in all somatic cells is perfectly normal (except for the increased risk of developing cancer). Heterozygosity for the RB gene does not affect cell behavior and cancer develops when the cell becomes homozygous for the mutant allele,a condition known as LOH, for loss of heterozygosity). Similarly,one or more genes on the short arm of chromosome 11 play a role in the formation of Wilms' tumor, hepatoblastoma, and rhabdomyosarcoma. The von Hippel-Lindau (VHL) gene is a tumor suppressor gene that causes familial clear cell renal carcinomas and is also involved in sporadic forms of the same tumor. Consistent and nonrandom LOH has provided important clues to the location of several tumor suppressor genes.

The p53 gene

is located on chromosome 17p13.1 . is the most common target for genetic alteration in

human tumors. critical gatekeeper against the formation of cancer/Molecular policeman. center of a large network of signals that sense cellular stress, such as DNA damage, shortened telomeres, and hypoxia inheritance of one mutant allele LiFraumeni syndrome, have a 25-fold greater chance of developing a malignant tumor by age 50 than the general population. 80% of point mutations present in human cancers DNA-binding domain of the protein

p53 thwarts neoplastic transformation by three interlocking mechanisms: activation of temporary cell cycle arrest (quiescence), induction of permanent cell cycle arrest (senescence), triggering of programmed cell death (apoptosis).

Chk1 and Chk2 kinases are serine/threonine kinases that are activated by the ATM and ATR kinases in response to DNA damage.

Ashwell S , Zabludoff S Clin Cancer Res 2008;14:4032-4037

p53 links cell damage with DNA repair, cell cycle arrest, and apoptosis. Hence it is considered guardian of genome. The new members of p53 family are p63 -differentiation of stratified squamous epithelia p73 - strong pro-apoptotic effects after DNA damage induced by chemotheraputic agents Mutations in Three musketeers is seen in the socalled basal subset of breast cancers and poor prognosis.

Adenomatous polyposis coli(APC) genes

a class of tumor suppressors whose main function is to downregulate growth-promoting signals. Germ-line mutations at the APC (5q21) loci are associated with familial adenomatous polyposis. a component of the WNT signaling pathway, which has a major role in controlling cell fate, adhesion, and cell polarity during embryonic development down-regulate -catenin.

Dysregulation of the APC/ catenin pathway causes

Colonic carcinoma HCC Hepatoblastoma

TGF

potent inhibitor of proliferation. Dimerization of the receptor upon ligand binding leads to activation of the kinase and phosphorylation of receptor SMADs (R-SMADs). R-SMADs can enter the nucleus, bind to SMAD-4, and activate transcription of genes, including the CDKIs p21 and p15/INK4b. leads to repression of c-MYC, CDK2, CDK4, and cyclins A and E.

TGF- type II receptor are seen in cancers of the colon, stomach, and endometrium SMAD 4 mutations causes pancreatic and colonic carcinoma.

PTEN (Phosphatase and tensin homologue) a membrane-associated phosphatase chromosome 10q23 that is mutated in Cowden syndrome, an autosomal dominant disorder marked by frequent benign growths, such as tumors of the skin appendages, and an increased incidence of epithelial cancers, particularly of the breast , endometrium, and thyroid. a tumor suppressor by serving as a brake on the prosurvival/pro-growth PI3K/AKT pathway.

NF1 gene develop numerous benign neurofibromas and optic nerve gliomas as a result of inactivation of the second copy of the gene and is called neurofibromatosis type 1 Neurofibromin, the protein product of the NF1 gene, contains a GTPase-activating domain, which regulates signal transduction through RAS proteins. Neurofibromin facilitates conversion of RAS from an active to an inactive state. With loss of neurofibromin function, RAS is trapped in an active, signal-emitting state

NF2 gene

predispose to the development of neurofibromatosis type 2,benign bilateral schwannomas of the acoustic nerve. somatic mutations affecting both alleles of NF2 have also been found in sporadic meningiomas and ependymomas.

The product of the NF2 gene, called neurofibromin 2 or merlin,

shows a great deal of homology with the red cell membrane cytoskeletal protein 4.1 is related to the ERM (ezrin, radixin, and moesin) family of membrane cytoskeleton-associated proteins. is a key member of the Salvador-WartsHippo (SWH) tumor suppressor pathway, originally described in Drosophila. controls organ size during development by modulating cell growth, proliferation, and apoptosis. Many human homologues of genes in the SWH pathway have been implicated in human cancers

Von Hippel-Lindau (VHL)

gene - chromosome 3p hereditary renal cell cancers, pheochromocytomas, hemangioblastomas of the central nervous system, retinal angiomas, and renal cysts. Mutations of the VHL gene have also been noted in sporadic renal cell cancers .

The VHL protein is part of a ubiquitin ligase complex.

In the presence of oxygen, HIF1 is hydroxylated and binds to the VHL protein, leading to ubiquitination and proteasomal degradation. in hypoxic environments the reaction cannot occur, and HIF1 escapes recognition by VHL and subsequent degradation. HIF1 can then translocate to the nucleus and turn on many genes, such as the growth/angiogenic factors vascular endothelial growth factor (VEGF) and PDGF.

PTCH1 and PTCH2 are tumor suppressor genes that encode a cell membrane protein (PATCHED), which functions as a receptor for a family of proteins called Hedgehog. The Hedgehog/PATCHED pathway regulates several genes, including TGF- and PDGFRA and PDGFRB. Mutations in PTCH are related to Gorlin syndrome, an inherited condition also known as nevoid basal cell carcinoma syndrome . PTCH mutations are present in 20% to 50% of sporadic cases of basal cell carcinoma. About one half of such mutations are of the type caused by UV exposure.

The WT1 gene

located on chromosome 11p13, is associated with

the development of Wilms' tumor, a pediatric kidney WT1 protein is a transcriptional activator of genes involved in renal and gonadal differentiation. It regulates the mesenchymal-to-epithelial transition that occurs in kidney development. a variety of adult cancers, including leukemias and breast carcinomas, have also been shown to overexpress WT1.

Another Wilms' gene, WT2, located on 11p15, is associated with the Beckwith-Wiedemann syndrome

p53 in cases of NSCLC

FLOURESCENT IN SITU HYBRIDISATION for bcr-abl transcript

POLYMERASE CHAIN REACTION

A B
A; Normal bronchial ept, Fhit +

B; Fhit mod + C, Fhit

TARGETED THERAPY

Normal epithelium

5q mutation or loss APC gene

Hyperproliferative epithelium Early adenoma

12p mutation KRAS

Intermediate adenoma

18q loss DCC

Late adenoma

17p loss p53

Carcinoma

Other alterations
Metastases
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