Oncogenes and tumour suppressor genes 1

Cancer mutations occur in two formsCancer mutations occur in two forms

OncogenesOncogenes

Gain-of-function dominant mutationsGain-of-function dominant mutations

Tumour suppressor genesloss of function mutations

Oncogenes

• Genes known as proto-oncogenes code for proteins that stimulate cell division

• mutated forms, called oncogenes, cause stimulatory proteins to be overactive, with the result that cells proliferate excessively

• gain of function mutations

Some acronyms!

• Myc• Sis• Erb• Src• Ras• Yes

• Abl• Fos• jun

Myelocytomatosis

Simian sarcoma

Erythroblastoma

Rous sarcoma virus

Rat sarcoma

2 viruses Y73 & ESH sarcoma, isolated from a chicken owned by Mr. Esh

Abelson murine leukaemia virus

Finkel biskis jinkins reilly mouse sarcoma

junana

Two approaches to identifying oncogenesTwo approaches to identifying oncogenes

• Analysis of tumor causing retroviruses

• Exposure of noncancerous cells to tumor DNA in culture– Human tumor DNA to

transform normal mouse cells

– Human DNA isolated from transformants

Activation of proto-oncogenes Activation of proto-oncogenes

• Viral insertion• Chromosomal rearrangements

– Altered regulation– Fusion genes

• Gene amplification • Point mutations • Loss of degradation signals

Viral insertion

Chromosomal rearrangements – altered regulationBurkitts lymphoma All patients show t(8:14) translocation of the

immunoglobulin gene on chromosome 14 to the c-myc oncogene locus on chromosome 8

c-myc is under regulatory control of IgH resulting in overexpression of the oncogene

Chromosomal rearrangements - fusion gene Chronic Myelogenous Leukaemia Translocation t(9:22)

Abl-bcr fusion gene encodes a constitutively active protein tyrosine kinase, which affects cell cycle, adhesion and apoptosis

Gene amplification

Metaplastic breast carcinomas (MBCs) account for less than 1% of all invasive mammary carcinomas. Approximately 70–80% of metaplastic breast carcinomas overexpress the epidermal growth factor receptor (EGFR). Human epidermal growth factor receptor (HER2)

EGFR gene amplification in MBC (>5 signals per nucleus). Note the bizarre

neoplastic cell with more than10 copies of EGFR.

Herceptin©

point mutations

Point mutations in ras, implicated in bladder carcinoma

e.g. GGC to GTC (G12V)

Loss of degradation signalsEpstein–Barr virus (EBV) associated with lymphoid and epithelial malignancies.

Three viral proteins, EBNA1, LMP-1 and -2A, constitutively activate c-myc oncogene by decreasing ubiquitin-dependent proteolysis of this protein and upregulate compensatory pathways in Burkitt’s lymphomas.

Seminars in Cancer Biology Volume 13, Issue 1 , February 2003, Pages 69-76

Cell Cycle Control is through the effects of growth factors which interact with membrane-bound glycoprotein receptors that transduce the message via a series of intracellular signals that promote or inhibit the expression of specific genes.

Growth factor signalling and Growth factor signalling and oncogenes oncogenes

Molecular components of each signaling system

• Growth factors – hormones and cell-bound signals that stimulation or inhibit cell proliferation

• Receptors – membrane bound proteins that accept signals– signal-binding site– transmembrane segment– intracellular domain

Fig. 18.15 a

Signal transducers relay messages and Signal transducers relay messages and transcription factors activate expression of transcription factors activate expression of

genesgenes

Fig. 18.15 c

Growth factors

Growth factor receptor

Figure 5.12a The Biology of Cancer (© Garland Science 2007)

Mutations in GF receptor can cause ligand-independent activation

Figure 5.10 The Biology of Cancer (© Garland Science 2007)

Other growth factor receptors

Figure 5.4a The Biology of Cancer (© Garland Science 2007)

Normal fibroblasts

+/- PDGF

PDGF receptor negative fibroblasts

+/- PDGF

+

+

-

-

Adaptor proteins

c-crk (cell cycle related kinase)

Small GTP-binding signalling molecule

Ras

V-ras or mutated ras has lost the ability to interact with accessory proteins and are either GEF independent or GAP insensitive (GTP state)

Guanine nucleotide exchange factor (GEF) - activation by GDP to GTP

GTPase activation proteins (GAP) - inactivation by GDP to GTP

Genetics of brain cancerGenetics of brain cancer

• Glioblastoma multiforme (GBM)– Aggressive cancer of glial cells– Heterogeneous condition resulting from mutation in different

subset of genes• Glial cells

– Astrocytes – provide support for neurons– Oligodendrocytes – produce myelin sheaths– Ependymal cells – line the brain cavities known as ventricles and

regulate cerebrospinal fluid production• Grades of gliomas

– Lowgrade (II)– Anaplastic (III)– GBM (IV)– Low grades progress to higher grades

Many genes in various combinations produce GBMsThree routes for evolution of GBM have been identified

Pathway from grade II astrocytoma to malignant GBM

Fig. 18.27

Some rapidly arising GBMs have Some rapidly arising GBMs have no apparent precursorsno apparent precursors

• Oncogenic amplification of the epidermal-growth-factor-receptor (EGFR) gene and loss of regions from 10p and 10q

• Arise de novo or so rapidly no precursors are detectable

• Rarely occur in astrocytoma-derived GBM tumors with p53 mutations and 17q deletions

• Occur in significantly older adults than GBMs with mutant p53 and chromosome 17 deletions

Summary of GBM• GBM phenotypes

– Develop by different combinations of mutations in different pathways

• Lower-grade astrocytomas via p53 and RB gene inactivations

• Oligodendroglial tumors via deletions of chromosome 1 and 19

• de novo via EGFR gene activation

– Mutational pathways are often more complicated• Not every GBM shows all genetic changes described• Some GBMs derived from one type of cell have

mutations associated with another type of cell

Further examples of oncogenesONCOGENES

Genes for growth factors or their receptors PDGF Codes for platelet-derived growth factor. Involved in glioma (brain cancer) erb-B Codes for the receptor for epidermal growth factor. Involved in

glioblastoma (brain cancer) and breast cancer erb-B2 Also called HER-2 or neu. Codes for a growth factor receptor. Involved in

breast, salivary gland and ovarian cancers RET Codes for a growth factor receptor. Involved in thyroid cancer Genes for cytoplasmic relays in stimulatory signaling pathways Ki-ras Involved in lung, ovarian, colon and pancreatic cancers N-ras Involved in leukemias Genes for transcription factors that activate growth promoting genes c-myc Involved in leukemias and breast, stomach and lung cancers N-myc Involved in neuroblastoma (a nerve cell cancer) and glioblastoma L-myc Involved in lung cancer Genes for other molecules

Bcl-2 Codes for a protein that normally blocks apoptosis. Involved in follicular B cell lymphoma

Bcl-1 Also called PRAD1. Codes for cyclin D1, a stimulatory component of the cell cycle clock. Involved in breast, head and neck cancers

MDM2 Codes for an antagonist of the p53 tumor suppressor protein. Involved sarcomas (connective tissue cancers) and other cancers

References

Chapter 5: Biology of Cancer by RA Weinberg

AND/OR

Chapter 6: Cancer Biology (2nd edition) by RJB King:

Optional reading:

Oncogenes by Amanda Perry (www.els.net)