Oncogenes and tumour suppressor genes 1

Cancer mutations occur in two forms

Oncogenes Gain-of-function dominant mutations

Tumour suppressor genes loss 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 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 Viral insertion Chromosomal rearrangements –Altered regulation –Fusion genes Gene amplification Point mutations Loss of degradation signals

Viral insertion

Chromosomal rearrangements – altered regulation Burkitts 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 than 10 copies of EGFR. Herceptin ©

point mutations Point mutations in ras, implicated in bladder carcinoma e.g. GGC to GTC (G12V)

Loss of degradation signals Epstein–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 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 a

Signal transducers relay messages and transcription factors activate expression of genes

Fig 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 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 GBMs Three routes for evolution of GBM have been identified

Pathway from grade II astrocytoma to malignant GBM Fig

Some rapidly arising GBMs have no 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 oncogenes

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 (