Lecture notes
Oncogenes
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- Brunel University (BU)
Oncogenes Oncogene activation Epigenetics Therapy
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2) OncogenesOncogenes vs proto-oncogenes? –
Proto-oncogene = NORMAL unmutated gene which
regulates cell proliferation = GOOD ANGEL
Oncogene = arises from a gain-of-function mutation
over-activates genes involved in cell proliferation
= EVIL DEMON
1) The discovery of src (retroviral transfer) –
1941 – Rous transformed normal cells tumour cells
In culture by infecting them with a virus
Varmus + Bishop showed src gene was originally an avian cellular
gene and was ‘stolen’ by the RSV virus & turned into an oncogene
by a viral promotor
2) The discovery of RAS (mammalian cell transfection) –
Begins with viruses in the 60s: HRAS + KRAS
By the 80s it became possible to transfect DNA into mammalian cells without viral
vectors
Could fragments of DNA from mammalian tumour cells transform normal cells into
cancer cells?
DNA transfection assay:
DNA from tumour cell lines
Transfected into mouse cultured cells
Transformed cells identified by growth and loss of
contact inhibition
Transformed cells produced tumours in athymic (nude)
mice
Multiple RAS genes exist:
1981-1984 – human homologues of HRAS, KRAS and
NRAS were discovered
HRAS = from DNA in EJ/T24 bladder
carcinoma line
KRAS = from DNA in lung and colon cancers
NRAS = from DNA in neuroblastomas
These oncogenes differed from the wildtype RAS gene by 1 single
point mutations
, 3) The discovery of the Philadelphia chromosome and ABL
(chromosomal translocations) –
1960 – Peter Nowell and his PhD student described an unusual
small chromosome
It was present in leukocytes from patients with chronic
myelogenous leukaemia (CML)
Called it Philadelphia chromosome after its city of discovery
Present in 95% of cases of CML
Reciprocal translocation:
Early 1980s – 3 labs identified Philadelphia chromosome was: a reciprocal
translocation between Chr 9 and 22
Translocation effects ABL gene on Chr 9 & fuses it to BCR gene on Chr 22
BCE-ABL fusion = ONCOGENE
4) MYC (oncogene amplification) –
1977- Discovered by Gilbert in neuroblastoma cell lines
Double minute chromosomes are ‘small chromatin bodies whose origin and function
are uncertain’
In neuroblastoma (up to 80%) they exist in multiple copies and contain the gene N-
MYC
5) More up to date: IDH1 (Next Generation DNA Sequencing) –
Discovered by Kenneth Kinnzler
By lab sequencing 20,611 protein coding genes from 22 human glioblastoma (GBS)
tumour samples
In 5 of the tumours they identified a mutated gene not previously known to be
mutated in GBS = IDH1
All 5 tumours had the same point mutation
IDH1 has been found to be mutated in many types of glioma, colon cancer, and AML
Other oncogenes identified by Next Generation DNA Sequencing:
Study involving IDH1 took around 3 years – compared with >60 for SRC
Almost all future oncogenes are likely to be discovered this way
Systemic sequencing of cancer genomics is now underway in many labs;
o The Cancer Genome Project
o Genomics England, 100,000 genomes project
o Other oncogenes found this way include: IDH2, EZH2
Summary: Oncogenes discovered via –
1) Retroviruses
2) Transfection (tumour normal)
3) Chromosomal translocations
4) Chromosomal amplifications
5) New genetic technologies
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