Cancer Genetics Regulated and unregulated cell proliferation L2 Flashcards
CDK- complexes help?
- CDK-cyclin complexes help regulate cell
cycle progression (checkpoints)
Malignant tumours of cancers are:
AGGREGATEs of cells,
DESCENDED from an INITIAL ABERRANT FOUNDER.
Virtually ALL CANCERS of SOMATIC CELLS arise
- due to a
SERIES OF MUTATIONS that ACCUMULATE
How?
2. Some mutations ALTER ACTIVITY OF A GENE
3., while
others ELIMINATE THE GENE’S ACTIVITY.
Cancer promoting mutations: 3
- INCREASE ability of cell to PROLIFERATE
2.DECREASE susceptibility of CELL TO APOPTOSIS
- INCREASE general MUTATION RATE in cell OR it LONGEVITY
Metastatic breast cancer …
- Metastatic breast
cancer masses (white protrusions) growing on a human liver (crowding out
normal cells) - Light Micrograph -
light pale-stained
cells are cancer cells
invading regions of
the darker normal
liver cells
MANY DIFFERENT CELL TYPES CAN BE CONVERTED TO MALIGNANT STATE …
Is there a common theme or does each arise in
different way?
- General way - due to accumulation of mutations -
single cell proliferates out of control - Cancer cell isolated state where they operate
without external constraint - “deaf” to signals from neighbouring cells to stop dividing or undergo apoptosis
Alfred Knudson (1971) proposed Rb results from two separate
genetic defects, both necessary for cancer to develop… STEPS = 5
- Rarely, a single cell undergoes 2 somatic mutations,…
- …resulting in a single tumour for example, in one eye.
- A predisposed person inherits one mutation.
- some cells undergo a single somatic mutation that produces cancer.
- because only a single mutation is required to produce cancer, the likelihoof of its occuring twise (in both eyes for example), INCREASES.
RETINOBLASTOMA in Children…
- Rare for a single
cell in one eye to
undergo two successive
mutations,
- Retinoblastoma is
rare and typically
develops in only
one eye. - Children with bilateral
retinoblastoma inherit
one of the two
mutations, and so
every cell contains this
initial mutation.
- All that
is required for cancer
to develop is for one
eye cell to undergo
the second mutation.
Clonal evolution of Tumors STEPS: 4
- A cell is predisposed to proliferate at an abnormally high rate.
- a 2nd mutation causes the cell to divide even more RAPIDLY
- After 3rd mutation, the cell undergoes STRUCTURAL CHANGES.
- A 4th mutation causes the cell to divide UNCONTROLLABLY and invade other tissues.
Cancer is the result
of a multistep process that = 5
- requires several mutations.
- Cells of the CLONE
divide more
RAPIDLY ; - they soon OUTGROW other cells.
- More AGRESSIVE PROLIFERATION
- ADVANCED CANCER CELLS tend to have
DEFECTIVE DNA REPAIR MECHANISMS
Colorectal cancer… STEPS = 9
- NORMAL CELL - loss of normal TUMOUR SUPPRESSOR gene ‘APC’
- A ‘polyp’ (small growth) forms on the COLON WALL
- A BENIGN, precancerous tumour grows.
- ACTIVATION OF ONCOGENE ras
- and ADENOMA (benign tumour) GROWS
- Loss of tumour - SUPPRESSOR GENE ‘p53’
- a CARCINOMA (malignant tumour) DEVELOPS
- Other changes: loss of ANTIMETASTASIS GENE
- The CANCER METASTASIZES (spreads to other tissue through BLOODSTREAM)
Mutations in multiple
genes contribute to the
progression of
COLORECTAL CANCER
Several distinct changes
seen in progression of
tissues from normal to
malignant state (10-35
years).
Common
mutational events in
progression
EXPLAIN Cancer cells exhibit aneuploidy -
EXAMPLE?
- Cancer cells exhibit aneuploidy
- possess chromosome
abnormalities, extra, missing and chromosome
rearrangements. - Colon cancer cell, mar = major chromosome rearrangements
Mutations in cancer cells
Two general kinds of mutations associated with tumours
list them:
- Proto-oncogene mutations
2.Tumour Suppressor gene mutations
EXPLAIN PROTO-ONCOGENE MUTATIONS
- Mutation only required in one allele for tumour
formation
(Dominant-acting mutation) - The gene in its normal mutated form = ONCOGENE
EXPLAIN Tumour Suppressor gene mutations:
For cancer to occur, both alleles of gene must be
mutated and have no activity
(Recessive-acting
mutation)
Oncogenes: Increase growth and division EXPLAIN - 2
- Proto-oncogenes normally produce factors that stimulate cell division
- MUTANT ALLELES (ONCOGENES) tend to be DOMINANT; one copy of the mutant is sufficient to INDUCE EXCESSIVE CELL PROLIFERATION.
Tumour-suppressor genes: Decrease growth and division EXPLAIN - 2
- Tumour-suppressor genes normally produce factors that INHIBIT CELL DIVISION
- Mutant alleles are RECESSIVE (both alleles must be mutated to produce Excessive cell proliferation)
EXPLAIN
Loss of heterozygosity – Inactivation of remaining WT allele
People heterozygous for tumour-suppressor gene are predisposed to CANCER.
(Aa) - this genotype is heterozygous for a tumour suppressor gene.
CHROMOSOME DELETION
leads to
(_a) loss of wild-type allele, in this case through chromosome deletion …CAUSES LOSS OF TUMOUR SUPPRESSOR ACTIVITY.
ONCOGENES
define PROTO-ONCOGENES:
- encode proteins that regulate normal cell proliferation
(eg. Signaling, control of
cell cycle, or apoptosis)
- Either positive or negative regulators
EXPLAIN proto-oncogenes
…Accumulate mutations to become oncogenes….4 WAYS
Accumulate mutations to become oncogenes:
1.– POINT MUTATIONS alter structure/function (eg. ras)
2 – LOSS OF PROTEIN domains resulting from DELETION
3.– GENE FUSIONS, often from TRANSLOCATION (eg. Bcr-ABL)
- – MUTATION may result in MIS-EXPRESSION (eg.
Bcl2-enhancer)
ras signal transduction pathway = 4
- Binding of growth factor to the receptor causes a conformational change and the addition of phosphate groups.
- Adaptor molecules bind to the receptor and link to Ras.
Ras binds GTP and is activated. - Activated Ras activated Raf, which activates MEK, which activates MAP kinase.
- Activated MAP KInase moves into the nucleus and activates transcription factors.
