Transcript Chapter 23 – Cancer Genetics

Chapter 23 – Cancer Genetics
Tumor
• Mass of abnormally dividing cells
– Normal cells exhibit contact inhibition in culture
• Benign
– Usually well-defined borders; unable to
metastasize
• Malignant
– Has ability to metastasize
– “cancer”
Knudson’s multistep model of
cancer
• Retinoblastoma
– Cancer of retina
– Sporadic
• Unilateral; adults
affected
• One cell needs to
accumulate
mutations in both
alleles
– Familial
• Bilateral; seen in
children
• One mutated allele
is inherited; seen in
every cell
• Only one additional
mutation is required
Multistep model of cancer cont Clonal evolution
• One cell acquires a
mutation which is passed
to all daughter cells
• Over time, additional
mutations accumulate
• Genes that are involved
with DNA repair or proper
chromosome segregation
are involved with cancer
Oncogenes
• Overstimulate cell division
• Normal form of the gene
is a proto-oncogene
– Produces growthstimulating factors
– Mutates into an oncogene,
which hyperstimulates the
cell
• Dominant
– Only one allele needs to be
mutated to show effects
Viruses associated with cancer
• Can carry host proto-oncogenes
– Can mutate into an oncogene which is then
introduced into the host
• Can interrupt normal proto-oncogene
sequence when viral genome is inserted
– retroviruses
• Proto-oncogene may become overexpressed if placed near a promotor or
enhancer
Tumor suppressor genes
• Inhibit cell division
• Recessive
– Both alleles must
be mutated; often
one is inherited
Other gene effects
• Loss of heterozygousity
– Normal allele is lost due to
deletion
• Haploinsufficiency
– A heterozygote for
recessive genes has half
the normal amount of gene
product
– Due to dosage ratios, a
heterozygote may be
affected with some type of
phenotypic change
Cell cycle control
• 3 main checkpoints in cell cycle
– G1-to-S
– G2-to-M
– Spindle assembly
• Cyclin-dependent kinases (CdKs)
– Enzymes that activate/inactivate other proteins by
adding phosphate groups to them
– Only functional when associated with a cyclin protein
• Concentration of cyclins change throughout cell cycle; CDK
concentration remains constant
• Cyclin type determines which proteins will be phosphorylated
G1-to-S transition
• Retinoblastoma (RB) gene
prohibits cell from entering S
– Binds to, and inhibits, E2F
molecule
• In G1, cyclin D and cyclin E
concentration increases, and
binds to their CDKs
– Phosphorylates RB, which can
then no longer bind to E2F
• E2F is now free – is a
transcription factor that will
express genes coding for
enzymes involved with DNA
replication
G2-to-M transition
• Mitosis promoting factor = cyclin B + CdK
• Levels of cyclin B are low in G1, increases until critical
level is reached near end of G2
• Phosphorylation of certain proteins cause:
– Nuclear envelope breakdown, chromosome condensation,
spindle formation
• MPF destroys cyclin – causes cell to exit mitosis
– Negative feedback
– Without cyclin, low level of MPF causes return to Interphase
Spindle-assembly checkpoint
• Anaphase is not entered until all
chromosomes are properly aligned
– If not, cyclin B destruction is blocked, MPF
remains active, and cell is stuck in mitosis
Genes in cancer
• DNA repair genes
– Either increase rate of errors, and/or decrease
repair of errors
• Telomerase regulation
– Inappropriate expression of telomerase
• Vascularization
– Growth factors stimulate angiogenesis
Chromosomes in cancer
• Translocations and inversions can create fusion
proteins
• CML t(9;22)
– #22 has BCR gene; #9 has cABL (proto-oncogene)
– Translocation creates a small #22 (Philadelphia
chromosome) and relocated BCR to #9
– BCR-ABL creates fusion protein – more active than
normal ABL gene
• Unregulated, overactive cell division
Chromosomes in cancer cont
• Translocations and
inversions can place a gene
under new regulatory control
• Burkitt lymphoma t 8
(cMYC) and 2, 14, or 22
(contain immunoglobin
genes)
• cMYC now under
transcriptional control of
immunoglobin genes
• Becomes expressed in B
cells; results in
overproliferation
Cancer cytogenetics
• Constitutional
vs acquired
abnormalities
• Diagnostic and
prognostic
applications