chapter 23 – cancer genetics. tumor mass of abnormally dividing cells –normal cells exhibit...
TRANSCRIPT
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Chapter 23 – Cancer Genetics
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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”
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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
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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
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Oncogenes• Overstimulate cell division
• Normal form of the gene is a proto-oncogene– Produces growth-
stimulating factors– Mutates into an oncogene,
which hyperstimulates the cell
• Dominant– Only one allele needs to be
mutated to show effects
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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 over-expressed if placed near a promotor or enhancer
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Tumor suppressor genes
• Inhibit cell division
• Recessive– Both alleles must
be mutated; often one is inherited
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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
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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
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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
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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
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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
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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
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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
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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
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Cancer cytogenetics
• Constitutional vs acquired abnormalities
• Diagnostic and prognostic applications