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 growth-

stimulating 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 over-expressed 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