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 –G 1 -to-S –G 2 -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