Cancer Genes: Oncogenes and Tumor Suppressors

1. Tumor Markers Epidemiology 243: Molecular Epidemiology

12. SEVERAL MUTATED OR ALTERED GENES IN CANCER • Cancer cells contain several (6-8) mutated genes. • Several categories of genes • 1. Oncogenes • An oncogene is a gene that when mutated or altered contributes to converting a normal cell into a cancer cell. • The term oncogene is derived from the Greek word "oncos," meaning tumor. • The cellular oncogenes in their normal form are called proto-oncogenes and do not cause cancer. They code for a variety of normal enzymes, growth factors and receptors that relay signals to a cell's nucleus, stimulating growth. • The activation to oncogene may result in overproduction of growth factors; flooding of the cell with replication signals; and/or unrestrained cell growth.

13. The activation of a proto-oncogene to oncogene can occur in several ways: • mistakes during DNA replication, ie. point mutation, chromosomal rearrangement, gene amplification • from damage to DNA cause by exposure to chemicals or radiation • from viral infection and insertion into the DNA resulting in more active production of oncogene • from other causes not yet known

14. To other points about oncogenes: - Oncogenes act as dominants; if the cell has one normal gene at a locus and one mutated gene, the abnormal product takes control. - No single oncogene can, by itself, cause cancer. It can increase the rate of mitosis of the cell. Dividing cells are at increased risk of acquiring mutations. - Oncogenes may be transmitted from generation to generation when a proto-oncogene mutates in the germ line. This results in a dominantly inherited tumor predisposition. For example, multiple endocrine neoplasia type 11 (MEN 2) is the outcome of a germline transmission of an activated RET oncogene.

15. NORMAL CELL DIVISION Regulated by tumor suppressor genes Proto-oncogenesCell growth and proliferation stimulate CANCER DUE TO ACTIVATION OF ONCOGENES Proto-oncogenes oncogenesIncreased rate of activation misregulation cell growth and proliferation Malignant transformation

16. CANCER DUE TO MUTATED TUMOR SUPPRESSOR GENES Loss or mutation of tumor suppressor gene Proto-oncogenesCell growthMalignant and proliferationtransformation 2. Tumor Suppressor genes - Suppress tumor formation. - Their protein products act to inhibit cell growth and the division cycle. - Mutations in tumor suppressor genes cause the cell to ignore one or more of the components of the network of inhibitory signals, resulting in a higher rate of uncontrolled cell proliferation.

17. One tumor suppressor locus is usually involved in controlling the development of several different kinds of tumors. • - Tumor suppressor genes are often associated with the loss of one chromosome or a part of a chromosome, resulting in a reduction to homozygosity (or loss of heterozygosity-LOH) through elimination of one allele of a tumor suppressor gene as well as surrounding markers; the remaining tumor suppressor allele is inactivated by either an inherited or a somatic mutation. • - Tumor suppressors behave as recessives. Both normal alleles must mutate before cancerous growth begins.

18. Examples of Tumor Suppressor genes • 1. p53 • 53 kD protein that prevents a cell from completing the cell cycle if its DNA is not properly replicated in S phase. It responds to cell damage. • - It binds to transcription factor (E2F) and prevents E21F from binding to the promoters of the proto-oncogenes c-myc and c-fos, needed for mitosis • - The p53 protein may triggers programmed cell death (apoptosis) if the damage to the cell is too great to be repaired. • - Defects in the p53 gene are found in most cancers.

30. Smoking and TP53 mutations in Bladder Cancer

34. Case 607Exon 8 Case 644Exon 7 1 2 3 1 2 3 Wild Type Mutant Wild Type Mutant G A T C G A T C G A T C G A T C A A C C G C/G G G A A/G A G Arg Thr Gly Ser A C/G A A/G G C Codon 280 Codon 244

39. Figure 8-1. IHC Analysis of p53, p21, and mdm2

44. Age and TP53 Mutations

45. Gender and TP53 Mutations

46. Race and TP53 Mutations

47. Education and TP53 Mutations

48. TP53 Mutations in Bladder Cancer

49. Smoking and TP53 Mutations in Bladder Cancer Adjusted for age, gender, and education

50. Cigarettes/day and TP53 Mutations in Bladder Cancer Adjusted for age, gender, and education