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-oncogenes Cell growth and proliferation stimulate CANCER DUE TO ACTIVATION OF ONCOGENES Proto-oncogenes oncogenes Increased 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 growth Malignant and proliferation transformation 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 607 Exon 8 1 2 3 Case 644 Exon 7 G A T C G A T CG A T C A C/G A A G A Thr Arg GlySer C G A/G G G C MutantWild TypeMutantWild Type A C/G A A/G G C Codon 280Codon 244

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

44. Age and TP53 Mutations AgeP53+ No. (%) P53- No. (%) Total No. (%) <506 (8.7)11 (10.0)17 (9.5) 50-5916 (23.2)18 (16.4)34 (19.0) 60+47 (68.1)81 (73.6)128 (71.5)

45. Gender and TP53 Mutations GenderTP53+ No (%) TP53- No (%) Total No (%) Male47 (71.2)89 (81.7)136 (77.7) Female19 (28.8)20 (18.4)39 (22.3)

46. Race and TP53 Mutations RaceTP53+ No (%) TP53- No (%) Total No. (%) White60 (87.0)100 (90.9)160 (89.4) Non-White9 (13.0)10 (9.1)19 (10.6)

47. Education and TP53 Mutations Education (years) TP53+ No. (%) TP53- No. (%) Total No. (%) <122 (2.9)4 (3.6)6 (3.4) 12-1658 (84.1)76 (69.1)134 (74.9) >169 (13.0)30 (27.3)39 (21.8)

48. TP53 Mutations in Bladder Cancer BP changesReported, n=200Current study Transitions GC  AT 41.0%37.5% (at CpG)14.0%12.5% AT  GC 10.0%15.0% Transversions GC  TA 13.0%12.5% GC  CG 19.0%10.0% AT  TA 3.0%0.0% AT  CG 2.0%2.5% Deletion/Insert.12.0%10.0%

49. Smoking and TP53 Mutations in Bladder Cancer SmokingTP53+TP53-OR95%CI No8241.00 Yes58836.271.29-30.2 Adjusted for age, gender, and education

50. Cigarettes/day and TP53 Mutations in Bladder Cancer Cig/dayTP53+TP53-OR95%CI No8241.00 1-208212.070.22-19.9 21-4036475.501.08-28.2 >40171810.41.90-56.8 TrendP=0.003 Adjusted for age, gender, and education

51. Years of Smoking and TP53 Mutations in Bladder Cancer Years of smoking TP53+TP53-OR95%CI No8241.00 1-205105.640.82-38.7 21-4042586.451.24-33.4 >4014186.201.17-32.8 TrendP=0.041 Adjusted for age, gender and education