Tumor Markers Epidemiology 243 Molecular Epidemiology SEVERAL MUTATED

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Tumor Markers Epidemiology 243: Molecular Epidemiology

Tumor Markers Epidemiology 243: Molecular Epidemiology

SEVERAL MUTATED OR ALTERED GENES IN CANCER Cancer cells contain several (6 -8) mutated

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.

- The activation of a proto-oncogene to oncogene can occur in several ways: -mistakes

- 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

To other points about oncogenes: - Oncogenes act as dominants; if the cell has

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.

NORMAL CELL DIVISION Regulated by tumor suppressor genes Proto-oncogenes Cell growth and proliferation stimulate

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

CANCER DUE TO MUTATED TUMOR SUPPRESSOR GENES Loss or mutation of tumor suppressor gene

CANCER DUE TO MUTATED TUMOR SUPPRESSOR GENES Loss or mutation of tumor suppressor gene Proto-oncogenes Cell 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.

-One tumor suppressor locus is usually involved in controlling the development of several different

-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.

Examples of Tumor Suppressor genes 1. p 53 -53 k. D protein that prevents

Examples of Tumor Suppressor genes 1. p 53 -53 k. D 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 (E 2 F) and prevents E 21 F from binding to the promoters of the proto-oncogenes c-myc and c-fos, needed for mitosis - The p 53 protein may triggers programmed cell death (apoptosis) if the damage to the cell is too great to be repaired. - Defects in the p 53 gene are found in most cancers.

Smoking and TP 53 mutations in Bladder Cancer

Smoking and TP 53 mutations in Bladder Cancer

Case 607 Exon 8 1 2 Wild Type G A T C Case 644

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

Figure 8 -1. IHC Analysis of p 53, p 21, and mdm 2

Figure 8 -1. IHC Analysis of p 53, p 21, and mdm 2

Age and TP 53 Mutations Age <50 P 53+ No. (%) 6 (8. 7)

Age and TP 53 Mutations Age <50 P 53+ No. (%) 6 (8. 7) P 53 No. (%) 11 (10. 0) Total No. (%) 17 (9. 5) 50 -59 16 (23. 2) 18 (16. 4) 34 (19. 0) 60+ 47 (68. 1) 81 (73. 6) 128 (71. 5)

Gender and TP 53 Mutations Gender TP 53+ No (%) TP 53 No (%)

Gender and TP 53 Mutations Gender TP 53+ No (%) TP 53 No (%) Total No (%) Male 47 (71. 2) 89 (81. 7) 136 (77. 7) Female 19 (28. 8) 20 (18. 4) 39 (22. 3)

Race and TP 53 Mutations Race TP 53+ No (%) TP 53 No (%)

Race and TP 53 Mutations Race TP 53+ No (%) TP 53 No (%) Total No. (%) White 60 (87. 0) 100 (90. 9) 160 (89. 4) 10 (9. 1) 19 (10. 6) Non-White 9 (13. 0)

Education and TP 53 Mutations Education (years) <12 TP 53+ No. (%) 2 (2.

Education and TP 53 Mutations Education (years) <12 TP 53+ No. (%) 2 (2. 9) TP 53 No. (%) 4 (3. 6) Total No. (%) 6 (3. 4) 12 -16 58 (84. 1) 76 (69. 1) 134 (74. 9) >16 9 (13. 0) 30 (27. 3) 39 (21. 8)

TP 53 Mutations in Bladder Cancer BP changes Transitions GC AT (at Cp. G)

TP 53 Mutations in Bladder Cancer BP changes Transitions GC AT (at Cp. G) AT GC Transversions GC TA GC CG AT TA AT CG Deletion/Insert. Reported, n=200 Current study 41. 0% 14. 0% 10. 0% 37. 5% 12. 5% 15. 0% 13. 0% 19. 0% 3. 0% 2. 0% 12. 5% 10. 0%

Smoking and TP 53 Mutations in Bladder Cancer Smoking TP 53+ TP 53 -

Smoking and TP 53 Mutations in Bladder Cancer Smoking TP 53+ TP 53 - OR No 8 24 1. 00 Yes 58 83 6. 27 Adjusted for age, gender, and education 95%CI 1. 29 -30. 2

Cigarettes/day and TP 53 Mutations in Bladder Cancer Cig/day TP 53+ TP 53 -

Cigarettes/day and TP 53 Mutations in Bladder Cancer Cig/day TP 53+ TP 53 - OR No 8 24 1. 00 1 -20 8 21 2. 07 0. 22 -19. 9 21 -40 36 47 5. 50 1. 08 -28. 2 >40 17 18 10. 4 1. 90 -56. 8 Trend P=0. 003 Adjusted for age, gender, and education 95%CI

Years of Smoking and TP 53 Mutations in Bladder Cancer Years of TP 53+

Years of Smoking and TP 53 Mutations in Bladder Cancer Years of TP 53+ smoking No 8 TP 53 - OR 24 1. 00 1 -20 5 10 5. 64 0. 82 -38. 7 21 -40 42 58 6. 45 1. 24 -33. 4 >40 14 18 6. 20 1. 17 -32. 8 Trend P=0. 041 Adjusted for age, gender and education 95%CI