Tumor Markers Epidemiology 243 Molecular Epidemiology SEVERAL MUTATED
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Tumor Markers Epidemiology 243: Molecular Epidemiology
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 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 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 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 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 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 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
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
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 (%) 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 (%) 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. 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) 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 - 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 - 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+ 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
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