Imad Fadl-Elmula Al Neelain University

1. The Biology and Genetic Base of Cancer Imad Fadl-Elmula Al Neelain University

2. Cancer ........an old........ new problem The oldest knowncases(Osteosarcomas)have been verifiedin Egyptianmummies that died4000

3. Karkinos

4. Incidence Uroepithelial cancer Uroepithelial cancer Rarely occur before the age of 40 years E One in three persons develops cancer at some time during their lives, and one in four dies from his disease 54,000 new cases E 12,500 deaths E €  Three times more frequently in than in E € 4th most common cancer in  7th most common cancer in E I n areas where Schistosoma haematobium is endemic E € The most common cancer (25%) in E

5. In Sudan? حالات السرطان فى السودان!! My personal advice ست الودع طالب دراسات عليا National Cancer registry (1968) Steps on the wrong direction The only available data The radiation and isotopes Center Khartoum and Madani

7. Commonest cancer for Sudanese Males 1997-2000 C.M. Leukemia Lymphosarcoma 4% 4% Oesophagus 5% 24% 6% Testis 7% Hypopharynx Bladder 10% Bone 17% 10% H.D 13% Thyroid gland Rectum

9. What is Cancer Genetics? • Molecular pathology. • Tumor biology. • Molecular genetics. • Cytogenetics. • Epidemiology. • Others.

10. Tumor Growth By the time a tumor is detected, it already contains about a billion cells. Does a tumor originate from a single abnormal cell?

11.                           What is Cancer?

12. Aging process!

13. Uncontrolled cell division Loss of Normal Growth Control

14. The whole scenario Mutation

15. Mutation Mutation

16. Disturbed apoptosis weeding ☻Immortal cells! ☻Deranged growth control ☻Continuous cell proliferation ☻Deranged growth control

17.                           What is Cancer?

18. The somatic mutation theory of cancer Theodor Boveri (1862-1915) Acquired genetic changes are the main causes of malignant transformation oftarget cells

19. Nowell&Hungerford, 1960

20. G-bands R-bands C-bands Q-bands Caspersson et al., 1970

21. Rowley, 1973

22. Summary

23. Carcinogens Diet Biological Chemicals Physical Heredity N z

25. Cancer & Ethnicity • Anglo men – higher rates of bladder cancer. • Hispanics – lowest rates of lung cancer but women have highest rates of cervix cancer. • Blacks – highest rates of prostate cancer. • Japanese – highest rates of stomach cancer. • Chinese- Americans lowest rates of liver cancer. • Northern Europeans – high rates of breast cancer.

26. Polymorphisms • Polymorphism in CYP1A1 found in 10% of Caucasians associated with increased inducibility produces heightened activation of carcinogens in tobacco smoke. • CYP genes also play a role in the metabolism of estrogens making them relevant to breast cancer. • N-acetyltransferases (NATs) play a role in detyoxifying aromatic amines in tobacco smoke. Individuals with 2 mutant NAT2 alleles exhibit “slow acetylator phenotype”with reduced detoxification of aromatic amines and an association with bladder cancer.

28. Style of live and cancer

30. Large number of dividing cells Large variable shaped nuclei Small cytoplasmic volume relative to nuclei Variation in cell size and shape Loss of normal specialized cell features Disorganized arrangment of cells Poorly defined tumor boundary

31. Cancer cell characteristics

32. Natural history of cancer Histology The development of Carcinomas Invasive Cancer In situ Cancer Dysplasia Hyperplasia Mutation

33. Initiation Promotion Biology of Cancer! Genetic (Oncogenes/ tr suppressor genes) Epigenetic (clonal expansion) Mitogenesis Immune surveillance Angiogenesis Progression

34. Ist Hit Normal Cell Mild Dysplasia Apoptosis 2nd Hit Repair Severe Dysplasia Apoptosis 3rd Hit Apoptosis Multihit theory Cancer

35. ? ? Well differentiated Moderately differentiated Poorly differentiated Undifferentiated Genetic alterations 100 GSTP expression inflammation Gene defects Proliferation Oxidative stress 0 30 year 80 year Normal PIA PIN PCA

36. Multistep Carcinogenesis in Prostate Cancer

37. Multistep Carcinogenesis of Prostate Cancer Hit 4 Hit 5 Hit 1 Hit 2 Hit 3 Ist oncogene activated 2nd oncogene activated Loss of Invasion suppressor gene Ist TSG deleted 2nd TSG deleted (e.g c-Erb) (e.g RB gene) (e.g c-myc) (e.g p53) E-cadherin) PIN (prostatic intraepithelial neoplasia) Microscopic latent CA prostate Metastatic CA prostate Normal Prostate cells Locally invasive CA prostate

39. The Big PictureMultihit ± Synergism "MUTATOR" ACTIVATED ONCOGENE 1 ONCOGENE 2 ACTIVATED INACTIVATED TSG CANCER

40. Activation of Oncogenes by Chromosomal Translocations

41. CRC

42. Cancer Cells Contain Multiple Mutations Normal Epithelium loss of APC Abnormal Proliferation Early Adenoma activation of RAS loss of DPC4 Late Adenoma loss of p53 Carcinoma

43. The Good, the Bad, and the Ugly • Tumor suppressor genes prevent transformation of cells [good] • Oncogenes cause transformation [Bad] • Loss of genomic integrity [Ugly] • Inactivation of tumor suppressor genes. • Activation of oncogenes.

44. Genetic changes contribute to carcinogenesis Gene amplification Retroviral insertion Point mutation Chromosome translocation Oncogenes Normal cell Tumor cell Tumor suppressor genes DNA repair genes Point mutation Imprinting (methylation) Deletion (LOH), partial or whole chromosome loss DNA tumor virus

45. Alterations of Specific Cellular Functions in Cancer DNA Repair Oncogenes Activation Tumor Suppressor Genes Inactivation Differentiation Apoptosis/Proliferation CANCER

46. Gene group Example Chromosomal location Oncogenes MYC, ABL 8q24, Tumor suppressor genes TP53, RB1 17p13, 13q14 DNA repair genes MSH2, PMS2 2p21, 3p21 Apoptosis regulating genes BCL2 18q21 Cell cycle regulator genes CDKN2A, MDM2 9p21, 12q14 Genes involved in tumorigenesis

47. Normal Hereditary Retinoblastoma Sporadic Retinoblastoma Germaine mutation Somatic mutation Occasional mutation of one allele - no tumor Rare second mutation Retinoblastoma Retinoblastoma Familial Cancer Syndromes Retinoblastoma Knudson’s “Two Hit” Hypothesis

48. Mutation Definition Germinal and/or acquired, stable alteration in DNA sequence or amount causing harmful, beneficial, or neutraleffects. Chromosome Gene DNA Molecule Chemical bases

49. Mutation …Bad ….Good It is good, it is bad also!! • Mutation in the long term it is essential to our existence. • Without mutation there Could be no change and without change life cannot evolve. Ex. Adaptive mutation

50. Definition of mutation A change in DNA • Arrangement. • Context. • Dosage. • Sequence.