Homework #3 is due 11/19 Bonus #2 is posted

1. Homework #3 is due 11/19 Bonus #2 is posted

2. Cancer: • is the loss of control over cell division. • Tumors are normal cells that are dividing inappropriately. • They stop performing their “normal” function, and are dividing repeatedly.

3. Multiple mutations are required for cancer to occur

4. How do these mutations arise?

5. Causes of mutations: • Replication errors • Exacerbated by poor DNA repair • Limited by telomere length

6. Causes of mutations: • Replication errors • Exacerbated by poor DNA repair • Limited by telomere length • Other biological agents • Viruses • Transposons

7. Causes of mutations: • Replication errors • Exacerbated by poor DNA repair • Limited by telomere length • Other biological agents • Viruses • Transposons • Environmental factors • Ultraviolet light • Mutagenic chemicals • smoking, industrial waste, natural toxins

8. 1. Heart Diseases 710,760 29.6 2. Cancer 553,091 23.0 3. Cerebrovascular diseases 167,661 7.0 4. Chronic lower respiratory diseases 122,009 5.1 5. Accidents (Unintentional injuries) 97,900 4.1 6. Diabetes mellitus 69,301 2.9 7. Influenza and Pneumonia 65,313 2.7 8. Alzheimer’s disease 49,558 2.1 Nephritis 37,251 1.5 10. Septicemia 31,224 1.3 US Mortality, 2000 # of deaths % of all deaths Rank Cause of Death Source: US Mortality Public Use Data Tape 2000, National Center for Health Statistics, Centers for Disease Control and Prevention, 2002.

9. Change in the US Death Rates* by Cause, 1950 & 2000 Rate Per 100,000 1950 2000 Cancer HeartDiseases Pneumonia/Influenza CerebrovascularDiseases * Age-adjusted to the 2000 US standard population. Source: US Mortality Volume 1950, National Vital Statistics Report, 2002, Vol. 50, No. 15.

10. 2003 Estimated US Cancer Cases* Men675,300 Women658,800 32% Breast 12% Lung & bronchus 11% Colon & rectum 6% Uterine corpus 4% Ovary 4% Non-Hodgkin lymphoma 3% Melanoma of skin 3% Thyroid 2% Pancreas 2% Urinary bladder 20% All Other Sites Prostate 33% Lung & bronchus 14% Colon & rectum 11% Urinary bladder 6% Melanoma of skin 4% Non-Hodgkin lymphoma 4% Kidney 3% Oral Cavity 3% Leukemia 3% Pancreas 2% All Other Sites 17% *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2003.

11. 2003 Estimated US Cancer Deaths* Men285,900 Women270,600 Lung & bronchus 31% Prostate 10% Colon & rectum 10% Pancreas 5% Non-Hodgkin 4%lymphoma Leukemia 4% Esophagus 4% Liver/intrahepatic 3%bile duct Urinary bladder 3% Kidney 3% All other sites 22% 25% Lung & bronchus 15% Breast 11% Colon & rectum 6% Pancreas 5% Ovary 4% Non-Hodgkin lymphoma 4% Leukemia 3% Uterine corpus 2% Brain/ONS 2% Multiple myeloma 23% All other sites ONS=Other nervous system. *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2003.

12. Cancer Death Rates*, for Men, US, 1930-1999 Rate Per 100,000 Lung Stomach Prostate Colon and rectum Pancreas Liver Leukemia *Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes 1960-1999, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2002.

13. Cancer Death Rates*, for Women, US, 1930-1999 Rate Per 100,000 Lung Uterus Breast Colon and rectum Stomach Ovary Pancreas *Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes 1960-1999, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2002.

15. Tobacco Use in the US, 1900-1999 Male lung cancer death rate Per capita cigarette consumption Female lung cancer death rate *Age-adjusted to 2000 US standard population. Source: Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2001. Cigarette consumption: Us Department of Agriculture, 1900-1999.

17. Tobacco Use in the US, 1900-1999 Male lung cancer death rate Per capita cigarette consumption Female lung cancer death rate *Age-adjusted to 2000 US standard population. Source: Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2001. Cigarette consumption: Us Department of Agriculture, 1900-1999.

19. Treating cancer: • Avoid it • Avoid mutagens • DNA repair gets less efficient as we age

20. Environment plays a large role in the chance of contracting cancer.

21. Our immune system protects us from cancer T-cells recognize and eliminate abnormal cells; such as cells with many mutations

22. P53 is activated by DNA damage

23. p53 can induce apoptosis via two pathways: Nuclear and/or Mitochondrial

24. Treating cancer: • Avoid it • Avoid mutagens • DNA repair gets less efficient as we age • Surgery • Must remove all cancer cells • Non-invasive

25. Treating cancer: • Avoid it • Avoid mutagens • DNA repair gets less efficient as we age • Surgery • Must remove all cancer cells • Non-invasive • Radiation • Directed at tumor; causes DNA damage -> cellular self-destruction • Mutagenic, side effects

26. Treating cancer: • Avoid it • Avoid mutagens • DNA repair gets less efficient as we age • Surgery • Must remove all cancer cells • Non-invasive • Radiation • Directed at tumor • Mutagenic, side effects • Chemotherapy • Toxins directed at rapidly dividing cells • Mutagenic, many side effects

27. Chemotherapy Toxin X X a rapidly dividing cell

28. Normal Multi-Drug Resistance protein toxin/hormone/etc MDR toxin/hormone/etc toxin/hormone/etc MDR MDR MDR toxin/hormone/etc

29. Some cancers over-express MDR toxin toxin toxin toxin Toxin MDR MDR MDR MDR I’m a cancer cell with over-expressing MDR. I laugh at your toxins. MDR toxin toxin MDR toxin MDR toxin MDR MDR MDR MDR MDR toxin toxin toxin toxin

30. Mutations continue after cancer develops The Epigenetic Progenitor Origin of Human Cancer (2007) A P Feinberg, R Ohlsson, S Henikoff Nature Reviews Genetics 7: 21-31

31. Evolution: changes in DNA as information transmitted O O O Cancer cell with mutation causing MDR over-production O O O O O O O O

32. Evolution: changes in DNA as information transmitted O O O Cancer cell with mutation causing MDR over-production O O O O O O O O Apply chemo-therapy X X X O O O X X X O O O O X X X X O O O O Kills most cells. Except if some have mutation that allow them to be resistant.

33. Evolution: changes in DNA as information transmitted O O O Cancer cell with mutation causing MDR over-production O O O O O O O O Apply chemo-therapy Continues to replicate O X X X O O O X X X O O O O X X X X O O O O Kills most cells. Except if some have mutation that allow them to be resistant.

34. Evolution: changes in DNA as information transmitted O O O Cancer cell with mutation causing MDR over-production O O O O O O O O Apply chemo-therapy Continues to replicate O X X X O O O X X X O O O O O O O O O O O X X X X O O O O Kills most cells. Except if some have mutation that allow them to be resistant. O O O O Tumor with cells expressing MDR

35. Some cancers over-express MDR toxin toxin toxin toxin Toxin MDR MDR MDR MDR I’m a cancer cell with over-expressing MDR. I laugh at your toxins. MDR toxin toxin MDR toxin MDR toxin MDR MDR MDR MDR MDR toxin toxin toxin toxin