Cellular Defenses Against Radiation-Induced Carcinogenesis:

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Li-Fraumeni Syndrome • Caused by a germline mutation in p53 gene (TP53) • Characterized by the occurrence of early onset: • sarcomas • breast cancer • brain tumours • leukemia • adrenocortical tumors NCI REB <strong>Radiation</strong> Epidemiology Course, May 14, 2007 TJJ
Mutations in Chk2 produce the Li-Fraumeni phenotype Family pedigree with proband (1265, arrow) diagnosed with both breast cancer and sarcoma. A heterozygous germline mutation in CHK2 is accompanied by loss of the wild type CHK2 allele in breast cancer of the proband. The mutant R145W allele encodes and unstable protein. (S.B. Lee et al. Cancer Res. 61: 8062, 2001) NCI REB <strong>Radiation</strong> Epidemiology Course, May 14, 2007 TJJ
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Cellular Defenses Against Radiation
Page 3 and 4: GOALS: • Provide an overall descr
Page 5 and 6: NCI REB Radiation Epidemiology Cour
Page 9 and 10: Cancer cells “evolve” into a hi
Page 11 and 12: WHY CHECKPOINTS Fidelity of cell di
Page 17 and 18: Cyclin/CDK complexes seem to be reg
Page 19 and 20: • At least two checkpoints are re
Page 21 and 22: DO DEFECTIVE CHECKPOINTS CAUSE CANC
Page 23 and 24: Radiation-Induced G2 delay in lymph
Page 27 and 28: Rothkamm and Lobrick, PNAS, 2003 NC
Page 29 and 30: Somatic Mutation and Cancer Environ
Page 31 and 32: Major DNA repair pathways: • Non-
Page 37 and 38: “… the failure of DNA repair in
Page 39 and 40: T. Lindahl and R.D. Wood, Science 2
Page 41 and 42: NER PATHWAY GENES GENE ALIASES DESC
Page 43 and 44: Mismatch repair associated tumors i
Page 45 and 46: Non-Homologous End Joining (NHEJ) N
Page 47 and 48: Illegitimate Recombination NCI REB
Page 49 and 50: TARGET THEORY NCI REB Radiation Epi
Page 51 and 52: A-T CELL CANCER CELL DEATH NCI REB
Page 53: OTHER TARGET QUESTIONS: • If DNA
Page 57 and 58: CASE STUDY: Finding Molecular Targe
Page 63 and 64: Environmental Causes of BCC • UV
Page 65 and 66: UV DAMAGE TO DNA NCI REB Radiation
Page 67 and 68: NER PATHWAY GENES GENE ALIASES DESC
Page 69 and 70: Skin cancers have unique p53 mutati
Page 71 and 72: For BCC, PTCH may be even a bigger
Page 73 and 74: Gorlin Syndrome • Nevoid basal ce
Page 75 and 76: Verónica Martín, Graciela Carrill
Page 77 and 78: Taipale J and Beachy PA Nature 411:
Page 79 and 80: PTCH may play a role in cell cycle
Page 83 and 84: Aszterbaum et al. Nature Med. 5:128
Page 85 and 86: Shh, PTCH, and SUFU mutations produ
Page 87 and 88: Thomas et al., J. Postgrad Med. 49:
Page 91 and 92: Veratrum californicum (corn lily) N
Page 93 and 94: Frank-Kamenetsky et al. J. Biol. 1:
Page 95 and 96: CONFOUNDERS: AGE SKIN COLOR DOSE NC
Page 97 and 98: • A disease of accelerated aging.
Page 99 and 100: Age-Dependent Reactive Oxygen Speci
Page 101 and 102: SKIN COLOR GENETICS NCI REB Radiati
Page 103 and 104: Am J Epidemiol 155: 614, 2002 Melan
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Melanocortin 1 Receptor gene (MC1R)
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SKIN COLOR GEOGRAPHY Photograph by
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DOSE NCI REB Radiation Epidemiology
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National Geographic Magazine April
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Aging genes (I.e. non-DNA repair) A
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RR for XP patients by age 8000 8000
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Radiation as a Model Carcinogen:
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