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Cancer Genetics - Denise Sheer

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Hallmarks of Cancer, Cancer Genetics, Genomics, Mutations, Chromosome Defects, DNA Damage, Oncogenes, Tumour Suppressor Genes, Cancer Risk, Diagnosis, Prognosis, Targeted Treatment, CML, Philadelphia …

Hallmarks of Cancer, Cancer Genetics, Genomics, Mutations, Chromosome Defects, DNA Damage, Oncogenes, Tumour Suppressor Genes, Cancer Risk, Diagnosis, Prognosis, Targeted Treatment, CML, Philadelphia Chromosome, ABL, HRAS, KRAS, MYC, EGFR, RB, TP53, BRAF, Molecular Pathology

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  • 1. Molecular Foundations of Cancer Prof Denise Sheer
  • 2. Overview 1. Understand the principles of the Hallmarks of Cancer 2. Discuss the types of genomic changes that occur during cancer development 3. Understand the roles of oncogenes and tumour suppressor genes 4. Account for the fact that cancer risk can be inherited 5. Identify the uses of genomics in cancer diagnosis and treatment 6. New directions
  • 3. At the cellular level, cancer is a disease of the genome • Cancer arises from the accumulation of genetic aberrations in somatic cells • These aberrations consist of mutations and chromosome defects • Epigenetic aberrations are also present • Together, they lead to altered gene expression • Over 500 genes are now known to be involved in cancer development
  • 4. Advances in cancer “omics” Whole Genome SequencingExome Sequencing RNA Sequencing Protein Sequencing mRNA ncRNA proteins DNA Methylated DNA Methylated DNA sequencing TRANSCRIPTOME PROTEOME GENOMEEXOME METHYLOME
  • 5. Advances in cancer “omics” E.D.Green et al, Nature 2011, 470:204-213
  • 6. Driver mutations in the multistage evolution of cancer Clearly seen in the development of colorectal cancer
  • 7. Cellular heterogeneity within tumours
  • 8. 1. Understand the principles of the Hallmarks of Cancer Cancer •  A disease of extraordinary diversity and complexity •  But - disparate malignancies share fundamental qualities •  The complexity merely reflects different solutions to the same challenge: Cancer cells must overcome multiple barriers used by the organism to prevent expansive cell proliferation Hanahan & Weinberg 2000, 2011
  • 9. Hanahan & Weinberg 2000, 2011 The Hallmarks are acquired capabilities that allow tumours to overcome these barriers
  • 10. Hanahan & Weinberg 2011 The Hallmarks are acquired capabilities that allow tumours to overcome these barriers
  • 11. Mechanisms for acquiring the Hallmarks of Cancer Hanahan & Weinberg, 2000 & 2011 Sustaining proliferative signaling Evading growth suppressors Avoiding immune destruction Enabling replicative immortality Tumor- promoting inflammation Activating invasion & metastasis Inducing angiogenesis Genome instability & mutation Resisting cell death Deregulating cellular energetics Activate cellular oncogenes Inactivate TP53 Produce IGF survival factor Switch on telomerase Inactivate DNA repair genes Induce VEGF Secrete TGFβ Inactivate E-cadherin Induce aerobic glycolysis Redirect Inflammation- promoting cells
  • 12. Major classes of cancer genes
  • 13. Genetic and epigenetic aberrations give rise to the hallmarks of cancer If we know which genes are involved, we can: •  Have a better understanding of cancer biology •  Develop diagnostic and prognostic markers •  Follow the clinical course •  Develop targeted treatment
  • 14. Genetic aberrations affect the DNA sequence in the cells that give rise to cancer 2. Types of genomic changes that occur during cancer development MUTATIONS CHROMOSOME DEFECTS can also be described as “mutations”
  • 15. Causes of genetic aberrations in cancer DNA damage by radiation & carcinogenic agents DNA repair defects Defects in the mitotic machinery Recombinase machinery Telomere dysfunction Adapted from Essential Cell Biology, Alberts et al, 3rd Ed.
  • 16. Mutation • Change in the DNA sequence • Germ-line or somatic •  Rate in humans ~5x10-9 /nucleotide / generation = 25 mutations /cell /generation •  Neutral, favourable, or non-favourable
  • 17. Types of mutation Missense TGC GTG TTT TGC CTG TTT C V P C L P Silent TGC GTG TTT TGC GTA TTT C V P C V P Nonsense TGC GTG TTT TGA GTA TTT C V P stop V P Frame shift TGC GTG TTT TGC AAG TGT TT C V P C K Y C = cysteine V = valine P = proline L = leucine K = lysine Y = tyrosine
  • 18. Chromosome aberrations STRUCTURAL translocation inversion insertion duplication amplification deletion NUMERICAL loss or gain of whole chromosome loss of gain of whole chromosome set
  • 19. Chromosome aberrations Metaphase spread Karyotype
  • 20. Chromosome aberrations Chromosome aberrations Metaphase spread Karyotype
  • 21. Glioblastoma (Grade IV Astrocytoma) Multiple chromosome rearrangements
  • 22. Chronic Myeloid Leukaemia Philadelphia Chromosome 9;22 translocation – t(9;22)
  • 23. Chronic Myeloid Leukaemia 9;22 translocation – t(9;22)
  • 24. Many layers of epigenetic regulation All can be disrupted in cancer Gene Expression Non-coding RNA DNA methylation Histone modifications N.Tsankova, Nat Rev Neurosc 2007
  • 25. 3. Oncogenes and tumour suppressor genes ONCOGENES •  First identified in transforming retroviruses •  Act by gain of function •  Dominant (activation of one allele sufficient) •  Activated by •  mutation •  chromosome translocation •  gene amplification •  retroviral insertion
  • 26. RAS genes – H-RAS, K-RAS, N-RAS Activated by mutations which change amino acids 12, 13 or 61 in ~30% of tumours RAF MEK1/2 ERK1/2 RAS P P Proliferation NF1 ONCOGENES RAS - Mutation Receptor  Tyrosine  Kinases   Extracellular  Signals  
  • 27. Incidence of HRAS, KRAS & NRAS gene mutations Adapted from Downward, Nature Rev Cancer 2003, & The Biology of Cancer (© Garland Science 2007) ONCOGENES - Mutation
  • 28. ONCOGENES - Mutation MYC MYC MYC genes – MYC, MYCN, MYCL Activated by mutations, chromosome translocation and amplification Note: MYC is also called c-MYC Transcription factor Proliferation MYC
  • 29. ONCOGENES Tumour Type Oncogene Interacting gene Chronic Myeloid Leukaemia (CML) ABL (9q34) BCR (22q11) Acute Lymphoblastoid Leukaemia (ALL) MLL (11q23) AF4 (4q21), AF9 (9p22), ENL (19p13) Acute Myeloid Leukaemia (AML) FUS (16p11) ERG (21q22) Burkitt’s lymphoma MYC (8q24) IGH (14q32) Follicular B-cell lymphoma BLC2 (18q21) IGH (14q32) T-cell leukaemia LMO1 (11p15), LMO2 (11p13), TAL1 (1p32) TRD (14q11) Ewing sarcoma EWS (22q12) FLI1 (11q24) Prostate cancer ERG (21q22) TMPRSS2 (21q22) Pilocytic astrocytoma BRAF (7q34) KIAA1549 (7q34) Glioblastoma FGFR3 (4p16) TACC3 (4p16) -  Gene fusion
  • 30. Chronic Myeloid Leukaemia 9;22 translocation – t(9;22) ONCOGENES -  Gene fusion (chromosome translocation)
  • 31. Glioblastoma D.Singh et al, Science 2012 x TACC3FGFR3 Gene fusion ONCOGENES -  Gene fusion (tandem duplication)
  • 32. - Gene Amplification multiple copies ONCOGENES Neuroblastoma MYCN MYC MYC MYC MYCMYC MYCL MYCN
  • 33. Frequencies of mutations across human tumours Thomas et al,Nat Genet, 2008 ONCOGENES
  • 34. TUMOUR SUPPRESSOR GENES • First identified for inherited Retinoblastoma and Wilm’s Tumour • Act by loss of function • Recessive (inactivation of both alleles necessary) • Inactivated by • mutations • deletions • DNA methylation (epigenetic) • Cause predisposition to cancer
  • 35. TUMOUR SUPPRESSOR GENES Knudson’s Two-Hit Model Adapted from Knudson, Proc Natl Acad Sci 1971 deletion / mutation: inherited or somatic Mutation Loss Loss & duplication Chromosome deletion Recombination
  • 36. TUMOUR SUPPRESSOR GENES RB - retinoblastoma •  Crucial regulator of the cell cycle •  Ubiquitously expressed •  Inactivating mutations and deletions in sporadic tumours •  Germ-line defects cause retinoblastoma and osteosarcomas 13
  • 37. TUMOUR SUPPRESSOR GENES RB – retinoblastoma – RB hyperphosphorylation allows the cell to enter late G1 The Biology of Cancer (© Garland Science 2007) A: cyclin A B: cyclin B D: cyclin D E: cyclin E
  • 38. TUMOUR SUPPRESSOR GENES • Transcription factor • Crucial role in the cell’s response to stress • Frequently mutated or deleted in cancer • Germ-line defects in the Li-Fraumeni syndrome cause bone and soft tissue sarcomas, brain tumours 17 p53 (TP53)
  • 39. The Biology of Cancer (© Garland Science 2007)
  • 40. Distribution of mutations over the p53 gene The Biology of Cancer (© Garland Science 2007)
  • 41. Skin Cancer Lung Cancer Liver Cancer High frequency of C->T transitions at dipyrimidine sites High frequency of transversions; hotspots at codons 157,158 High frequency of transversions; hotspot at codon 249 http://p53.free.fr/ TUMOUR SUPPRESSOR GENES p53 (TP53)
  • 42. TUMOUR SUPPRESSOR GENES p53 (TP53) – response to stress The Biology of Cancer (© Garland Science 2007)
  • 43. Variation in the numbers of mutations in different malignancies
  • 44. The six most frequently mutated genes in selected malignancies
  • 45. 4. Account for the fact that cancer risk can be inherited Inherited genetic defects can cause predisposition to cancer Adapted from Knudson, Proc Natl Acad Sci 1971 deletion / mutation: inherited or somatic Mutation Loss Loss & duplication Chromosome deletion Recombination
  • 46. Examples of tumour suppressor genes and associated cancer syndromes Adapted from The Biology of Cancer (© Garland Science 2007) Gene Location Familial Cancer Syndrome Sporadic Cancer Function of Protein VHL 3p25 Von-Hippel Lindau syndrome Renal Cell Carcinoma Ubiquitylation of HIF APC 5q21 Familial Adenomatous Polyposis Coli Colorectal, Pancreatic, Stomach, Prostate Carcinomas Degradation of β-catenin WT1 11p13 Wilms tumour Wilms tumour Transcription Factor RB 13q14 Retinoblastoma, Osteosarcoma Retinoblastoma, Sarcomas, Bladder, Breast, Oespohageal and Lung Carcinomas Control of E2F, Transcriptional Repression TP53 17p13 Li Fraumeni syndrome Many types Transcription Factor NF1 17q11 Neurofibromatosis Type 1 Colon Carcinoma, Astrocytoma Negative Regulator of MAPK Pathway BRCA1 17q21 Familial breast/ovarian cancer Breast, Ovary, Cervix, Endometrium,Colon, Stomach, Thyroid carcinomas DNA double-strand break repair SNF5 22q11 Rhabdoid Predisposition syndrome Malignant Rhabdoid Tumours Chromatin Remodelling
  • 47. 4. Identify the uses of genetics in cancer diagnosis and treatment Adapted from Stratton 2011 Biology of neoplastic change Drug targets Monitoring cancer burden Early diagnosis Evolution of the cancer clone Metastasis Drug resistance Progression & response to therapy Classification of cancer DNA repair processes Mechanisms of DNA damage
  • 48. Cancer Diagnosis Many tumours have specific genetic abnormalities x ABL xPML RARA PML-RARA BCR-ABL IgH-MYC IgH MYCx Chronic myeloid leukaemia Acute promyelocytic leukaemia Ewing’s sarcoma Burkitt’s lymphoma, B-cell acute lymphoblastic leukaemia BCR t(15;17) t(9;22) t(8;14) xEWS FLI1 EWS-FLI1 t(11;22)
  • 49. Opportunities for targeted treatment Hanahan & Weinberg 2011
  • 50. Examples of targeted treatment Genetic changes indicate which processes and pathways can be targeted GLEEVEC/STI571 RETINOIC ACID x ABL xPML RARA PML-RARA BCR-ABL Chronic myeloid leukaemia Acute promyelocytic leukaemia BCR t(15;17) t(9;22)
  • 51. Targeted treatment of the MAPK pathway Proliferation RAF MEK1/2 ERK1/2 RAS NF1 Specific inhibitors P P Receptor  Tyrosine  Kinases   Extracellular  Signals  
  • 52. G Bollag et al. Nature 467, 596-599 (2010) Targeting mutated BRAF in metastatic melanoma BRAF MEK1/2 ERK1/2 RAS NF1 Proliferation PLX4032 P P
  • 53. Hanahan & Weinberg (2000) Hallmarks of Cancer. Cell 100: 57-70 Hanahan & Weinberg (2011) Hallmarks of Cancer: The Next Generation. Cell 144: 646-674 Weinberg (2014) The Biology of Cancer, 2nd edition. Garland Science, Taylor & Francis Group, LLC Stratton et al (2009) The Cancer Genome Nature 458: 719-724 Stratton (2011) Exploring the Genomes of Cancer Cells: Progress & Promise. Science 331: 1553-1558 McDermott et al (2011) Genomics and the Continuum of Cancer Care. N Engl J Med 364(4): 340-50 Vogelstein et al (2013) Cancer Genome Landscapes. Science 339(6127): 1546-58 Garraway & Lander (2013) Lessons from the Cancer Genome. Cell 153(1): 17-37 For more information (and really great to read!)
  • 54. Contact me if you have any questions….. D.Sheer@qmul.ac.uk

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