Principles of Cancer Genetics

<p> </p> <p>Preface</p> <p>Chapter 1: The Genetic Basis of Cancer</p><p>The cancer gene theory</p><p>Cancers are invasive tumors</p><p>Cancer is a unique type of genetic disease</p><p>What are cancer genes and how are they acquired?</p><p>Mutations alter the human genome</p><p>Genes and mutations</p><p></p>Single nucleotide substitutions<p></p><p>Gene silencing is marked by cytosine methylation: epigenetics</p><p>Environmental mutagens, mutations and cancer</p><p>Inflammation promotes the propagation of cancer genes</p><p>Stem cells, Darwinian selection and the clonal evolution of cancers</p><p>Selective pressure and adaptation:  hypoxia and altered metabolism</p><p>Multiple somatic mutations punctuate clonal evolution</p>Tumor growth leads to cellular heterogeneity<p></p><p>Tumors are distinguished by their spectrum of driver gene mutations and passenger gene mutations</p><p>Colorectal cancer: a model for understanding the process of tumorigenesis</p><p>Do cancer cells divide more rapidly than normal cells?</p><p>Germline cancer genes allow neoplasia to bypass steps in clonal evolution</p><p>Cancer syndromes reveal rate-limiting steps in tumorigenesis</p><p>The etiolog</p>ic triad: heredity, the environment, and stem cell division<p></p><p>Understanding cancer genetics</p><p> </p><p>Chapter 2:  Oncogenes</p><p>What is an oncogene?</p><p>The discovery of transmissible cancer genes</p><p>Viral oncogenes are derived from the host genome</p><p>The search for activated oncogene</p><p></p><p></p><p></p><p></p><p></p>s:  the RAS gene family<p></p>Complex genomic rearrangements: the MYC gene family<p></p><p>Proto-oncogene activation by gene amplification</p><p>Proto-oncogenes can be activated by chromosomal translocation</p><p> </p><p>Chromosomal translocations in liquid tumors</p><p>Chronic myeloid leukemia and the Philadelphia chromosome</p><p>Oncogenic activation of transcription factors in Prostate cancer and Ewing’s sarcoma </p>Oncogene discovery in the genomic era: mutations in PIK3CA <p></p><p>Selection of tumor-associated mutations</p><p>Multiple modes of proto-oncogene activation</p><p>Oncogenes are dominant cancer genes</p><p>Germline mutations in RET and MET confer cancer predisposition</p><p>Proto-oncogene activation and tumorigenesis</p><p> </p><p></p>Chapter 3:  Tumor Suppressor Genes<p></p><p>What is a tumor suppressor gene?</p><p>The discovery of recessive cancer phenotypes</p><p>Retinoblastoma and Knudson’s two-hit hypothesis</p><p>Chromosomal localization of the retinoblastoma gene</p><p>The mapping and cloning of the retinoblastoma gene </p><p>Tumor suppressor gene inactivation: the second ‘hit’ and loss of heterozygosity</p>Recessive genes, dominant traits<p></p><p>APC inactivation in inherited and sporadic colorectal cancers</p><p>TP53 inactivation: a frequent event in tumorigenesis </p><p>Functional inactivation of p53: tumor suppressor genes and oncogenes interact</p><p>Mutant TP53 in the germl</p>ine:  L<p></p>i Fraum<p></p>eni syn<p></p>drome<p></p><p>Ga</p>ins-of-function caused by cancer-associated mutations in TP53<p></p><p>Cancer predisposition: allelic penetrance, relative risk and the odds ratio</p><p>Breast cancer susceptibility:  BRCA1 and BRCA2</p><p>Genetic losses on chromosome 9:  CDKN2A</p><p>Complexity at CDKN2A:  neighboring and overlapping genes</p><p>Genetic losses on chromosome 10:  PTEN</p><p>SMAD4 and the maintenance of stromal architecture</p>Two distinct genes cause neurofibromatosis<p></p><p>From flies to humans, Patched proteins regulate developmental morphogenesis</p><p>von Hippel-Lindau disease</p><p>NOTCH1: tumor suppressor gene or oncogene?</p><p>Multiple endocrine neoplasia type 1</p><p>Most tumor suppressor genes are tissue-specific </p><p>Modeling cancer syndromes in mice</p><p></p>Genetic variation and germline cancer genes<p></p><p>Tumor suppressor gene inactivation during colorectal tumorigenesis</p><p>Inherited tumor suppressor gene mutations: gatekeepers and landscapers</p><p>Maintaining the genome: caretakers </p><p> </p><p>Chapter 4:  Genetic Instability and Cancer</p><p>What is genetic instability?</p><p></p>The majority of cancer cells are aneuploid<p></p><p>Aneuploid cancer cells exhibit chromosome instability</p><p>Chromosome instability arises early in colorectal tumorigenesis</p><p>Chromosomal instability accelerates clonal evolution</p><p>Aneuploidy can result from mutations th</p>at directly im<p></p>pact mitosis<p></p><p>STAG2</p> and<p></p> the cohesion <p></p>of sister chromatids<p></p><p>Other genetic and epigenetic causes of aneuploidy</p>Transition from tetraploidy to aneuploidy during tumorigenesis  <p></p><p>Multiple forms of genetic instability in cancer</p><p>Defects in mismatch repair cause hereditary nonpolyposis colorectal cancer</p><p>Mismatch repair-deficient cancers have a distinct spectrum of mutations</p><p>Defects in nucleotide excision repair cause xeroderma pigmentosum</p><p>NER syndromes: clinical heterogeneity and pleiotropy</p><p></p>DNA repair defects and mutagens define two steps towards genetic instability<p></p><p>Defects in DNA crosslink repair cause Fanconi anemia</p><p>A defect in DNA double strand break responses causes ataxia-telangiectasia</p><p>A unique form of genetic instability underlies Bloom syndrome </p><p>Aging and cancer:  insights from the progeroid syndromes</p><p>Instability at the end: telomeres and telomerase</p><p>Overview: genes and genetic stability</p><p></p> <p></p><p>Chapter 5:  Cancer Genomes</p><p>Discovering the genetic basis of cancer: from genes to genomes</p><p>What types of genetic alterations are found in tumor cells?</p><p>How many genes are mutated in the various types of cancer?</p><p>What is the significance of the mutations that are found in cancers?</p><p>When do cancer-associated mutations occur?</p><p></p>How many different cancer genes are there? <p></p>How many cancer gene</p>s are required for th<p></p>e development <p></p>of cancer?<p></p><p>Cance</p>r genetics sha<p></p>pes our understanding<p></p> of metastasis<p></p><p>Tumors are genetically heterogenous</p><p>Beyond the exome: the ‘dark matter’ of the cancer genome</p><p>A summary:  the genome of a cancer cell</p><p> </p><p></p>Chapter 6:  Cancer Gene Pathways<p></p><p>What are cancer gene pathways?</p><p>Cellular pathways are defined by protein-protein interactions</p><p>Individual biochemical reactions, multistep pathways, and networks</p><p>Protein phosphorylation is a common regulatory mechanism </p><p>Signals from the cell surface:  protein tyrosine kinases </p><p>Membrane-associated GTPases:  the RAS pathway</p><p></p>An intracellular kinase cascade: the MAPK pathway<p></p><p>Genetic alterations of the RAS pathway in cancer </p><p>Membrane-associated lipid phosphorylation: the PI3K/AKT pathway</p><p>Control of cell growth and energetics:  the mTOR pathway </p><p>Genetic alterations in the PI3K/AKT and mTOR pathways define roles in cell survival</p><p>The STAT pathway transmits cytokine signals to the cell nucleus</p><p>Morphogenesis and cancer:  the WNT/APC pathway</p>Dysregulation of the WNT/APC pathway in cancers<p></p><p>Notch signaling mediates cell-to-cell communication</p><p>Morphogenesis and cancer:  the Hedgehog pathway</p><p>TGF-/ SMAD signaling maintains adult tissue homeostasis</p><p>MYC is a downstream effector of multiple cancer gene pathways</p> activation is triggere</p>d by damaged or incompletely<p></p> replicated chromosom<p></p>es <p></p><p>p53 is controlled b</p>y protein kinases enc<p></p>oded by <p></p>tumor suppressor genes<p></p><p>p53 induces the transcription of genes that suppress cancer phenotypes</p><p>Feedback loops dynamically control p53 abundance </p><p>The DNA damage signaling network activates interconnected repair pathways</p><p>Inactivation of the pathways to apoptosis in cancer</p><p>RB1 and the regulation of the cell cycle</p><p>Several cancer gene pathways converge on cell cycle regulators</p><p></p>Many cancer cells are cell cycle checkpoint-deficient<p></p><p>Chromatin modification is recurrently altered in many types of cancer</p><p>Summary: putting together the puzzle  </p><p> </p><p>Chapter 7:  Genetic Alternations in Common Cancers</p><p>Cancer genes cause diverse diseases</p><p>Cancer incidence and prevalence</p><p>Lung cancer</p><p></p><p>Prostate cancer</p><p>Breast cancer</p><p>Colorectal cancer</p><p>Endometrial cancer</p><p>Melanoma of the skin</p><p>Bladder cancer</p><p>Lymphoma</p><p>Cancers in the kidney</p>Thyroid cancer<p></p><p>Leukemia</p><p>Cancer in the pancreas</p><p>Ovarian cancer</p><p>Cancers of the oral cavity and pharynx</p><p>Liver cancer</p><p>Cancer of the uterine cervix</p><p>Stomach cancer</p><p></p>Brain tumors<p></p><p> </p><p>Chapter 8: Cancer Genetics in the Clinic</p><p>The uses of genetic information</p><p>Elements of cancer risk:  carcinogens and genes </p><p>Identifying carriers o</p>f germline cancer genes<p></p><p>Cance</p>r genes as biomarkers of ear<p></p>ly stage malignancies <p></p><p>Cancer </p>genes as biomarkers f<p></p>or diagnosis, prognosis and recurrence<p></p><p>Conventional anticancer therapies inhibit cell growth</p><p>Exploiting the loss of DNA repair pathways: synthetic lethality</p><p>On the horizon: achieving synthetic lethality in TP53-mutant cancers</p><p>Molecularly targeted therapy:  BCR-ABL and imatinib</p><p>Clonal evolution of therapeutic resistance</p><p>Targeting EGFR mutations</p><p></p>Antibody-mediated inhibition of receptor tyrosine kinases<p></p><p>Inhibiting Hedgehog signaling</p><p>A pipeline from genetically-defined targets to targeted therapies </p><p>Neoantigens are recognized by the immune system</p><p>The future of oncology </p><p>Index</p><p> </p><p></p> <p></p>