Genetic Predisposition to Cancer Table

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Genetic Predisposition to Cancer Table

• Genetic predisposition to cancer can be divided
  into 3 categories
• 1. Autosomal dominant inherited cancer syndromes
  are characterized by inheritance of single mutant
  genes that greatly increase the risk of certain
  tumors. These are usually point mutations
  occurring in a single allele of a tumor
  suppressor gene subsequently the remaining
  allele is lost either by chromosome deletion,
  recombination or a second mutation. Examples of
  this type are retinoblastoma and familial
  adenomatous polyposis. Incomplete penetrance and
  variable expressivity are seen in these
  associations.
• Inherited cancer syndromes have some
  characteristic features
• 1. Tumor site is at specific sites or tissues
  retinoblastoma
• 2. Tumors usually have an associated marker
  phenotype (MEN associated with familial polyposis
  of the colon, Familial melanoma associated with
  large number of moles on trunk thorax)

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• 2. Defective DNA repair syndromes are
  characterized by DNA instability that greatly
  increase the predisposition to environmental
  carcinogens (Xeroderma pigmentosa and UV
  exposure)
• 3. Familial cancers are characterized by familial
  clustering of specific cancers but the
  transmission pattern is not clear for individual
  cases breast, colon, brain and ovarian cancers
  can exhibit familial clustering. Familial
  cancers have some common features
• Early age of onset
• Increased incidence of bilateral or multiple
  tumors
• No marker phenotype (familial colon cancers do
  not arise in preexisting colon polyps)
• 4. The predisposition to familial tumors is
  usually autosomal dominant, but Multifactorial
  inheritance is possible as is increased risk due
  to a number of low penetrance alleles.

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• Table 7-6

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Nonhereditary Predisposing Conditions

• Certain clinical conditions are associated with
  an increased risk of developing cancer (liver
  cirrhosis and hepatocellular carcinoma,
  ulcerative colitis and colon cancer).
• Chronic Inflammation
• Chronic inflammation is associated with increased
  carcinogenesis (Virchow 1863). There is an
  increased risk for GI cancers among patients with
  Crohns disease. , H. pylori gastritis, viral
  hepatitis and chronic pancreatitis all
  inflammatory states. This may be associated with
  chronic cytokine production, increased tissue
  stem cells due to ongoing inflammation
  attempted repair or the effects of chronic
  generation of ROS in the inflammatory process.
• Precancerous conditions
• Certain non-neoplastic disorders have such a well
  defined association with cancer that they are
  labeled precancerous conditions solar keratosis
  of the skin, leukoplakia, chronic ulcerative
  colitis, etc. Certain benign tumors are also
  associated with the subsequent development of
  cancer, villous adenomas of the colon often
  developed into cancer. The presence of these
  predisposing conditions warrants close monitoring
  for early diagnosis of cancer.

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THE MOLECULAR BASIS OF CANCER

• Some fundamental principles
• Nonlethal genetic damage lies at the heart of
  carcinogenesis this damage may be acquired
  through the action of environmental agents, may
  be inherited via the germ line or may be the
  result of a spontaneous mutation.
• A tumor is formed by the clonal expansion of a
  single tumor stem cell created as a result of
  genetic damage.
• Four classes of normal regulatory genes are the
  principle targets of genetic damage
• 1. Growth promoting proto-oncogenes
• 2. Growth-inhibiting tumor suppressor genes
• 3. Apoptosis regulating genes
• 4. DNA repair genes

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• Fig 7-26

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• Proto-oncogene mutations appear to be dominant
  in that a single mutated allele can induce
  transduction, both alleles of a tumor suppressor
  gene must be eliminated to promote growth.
  Apoptosis controlling genes may also be dominant.
• DNA repair genes affect cell proliferation by
  influencing the ability of the organism to repair
  non-lethal damage in other genes including 1, 2,
  3. Defects in DNA repair can predispose to
  transforming mutations. Both alleles of a DNA
  repair gene generally need to be damaged to
  induce a mutator phenotype.
• Carcinogenesis is a multi-step process at both
  phenotypic and genotypic levels malignant
  neoplasms possess a series of attributes that are
  acquired in a stepwise fashion. This process of
  tumor progression results from the accumulation
  of a series of genetic lesions a process which
  may be accelerated by defects in DNA repair.

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Essential Alterations for Malignant Transformation

• There are seven fundamental changes in cell
  physiology that in combination determine the
  malignant phenotype
• Self sufficiency in growth signals tumors have
  the capacity to proliferate without external
  stimuli usually as a consequence of inappropriate
  proto-oncogene activation
• Insensitivity to growth inhibitory signals,
  tumors may not respond to molecules that are
  inhibitory to the proliferation of normal cells
  (TGF-ß) and inhibitors of cyclin-dependent
  kinases (CDKs).
• Evasion of apoptosis, tumor cell may be resistant
  to directed cell death.
• Defects in DNA repair
• Limitless replicative potential associated with
  maintenance of telomere length
• Sustained angiogenesis, induction of
  vasculogenesis (usually via VEGF) is necessary
  for continued tumor growth
• Ability to invade and metastasize, metastasis
  depends on intrinsic capabilities of tumor cell
  metastatic disease is responsible for the
  majority of cancer deaths.

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The Molecular Basis of Cancer

• Fig 7-27

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Normal Cell Cycle

• The orderly progression of cells through the cell
  cycle is orchestrated by cyclins and
  cyclin-dependent-kinases and their inhibitors.
  CDKs are expressed constitutively and drive the
  cell cycle by phosphorylating certain target
  proteins CDK activity is regulated by cyclins
  that are selectively synthesized and degraded
  during the cell cycle, after cyclin-CDK
  activation the cyclin is degraded resulting in
  decreased CDK activity.

• Fig 3-3

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• Fig 7-28

• The first critical step in cell division is the
  G1/S restriction point the cyclin D- CDK complex
  functions at this point by phosphorylating a
  protein that allows the initiation of DNA
  replication.
• The second critical restriction point is at G2/M
  transition. Cyclin A-CDK2 and cyclin B-CDK1
  complexes activate this transition.
• CDK inhibitors are important in regulation of CDK
  activity
• The role of p53 in the cell cycle is
  surveillance, particularly with respect to DNA
  integrity, p53 is able to stop or slow cycle
  progression allowing damaged components to be
  repaired, and if irreparable it directs induction
  of apoptosis.

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Self-Sufficiency in Growth Signals

• Tumor growth autonomy occurs when the normal
  steps of cell proliferation occur in the absence
  of growth-promoting signals.
• Dysfunction at every step in signal transduction
  receptor binding, trans-membrane signal
  transduction, second messenger generation
  function, activation of nuclear factors involved
  in DNA expression and progression through the
  cell cycle has been identified in oncogenesis.

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Proto-oncogenes, Oncogenes and Oncoproteins

• Proto-oncogenes are normal cellular genes that
  affect normal growth differentiation.
• Oncogenes are genes that promote autonomous cell
  growth, they are created by mutations of
  proto-oncogenes.
• Oncoproteins are the protein products of
  oncogenes, similar to the products of
  proto-oncogenes but they are devoid of the normal
  regulatory elements.

• Fig 3-10

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Fig 7-31
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• Proto-oncogenes may be converted to oncogenes by
• Point mutations
• Chromosomal rearrangements
• Gene amplification
• Proto-oncogene products include
• Growth factors
• Growth factor receptors
• Signal transduction proteins

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Insensitivity to Growth Inhibitory Signals
Tumor-Suppressor Genes

• Cancer may arise from inactivation or malfunction
  of genes that normally suppress cell
  proliferation.
• Tumorogenesis through loss of inhibition usually
  requires acquisition of abnormalities in both
  alleles of a particular tumor suppressor gene.
• Individuals born with one defective allele would
  only require one mutation to induce tumor
  formation this explains the inherited pattern of
  a number of particular tumors while accounting
  for isolated cases.

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Evasion of Apoptosis

• The accumulation of neoplastic cells requires not
  only the activation of oncogenes or inactivation
  of tumor suppressor, but also the inhibition or
  avoidance of apoptosis.
• Cell division is a highly regulated
  orchestrated process, however mistakes are a
  regular occurrence, these abnormal mitotic
  products are directed to apoptosis either
  self-induced or through interaction with classes
  of immune cells.

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DNA Repair Genomic Instability in Cancer Cells

• DNA repair genes contribute to abnormal cell
  growth indirectly by allowing cells with damaged
  DNA to continue through the cell cycle, this lack
  of repair mechanisms creates an increased risk of
  oncogenesis by permitting the propagation of
  mutations.
• Disorders of DNA repair create genomic
  instability syndromes indicating the increased
  incidence of mutations in these individuals.
• Xeroderma pigmentosum patients have defective DNA
  repair and are at high risk of developing skin
  cancer after exposure to UV light.
• BRCA-1 BRCA-2 mutations are found in 80 of
  familial breast cancers, they also have a 15-40
  incidence of ovarian cancer. Males with BRCA-2
  mutations have a 6-10 risk of breast cancer.
  These genes are involved in the repair of double
  stranded DNA breaks.

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Limitless Replicative Potential Telomerase

• Passage through the cell cycle results in a
  shortening of telomeres, once a certain length is
  attained the cell enters senescence. Telomeres
  are lengthened by telomerase an enzyme that is
  inactive in most somatic cells. 90 of human
  tumor cells have shown reactivation of telomerase
  with resulting replicative immortality

• Fig 1-45

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Development of Sustained Angiogenesis

• Tumor survival at a size gt than 1-2 mm requires
  the induction of angiogenesis. Tumors elaborate
  a number of vasculogenesis factors (PDGF, VEGF,
  FGF etc.). Normal cells also produce
  anti-angiogenic factors (angiostatin
  endostatin) loss of this function may also
  promote tumor angiogenesis. Blocking
  angiogenesis is being studied as an avenue of
  intervention.

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Invasion Metastasis

• Invasion metastasis involves a sequence of
  steps that may be interrupted at any stage by
  host factors. The ability to invade and
  metastasize requires a number of capabilities
  resulting form the accumulation of functional
  abnormalities. This is supported by the clinical
  observation that metastatic disease tends to be a
  function of the duration of neoplastic disease
  however some tumors routinely develop metastasis
  early in the course of the disease.

• Fig 7-26

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Fig 7-43
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The steps in metastasis

• Detachment of tumor cells cadherins are surface
  glycoproteins involved in cell-cell adhesion
  down regulation of cadherin production has been
  identified in several carcinomas.
• Attachment to matrix components allow tumor cells
  to adhere to ECM components
• Degradation of extracellular matrix after
  attachment tumor cells secretion of matrix
  proteolytic enzymes particularly type IV
  collagenases (basement membrane collagen) is
  correlated with metastatic capability.

• Fig 7-42

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Fig 7-44
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• 4. Migration of tumor cells
• 5. Vascular dissemination of tumor cells
  emboli of tumor cells from aggregates with
  lymphocytes platelets, this affords some
  protection from anti-tumor directed T-cells.
• 6. Tissue homing, adhesion and invasion some
  tumors show a distinct preference for metastatic
  involvement. Local tissues may be involved by
  direct extension, however the predilection of
  tumors for certain tissue is due to specific
  organ specific receptor of the tumor emboli.

• Fig 7-42

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Dysregulation of Cancer-Associated Genes

• In addition to mutational activation of oncogenes
  or loss of function of tumor suppressor genes,
  large chromosomal changes as well as epigenetic
  changes can induce malignancy.
• Chromosomal Changes
• Chromosomal translocations inversions can
  activate proto-oncogenes or disrupt tumor
  suppression by removing these genes from their
  normal regulatory environment or the formation of
  hybrid genes that affect transformation and
  malignant characteristics.

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• Gene Amplification
• Amplification of normally suppressed
  proto-oncogenes may induce tumor-genesis by
  overwhelming the ability of the cell to respond
  with adequate tumor suppressor molecules
• Epigenetic Changes
• Methylation of DNA is a mechanism of control of
  gene expression, methylation in the promoter
  region of tumor suppression genes has been
  identified in some GI malignancies. Directed
  methylation/demethylation is being investigated
  as a therapeutic method.

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