GENES AND CANCER

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GENES AND CANCER

• ????? ?????? 463020349-8
• ???????????????
• ?????????????? ??????????????????

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GENES

• Gene ?

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GENESDNA
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Mutation

• ????????????? ??????????? 2 ????????????????????
• 1.??????????????? (base substitution)
• Transition
• Transversion
• 2.frameshift mutation ????????????????????????????
  ??????????????????????
• ?????????????????????????????????????????????????
  ???????????????????????????????????
  ??????????????????????

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Mutation

• Endogenous mutation ?????????????????????????????
  ?? ????????????????????????????????
  ???????????????? ?????????????????????????????????
  ??????????? ???????????????????????????????
  ?????????????????????? ???????????????????????????
  ???????????????????????
• deamination of cytosine
• 5-methylcytosine
• ?????????????? DNA polymerase
• ??????????? (free radical)??? ????????????????????
  ??????

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Mutation

• Deamination of 5-methylcytosine
  ??????????????????????????????????????????????????
  ???????????? ????????? cytosine ???
  5-methylcytosine ?????? deaminate ????????????
  uracil ??? thymine ???????? ???????????????????
  ??????????????????????????????? GC ???? AT
  ?????????? ?????????? cytosine ?????????? guanine
  (???????? CpG dinucleotide)

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Acetylation and Methylation of Lysine
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Mutation

• Exogenous mutation ?????????????????????????????
  ????????????????????????????????????????????
  ??????????????????? ??????????????????????????????
  ??? DNA adduct ???????????? ????? DNA polymerase
  ????????????????????????????????
• 6-methylguanine ??????????? alkylating agent
  ?????????????? ????? DNA polymerase ????????????
• carcinogen-DNA adduct ??????????????????
  ??????????????????? DNA polymerase

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CANCER
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CANCER

• ?????? (cancer)???????????????????????????????????
  ??????????????????????
• tumor (neoplasm)
• Beneign tumor ???????????????????????????????????
  ????? ?????? transform ???????? malignant tumor
  ???
• Malignant tumor ?????????????? ??????????
  metastasis ???

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CANCER

• ??????????????????????????????????????????????????
  ????????????????????????????
• ??????????????????????????????????????????????????
  ???????????????? multigene disease
• ????????????????????????????????????????????????
  (multistage) ???????????????????????????????
  (initiation) ???????????????????? (promotion)
  ??????????????????????????????????????????????????
  ?????? ???????????????????????????????????????????
  ????????
• ???????????? (oncogene)
• ????????????? (tumor suppresser gene)
• ??????????????????(DNA repair gene)

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CANCER metastasis
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?????????????????????????

• Chemicals (e.g., from smoking), radiation,
  viruses, and heredity all contribute to the
  development of cancer by triggering changes in a
  cell's genes.
• Chemicals and radiation act by damaging genes,
  viruses introduce their own genes into cells, and
  heredity passes on alterations in genes that make
  a person more susceptible to cancer.
• Genes are inherited instructions that reside
  within a person's chromosomes. Each gene
  instructs a cell how to build a specific
  product--in most cases, a particular kind of
  protein.
• Genes are altered, or "mutated," in various ways
  as part of the mechanism by which cancer arises.

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???????????????????????

• Autonomy ???????????????????????????????????????
• Metastasis ??????????????????????????????????????
  ???????????????? ?????????????????????????
• 1.??????????????????????growth factor
  ????????????
• 2. ??????????????????????receptor
  ?????????????????????????????????????
• 3.???? intracellular signal transduction
  ?????????????????????

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???????????????????????

• 4. ??????????????????????????????????????? cell
  cycle ?????????????????????????????(genomic
  instability)
• 5.??????????? DNA (DNA repair system)
  ????????????????????????? ???????????????????????
  apoptosis

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CELL DIVISION
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CELL DIVISION
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Molecular Biology of Cancer
Causation

• 1. Oncogenes
• 2. Tumor-Suppressor genes
• 3. Apoptosis genes
• 4. DNA repair genes

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Molecular Biology of Cancer
Causation
H-ras
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Molecular Biology of Cancer
Causation

• 1. Oncogenes ?????????????????????????????
• Rous sarcoma virus (RSV)
• RNA virus
• non acute virus
• acute transforming virus

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Selected example of oncogenes (Thomson Thomson,
1991).
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Oncogenes are Mutant Forms of Proto-Oncogenes

• Oncogenes arise from the mutation of
  proto-oncogenes.
• They resemble proto-oncogenes in that they code
  for the production of proteins involved in growth
  control.
• However, oncogenes code for an altered version
  (or excessive quantities) of these growth-control
  proteins, thereby disrupting a cell's
  growth-signaling pathway.
• By producing abnormal versions or quantities of
  cellular growth-control proteins, oncogenes cause
  a cell's growth-signaling pathway to become
  hyperactive.
• To use a simple metaphor, the growth-control
  pathway is like the gas pedal of an automobile.
  The more active the pathway, the faster cells
  grow and divide. The presence of an oncogene is
  like having a gas pedal that is stuck to the
  floorboard, causing the cell to continually grow
  and divide.
• A cancer cell may contain one or more oncogenes,
  which means that one or more components in this
  pathway will be abnormal.

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Molecular Biology of Cancer
Causation

• Tumor-Suppressor Genes ??????????????????????????
  ????? ????????????????????????
  ?????????????????????????????????????
  ??????????????????????????? ????
• 1.retinoblastoma gene (RB gene)
• 2.p53 gene

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1.retinoblastoma gene (RB gene)
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 retinoblastoma

• ???????????????
• Rb gene
• Rb protein ??????????????? cell cycle
• Autosomal dominance
• Chromosome ??? 13
• ??????????????????? cell cycle ???????
  transcription factor ????????

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???????????? retinoblastoma protein
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??????????????? Rb protein

• G1 pRb ?????? E2F (transcriptional factor)
  ????????????? DNA ??????????
• G1/sCDK ,cyclin D complex ???? phosphat ??????
  pRb
• free E2F

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??????????????? Rb protein
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Transcriptional regulation of E2F-responsive genes
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Transcriptional regulation of E2F-responsive genes

• The retinoblastoma protein is a key protein in
  cell cycle control.
• At the beginning of G1, Rb is hypophosphorylated
  and active.
• At the end of G1, Rb is phosphorylated and
  inactivated by cyclin-dependent kinases.

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Tumor-Suppressor Gene p53

• ????????????? (mutation) ?????? p53
  ?????????????? ???????????????????????????????????
  ??????? ?????????????? 50 ?????????????????3,5,6
  ?????? p53 ??????????????????????????????????
  ??????????????????????? ??????????????????????????
  ??????????????????????? ????????????? ??????
  ??????????????????????????????????????????????????
  ????????????????????????????????????????
• ??? p53 ??????????????????????????????????????????
  ???????????????????????????????????????????
  ?????????????????????????????????
  ????????????????????????????? ????????????????????
  ?????????? ???????????????

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Tumor-Suppressor Gene p53

• ??????????? 16-20 ???????
• ????????????????? ????????????????? 17 ??????????
  17p13.116
• ?????????? 11 exon
• ???????????????????????????????????????? 393 ???
  ???????????????? 53 ??????????
• ??? p53 ?????????????????????????????????????????

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Tumor-Suppressor Gene p53

• ??? p53 ????????????????????????????? (tumor
  suppressor gene)?????????????????????????????????
  ???????? ????????????????????? (cell cycle)
  ??????????? G1 ??????????????? S
  ???????????????????? ????????????????????????
  ???????????????? ?????????????? apoptosis
  ????????????????????????????????? ????????
  ????????????????? ????????????????????????????????
  ? p53 ???????????????? ?????????
• ??????????????????????????????????????????????????
  ???? (transcription)?????????????????? ??????
  GADD45, MDM2, WAF1/Cip1 ???????????????????? p53
  ?????????????????????????????????
  ?????????????????????? ???????????????????????????
  ?????

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Tumor-Suppressor Gene p53
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???????????? p53 protein
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??????????????? p53 protein
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Translocations

• Translocations are the transfer of a piece of one
  chromosome to a nonhomologous chromosome.
• Translocations are often reciprocal that is, the
  two nonhomologues swap segments.

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Translocations

• the breakpoint may occur within a gene creating a
  hybrid gene. This may be transcribed and
  translated into a protein with an N-terminal of
  one normal cell protein coupled to the C-terminal
  of another.
• the Philadelphia chromosome found so often in
  the leukemic cells of patients with chronic
  myelogenous leukemia (CML) is the result of a
  translocation which produces a compound gene
  (bcr-abl).

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The Philadelphia Chromosome (Ph1)
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Translocations
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The Philadelphia Chromosome (Ph1) Micrograph
courtesy of Douglas C. Tkachuk.

• This micrograph uses fluorescence in situ
  hybridization (FISH) to reveal the ABL DNA (red)
  and the BCR DNA (green) in the interphase nuclei
  of the leukemic cells of a patient with CML.
• The red dot at left center reveals the location
  of ABL on the normal chromosome 9 the green dot
  (top center) shows BCR on the normal chromosome
  22.
• The combined dots (red green yellow) at the
  lower right reveal the fused BCR-ABL gene on the
  Philadelphia chromosome.

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KaryotypesThe Philadelphia Chromosome (Ph1)
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The Philadelphia Chromosome Micrograph
courtesy of Douglas C. Tkachuk.

• chromosomeThe view on the right side of the
  schematic below should help you interpret the
  micrograph.

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Translocations

• Transcription and translation of the hybrid
  BCR-ABL gene produces an abnormal ("fusion")
  protein that activates constitutively (all the
  time) a number of cell activities that normally
  are turned on only when the cell is stimulated by
  a growth factor,such as platelet-derived growth
  factor (PDGF).

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DNA Repair Genes

• DNA Repair Genes A third type of genes implicated
  in cancer are called "DNA repair genes.
• DNA repair genes code for proteins whose normal
  function is to correct errors that arise when
  cells duplicate their DNA prior to cell division.
  
• Mutations in DNA repair genes can lead to a
  failure in repair, which in turn allows
  subsequent mutations to accumulate.
• People with a condition called xeroderma
  pigmentosum have an inherited defect in a DNA
  repair gene.
• As a result, they cannot effectively repair the
  DNA damage that normally occurs when skin cells
  are exposed to sunlight, and so they exhibit an
  abnormally high incidence of skin cancer. Certain
  forms of hereditary colon cancer also involve
  defects in DNA repair.

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DNA Repair Agents that Damage DNA

• Certain wavelengths of radiation
• ionizing radiation such as gamma rays and x-rays
• ultraviolet rays, especially the UV-C rays (260
  nm) that are absorbed strongly by DNA but also
  the longer-wavelength UV-B that penetrates the
  ozone shield
• Highly-reactive oxygen radicals produced during
  normal cellular respiration as well as by other
  biochemical pathways.
• Chemicals in the environment
• many hydrocarbons, including some found in
  cigarette smoke Link to description of a test
  measuring the mutations caused by the hydrocarbon
  benzopyrene.
• some plant and microbial products, e.g. the
  aflatoxins produced in moldy peanuts
• Chemicals used in chemotherapy, especially
  chemotherapy of cancers

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Agents that Damage DNA
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Agents that Damage DNA

• betanaphthylamine
• 1,8-DINITROPYRENE
• 
  Chlorozotocin

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DNA Repair

• A failure to repair DNA produces a
• mutation

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DNA Repair Types of DNA Damage

• All four of the bases in DNA (A, T, C, G) can be
  covalently modified at various positions.
• One of the most frequent is the loss of an amino
  group ("deamination") resulting, for example,
  in a C being converted to a U.
• Mismatches of the normal bases because of a
  failure of proofreading during DNA replication.
• Common example incorporation of the pyrimidine U
  (normally found only in RNA) instead of T.
• Breaks in the backbone.
• Can be limited to one of the two strands (a
  single-stranded break, SSB) or
• on both strands (a double-stranded break (DSB).
• Ionizing radiation is a frequent cause, but some
  chemicals produce breaks as well.
• Crosslinks Covalent linkages can be formed
  between bases
• on the same DNA strand ("intrastrand") or
• on the opposite strand ("interstrand").
• Several chemotherapeutic drugs used against
  cancers crosslink DNA

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DNA RepairRepairing Damaged Bases

• Damaged or inappropriate bases can be repaired by
  several mechanisms
• Direct chemical reversal of the damage
• Excision Repair, in which the damaged base or
  bases are removed and then replaced with the
  correct ones in a localized burst of DNA
  synthesis. There are three modes of excision
  repair, each of which employs specialized sets of
  enzymes.
• Base Excision Repair (BER)
• Nucleotide Excision Repair (NER)
• Mismatch Repair (MMR)

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DNA Repair Direct Reversal of Base Damage

• Perhaps the most frequent cause of point
  mutations in humans is the spontaneous addition
  of a methyl group (CH3-) (an example of
  alkylation) to Cs followed by deamination to a T.
  
• Fortunately, most of these changes are repaired
  by enzymes, called glycosylases, that remove the
  mismatched T restoring the correct C.

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Apoptosis

• Some viruses associated with cancers use tricks
  to prevent apoptosis of the cells they have
  transformed.
• Several human papilloma viruses (HPV) have been
  implicated in causing cervical cancer.
• One of them produces a protein (E6) that binds
  and inactivates the apoptosis promoter p53.
• Epstein-Barr Virus (EBV), the cause of
  mononucleosis and associated with some lymphomas
• produces a protein similar to Bcl-2
• produces another protein that causes the cell to
  increase its own production of Bcl-2. Both these
  actions make the cell more resistant to apoptosis
  (thus enabling a cancer cell to continue to
  proliferate).
• Even cancer cells produced without the
  participation of viruses may have tricks to avoid
  apoptosis.

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Apoptosis

• programmed cell death, is a normal cell suicide
  process in response to cell signals.
• It is mediated by a group of gene coded
  protein-digesting enzymes called caspases that in
  an ordered series of events dismantles the
  interior of a cell.  
• Caspases are a family of cysteine proteases

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Apoptosis
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Apoptosis

• Some B-cell leukemias and lymphomas express high
  levels of Bcl-2, thus blocking apoptotic signals
  they may receive.
• The high levels result from a translocation of
  the BCL-2 gene into an enhancer region for
  antibody production. Melanoma (the most dangerous
  type of skin cancer) cells avoid apoptosis by
  inhibiting the expression of the gene encoding
  Apaf-1.
• Some cancer cells, especially lung and colon
  cancer cells, secrete elevated levels of a
  soluble "decoy" molecule that binds to FasL,
  plugging it up so it cannot bind Fas. Thus,
  cytotoxic T cells (CTL) cannot kill the cancer
  cells by the mechanism shown above.
• Other cancer cells express high levels of FasL,
  and can kill any cytotoxic T cells (CTL) that try
  to kill them because CTL also express Fas (but
  are protected from their

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Heredity Can Affect Many Types of Cancer

• Inherited mutations can influence a person's risk
  of developing many types of cancer in addition to
  breast cancer.
• For example, certain inherited mutations have
  been described that increase a person's risk of
  developing colon, kidney, bone, skin or other
  specific forms of cancer.

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?????????????

• ???? ???????????. (???.). ????????????????.
  ????????. ????????????????????????????????
• ?????? ???????? ??????.2547.??????????????????.???
  ??????.????????????
• ?????? ?????????????? ???????? ??????????.2544.???
  ??????????????.????????. ???.
• ??????? ?????????????? ????? ???????????.
  2548.??? http//web.kku.ac.th/amspr/project02.htm
  . ????????????????? ?????????????????????????????
  ??????.

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?????????????

• ??????. ??? www.rihes.cmu.ac.th.
  ???????????????????????????? ????????????????????
  
• ????? ?????????. ????????????????? AFLATOXIN. ???
  www.elib-online.com.
• ????????? ?????????. ???????????????. ???
  www.elib-online.com.
• ??????? ???????. ????????????? DNA. ???
  www.elib-online.com.

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?????????????

• P53 from http//p53.genome.ad.jp/documents/about_p
  53.html. Institute of Medical Science The
  University of Tokyo
• common type of cancer. from
  http//www.cancer.gov/cancertopics/understandingca
  ncer/cancer/Slide39. national center institut
• Apoptosis. From.http//users.rcn.com/jkimball.ma.u
  ltranet/BiologyPages/A/Apoptosis.htmlcancer

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?????????????

• Thongsuksai P. Pattern of mutations in p53 gene
  an insight into cancer molecular
  biology.Department of Pathology, Faculty of
  Medicine, Prince of Songkla University, Hat Yai,
  Songkhla, 90110, Thailand.

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