Neoplasia

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Neoplasia
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• Epidemiology study of cancer patterns in
  populations (not on individual basis)
• Cancer incidence
• Geographic and environmental factors
• Age
• Genetic predisposition to cancer
• Nonhereditary predisposing conditions
• 1. Cancer incidence
• 2nd MCC of all the deaths in USA
• MC cancers in men
• Prostate - 33
• Lung - 14.0
• Colon and rectum - 11
• MC cancers in women
• Breast - 25
• Lung -12
• Colon and rectum - 11
• MC cancer causing deaths among both sexes ? LUNG
  CANCER

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EpidemiologyIncidence
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EpidemiologyIncidence
Why the incidence and deaths ? ? in case of Lung
cancer ??in stomach cancer?
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• Epidemiology study of cancer patterns in
  populations (not on individual basis)
• 2. Geographic and environmental factors
• Geographic
• Stomach Cancer Japan (7-8 times high)
• Lung Cancers USA ( 2 times)
• Skin cancers New Zealand
• Environmental
• immigration ?Stomach carcinoma of Japanese's
  immigrants to USA
• sun exposure Skin cancers Ultraviolet rays
• Occupational Asbestos, Vinyl chloride,
  2-naphthylamine
• Obesity 52 62 ? risk of cancers in Males
  Females respectively
• Alcohol ? GIT cancers
• Cigarette smoking ? Lung cancers
• Sexual Practices ? Cervical Cancers

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Epidemiology Environmental factors
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• Epidemiology study of cancer patterns in
  populations (not on individual basis)
• 3. Age
• Incidence of cancers ?? with age
• MC cancer age group 50 yrs.
• MC cancers in Infants Children - Blastomas
• MC cancers in Older Children ( 15 years) Acute
  leukemia CNS neoplasms (2nd MCC of deaths)
• 4. Genetic predisposition to cancer
• MC predisposing factors? Environmental (acquired)
  Hereditary (Familial)
• Hereditary Predisposition ? 10
• Three categories
• Environmental ? proliferations ? possible origins
  of malignant neoplasms
• Regenerative (Cirrhosis )
• Hyperplastic (Endometrial)
• Dysplastic ( cervical)

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Molecular basis of cancer
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• Molecular basis of cancer
• 1. Fundamental Principles
• Non lethal genetic damage Most important
• Monoclonal origin Leukemia, Lymphoma
• Certain regulatory genes are principal
• 1.Protooncogenes ?growth promoting normal
• Mutations in Proto-oncogene ? Oncogenes
  (abnormal)
• 2.Anti-oncogenes (growth-inhibiting/
  Tumor-suppressor genes (TSG) p53 Rb.
• normally suppress cell proliferation.
• Mutations of TSG ? release cells from growth
  suppression lead to hyper-proliferation.
• 3.Apoptotic genes (regulate programmed cell
  death) ?Act as dominant or TS genes
• 4. Genes regulating damaged DNA

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• Molecular basis of cancer
• 2. Essential Alterations
• Self sufficiency in growth signals? no need of
  external stimuli
• Insensitivity of growth inhibitory signals? TGFß
• Evasion of Apoptosis? Ca. cells resistant
  apoptosis ( inactivation of p53)
• Defects in DNA repair ? NER
• Limitless replication potential ? telomerase
  reactivation
• Sustained angiogenesis? VEGF
• Ability to invade metastasis ? ?cancer deaths
• 3. Normal Cell cycle

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• Molecular basis of cancer
• 3. Normal Cell cycle
• Cell-Cycle Checkpoints
• Two main checkpoints
• 1. G1/S transition
• S phase ?point of no return
• ?checks for DNA damage (if yes) ?arrest the cell
  cycle (??p53)?if damage is not repairable
  ?apoptotic pathways
• 2. G2/M
• ?monitors the completion of DNA replication
• ?arrest in G2
• ?important in cells exposed to ionizing
  radiation? chromosomal abnormalities
• G0 stage ?resting (nondividing) cells
• Cyclins and cyclin -dependent kinases (CDKs),
  and inhibitors ? control orderly progression of
  cells

Major cause of genetic instability in cancer
cells Defect in cell-cycle checkpoint components
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• Molecular basis of cancer
• 3. Normal Cell cycle
• Cyclins
• ?synthesized during specific phases
• ?activate the CDKs
• ?decline rapidly
• CDKs
• ?phosphorylating critical target proteins
• ?cause progression of cells to the next phase of
  the cell cycle
• ?bind to cyclins
• Cyclin D and RB Phosphorylation
• Cyclin D ? first cyclin to increase in the cell
  cycle (mainly mid G1 )
• Cyclin D binds to and activates CDK4 in G1 phase
  ? cyclin D-CDK4 complex ? Phosphorylation of RB ?
  ON-OFF switch for the cell cycle
• Cell-Cycle Progression beyond the G1/S
  Restriction Point
• Need active complex between cyclin E and CDK2
• next decision point ?G2/M transition
• Absence of cyclin E ? prevent G0 cells from
  entering cell cycle

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• Molecular basis of cancer
• 3. Normal Cell cycle
• Cell-Cycle Inhibitors
• Function as tumor suppressors
• Altered in tumors
• 1. Cip/Kip ? p21, p27, and p57
• ?activation of p21 is under the control of p53)
• 2. INK4/ARF families ? p16INK4a and p14ARF
• ?block the cell cycle and act as tumor suppressors