10: Oncogenes and Tumor Suppressor genes Flashcards

1
Q

What are the 6 original hallmarks of cancer?

A

SARCOMA
S – Self-sufficiency of growth signaling
A – Apoptosis evasion
R – Resistance to anti-growth factor signaling
CO – Continuous replication (Immortality)
M – Metastasis
A – Angiogenesis

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2
Q

What are the 4 additional Hallmarks of cancer?

A
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3
Q

What are proto-oncogenes?

A

Genes that code for essential proteins involved in maintenance of cell growth, division and differentiation

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4
Q

What happens when a proto-oncogene mutates?

A

It can convert into an oncogene

  • no longer responds to control influences
  • can be aberrantly expressed, over-expressed or aberrantly active
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5
Q

What kind of mutations normally occur in proto-oncognes that convert them into oncogenes?

A

A single mutation can be enough:

  • point mutation
  • deletion
  • Gene-amplification
  • Chromosomal translocations / Insertional mutagenes
    • E.g. Philadelphia chromosome – > hyperactiveness of transcribed gene
    • E.g. Burkitts lymphoma –> stonger enhancer in front of gene increase normal protein levels
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6
Q

What kind of mutation is the phildelphia chromosome?

How does it lead to the formation of cancer?

A

It is a chromosomal translocation resulting in

  • via the BCR-ABL gene fusion product
  • BCL causes permanent activation of the ABL-gene product
  • ABL is important in proliferation
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7
Q

Name some commonly mutated oncogenes and their location/MOA

A
  1. Transcription factors
    • c-Myc
    • JUN
  2. RAS, raf –> activation of kinase cascade
  3. Tyrosin kinases
    • SRC

–> Leading to permanent activation of proliferation!

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8
Q

What are the characteristics of tumor-supressor genes?

A
  1. Normally proteins that regulate (supress) cell proliferation and function
  2. Each cell: 2 copies of each TSG
    1. normally loss of both copies required to induce malignancy
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9
Q

explain how tumour suppressor genes have been discovered through heritable malignancies

A

Via the Retinoblastoma gene, development of the 2 hip hypothesis

  1. Each cell has 2 copies of a TSG
  2. Need loss of both copies for Cancer
  3. If one is already damaged –> can be inherited and only one hit is required to develop malignangy, leading to
  • Family history of related cancers.
  • Unusually early age of onset.
  • Bilateral tumours in paired organs.
  • Synchronous or successive tumours.
  • Tumours in different organ systems in same individual.
  • Mutation inherited through the germline.
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10
Q

Explain the role of APC in Familial adenomatous polyposis coli

A

APC is a tumor supressor gene, regulating the break down of ß-catnin

  • Damage on APC can be inherited leading to
  • formation of multiple benign adenomatous polyps of the colon.
  • There is a 90% risk of developing colorectal carcinoma.
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11
Q

At the example of colorectal cancer, explain how gene mutations can lead to cancer

A
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12
Q

When does p53 get activated?

A

It gets activated at cellular damage

  • cellular stress
    • hypoxia
    • nitric oxide
    • oxidative stress
  • Damage
    • oncogene activation
    • Double strand breaks
    • Telomere erosion
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13
Q

How does p53 get activated?

A

Via inhibiton of MDM2

  • Normally: MDM2 inhibits p53 activtiy
  • When activated: sets off repair mechanisms
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14
Q

Explain the function of PTEN and its role in carciogenesis

A

It is a Tumor supressor gene

  • PTEN can induce apoptosis by inhibiting the phosphorylation of PIP2 into PIP3 (and thereby the pro survival signaling)
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15
Q

Explain the role of BRCA in carciogenesis

A

BRCA is a tumor supressor gene normally

  • repairing DNA damage
  • often mutated in Breast cancer
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16
Q

Name 4 Tumor supressor genes

A
  1. PTEN
  2. p53
  3. BRCA
  4. APC
17
Q

Oncogenes

A
  • EGFR/HER2, mutationally activated or overexpressed in many breast cancers
  • Ras, mutationally activated in many cancers (>15%)
  • CyclinD1, overexpressed in 50% of breast cancers
  • B-Raf, mutationally activated in melanomas;; v-Raf (deletion of regulatory domain)
  • c-Myc, overexpressed in many tumours
18
Q

TSG

A
  • p53 – mutated in ~50% of human cancers
  • PTEN (Phosphatase and tensin homologue deleted on Chr ten) - dephosphorylates
  • phosphoinositides at 3’-position - loss of PTEN activates the PKB/Akt pathway, promotes cell survival.
    • mutated in multiple advanced cancers - frequency similar to p53. Deletion in chromosomal region 10q22-25 observed in many cancers: prostate, renal, endometrial, melanoma, glioma, meningioma
  • pRb, inactivated in many cancers
  • p27KIP1, underexpression correlates with poor prognosis in many malignancies