Genetics-Cancer Genes Flashcards

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1
Q

Mutation in sporadic retinoblastoma vs. familial retinoblastoma

A

In sporadic event, the same mutation has to happen 2x to each chromosome in the same cell. In familial, you inherit on diseased allele and just need a second hit in any other cell. Note that familial form is most often bilateral.

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2
Q

Causes of second hit mutations in retinoblastoma

A

Loss of chromosome 13 due to cell division error, independent mutation in Rb gene, mitotic crossover and loss of chromosome with reproduction of disease allele.

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3
Q

Why is p53 the “guardian” of the genome that maintains genome stability?

A

Cell senses DNA damage -> p53 levels increase -> p21 transcription (CDK inhibitor inhibits G1->S transition), transcription of GADD45 (DNA repair enzyme) and promotes cell apoptosis.

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4
Q

Why is p53 mutation so prone to allowing for retinoblastoma?

A

DNA damage -> p53 transcription factor doesn’t activate -> p21 CDK inhibitor not transcribed -> CDK-cyclin remains active -> RB1 phosphorylated -> dissociates from E2F -> E2F translates mRNAs encoding enzymes for DNA synthesis -> cell proliferation. Note that both RB1 and p53 are tumor suppressors in this cycle.

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5
Q

How can HPV cause cervical cancer?

A

The viral protein E7 binds RB and frees E2F, allowing for cell proliferation. The viral protein E6 binds and inactivates p53 so the cell cannot repair DNA or promote apoptosis.

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6
Q

What role do BRCA1 and BRCA2 mutations have in increasing risk for breast cancer?

A

BRCA1 is necessary for signaling response to DNA damage. BRCA2 is involved in DNA repair. Mutations in these allows for lots of other mutations.

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7
Q

Why is APC associated with familial adenomatous polyposis related colon cancer?

A

It is the trigger in the adenoma carcinoma sequence. Its domains binds beta-catenin (decreases transcription for mitosis) and microtubules (affects mitosis and genome stability). Ironically aneuploidy can cause loss of tumor suppressor genes.

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8
Q

How many mutations do you usually need to activate an oncogene? To inactivated a tumor suppressor gene?

A

Oncogene: one dominant mutation. Tumor suppressor inactivation: two hit mutation (common in familial diseases)

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9
Q

What signaling pathway do cancer cells not have which results in them not arresting in G1 and piling on top of each other in a petri dish?

A

Absence of contact inhibition.

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10
Q

How is Burkitt lymphoma a product of oncogene expression?

A

t(8;14) puts the Ig promotor next to the c-myc protoncogene and c-myc gets over expressed

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11
Q

How is CML a product of oncogene expression?

A

t(9;22) puts the BCR-ABL next to each other and makes a constitutively active tyrosine kinase. This is why you can treat with Gleevec, a tyrosine kinase inhibitor.

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12
Q

Why is raf a potent oncogene?

A

Ras is activated by GEF (guanine nucleotide exchanging factor) that adds GTP -> Raf is activated -> MEK is phosphorylated -> MAP kinase is phosphorylated -> cell proliferation occurs. Ras is inactivated by GAP (GTPase activating protein). Mutations that lock raw in the GTP-bound form promote tumor growth.

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13
Q

What cyclin is activated by growth factors?

A

Growth factor binds -> Ras/Raf signaling -> Induces Cyclin D -> Cyclin D binds Cdk4/6 -> Rb is phosphorylated & deactivated -> E2F is freed and activated -> Gene transcription takes place -> Cell proliferation

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14
Q

How are CDKs regulated?

A

Phosphorylation, degradation, synthesis and inhibition

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15
Q

Knudson hypothesis

A

Multiple hits to DNA are required to cause cancer

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