Genetic Changes in Cancer Flashcards

1
Q

Which cells skip the G0 phase entirely?

A

bone marrow cells (rapidly divide)

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2
Q

When does DNA replication occur in cell division?

A

S phase (interphase includes G1, S, and G2)

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3
Q

What is the difference between G1 and G2 phases?

A

In G1, the cell synthesizes DNA and proteins and increase cytosokeletal and chromatin are made (chromatin is long and slender),

while in G2 RNA and proteins are synthesized and proof-reading occurs. Cell repair for DNA from S phase occurs here.

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4
Q

What follows interphase (specifically G2)?

A

Mitosis (prophase, metaphase, anaphase, and telophase)

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5
Q

Where is the cell-cycle controlled?

A

between G1 and S before DNA replication and between G2 and mitosis

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6
Q

What are cyclin-dependent kinases (CDKs)?

A

kinases add phosphate groups to activate or inactive them (control cell cycle)

always present in a cell but default form is inactive- activated by cyclins

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7
Q

What are specific cyclins?

A

cyclin made at specific times to activate CDKs by binding to them.

NOT always available

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8
Q

Which cyclins are made before entering S from G1? Which CDKs do they bind to?

A

cyclins D and E. These bind to CDK2 (cyclin E) and CDK4 (bound to cyclin D).

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9
Q

What does CDK4 (complexed with cyclin D) do?

A

phosphorylates the RB protein, keeping it from inhibiting the S phase

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10
Q

What cyclins are made in the S phase? What CDK does it complex with?

A

cyclin A (complexes with CDK2 to activate it)

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11
Q

What does CDK2 bound to cyclin A do?

A

activates DNA replication during S phase

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12
Q

What cyclins are made in the G2 phase? Which CDK does it complex with?

A

cyclin B (complexes with CDK1) to activate mitosis

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13
Q

What are cancer genes?

A

Genes that, in their normal form, are responsible for critical aspects of human development, control of the cell cycle, etc. but have caused malignancy when they are out of control aka Genes that, when mutated, enable dysregulated cell growth

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14
Q

T or F. Loss of heterozygosity is not relevant to oncogenes

A

T. It only has to do with tumor suppressor genes

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15
Q

What are oncogenes?

A

growth promoting genes. Carcinogenic mutation of these gains often manifest as a gain of function, in which growth in unregulated

In contrast, cancer causing mutations in tumor suppressor genes are loss of function

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16
Q

At the CELLULAR level, what does it mean that oncogenes have a dominant cellular phenotype, while TSGs have a recessive cellular phenotype?

A

This means that mutation of one allele of an oncogene will result in gain of function, while it will take mutation of both TSGs to result in loss of function

17
Q

What are the main ways through which an oncogene can mutate to a gain of function cancerous gene?

A

1) mutation in coding sequence- hyperactive protein made in normal amounts (Ras)
2) gene amplification- normal protein overproduced (Myc, Cyclin D, Erb-B1)
3) balanced translocation- nearby regulatory DNA sequence causes normal protein to be overproduced (Myc, Cyclin D, Bcl-2, Src, Raf) or

fusion to actively transcribed gene greatly overproduces fusion proteins; or fusion protein is hyperactive (Abl)

18
Q

How does point mutation cause gain of function of the RAS gene (which is activated in many tumors)?

A
  • GTP hydrolysis required for normal inactivation of RAS.
  • Somatically acquired mutations in the RAS gene that interfere with the ability of the protein to bind/hydrolyze GTP allow RAS protein to remain constitutively active
19
Q

What is the basis of gene amplification?

A

Tumor cells with hundreds of copies of a proto-oncogene, conferring selective growth advantage

20
Q

What are the two types of microscopic gene amplification?

A

– HSR (Homogeneously Staining Regions)
• visible in chromosomes as an extra, non-banded region

– DM (Double Minutes)
• extrachromosomal gene able to replicate and segregate randomly, circular with no centromere or telomeres
• Segregate randomly at cell division (unstable)

21
Q

Cancer As a Multi-Step Process

A
  • Malignant transformation involves multiple acquired (somatic) mutations
  • Tumors evolve and progress by clonal evolution

• Advanced malignancies have a large burden of genetic abnormalities as well as genomic instability.
– Multiple driver mutations (“cancer genes”)
– Many passenger mutations

22
Q

What are constitutional mutations?

A

present in all cells of the body (germline & somatic). Includes (and doesn’t differentiate between) inherited mutations & new mutations.

23
Q

What are acquired mutations?

A

mutation that arises in a somatic cell. It will be passed ONLY to its own daughter cells (clonal expansion). It will NOT be passed to offspring.

24
Q

What is an inherited mutation?

A

genetic variant inherited from a parent and present in gametes and in all somatic cells of the body.

25
Q

Oncogenes Do Their Damage via Somatic (Acquired) Mutations

A

– Overwhelmingly, tumorigenic changes in oncogenes arise as somatic mutations.

– Although almost every tumor will have abnormal function of one or more oncogenes, the same loci are homozygous normal in somatic tissue.

– Very few hereditary cancers are caused by oncogenes
• Exception: RET proto-oncogene and MEN2 [multiple endocrine neoplasia type 2]

Tumor suppressor genes account for the majority of hereditary cancers

26
Q

What is BRAF V600/Venumafenib?

A

This is targeted therapy

Patient with late-stage or unresectable melanoma

Genetic testing of tumor DNA – targeted test for acquired BRAF V600E missense mutation in tumor cells

Patient is a candidate for vemurafenib therapy ONLY if BRAF V600E is present. (Drug is not effective against normal BRAF protein.)

27
Q

What is the basis of a liquid biopsy?

A

In a tumor patient, there is cell free DNA from the tumor in the blood. You can take blood sample and look for mutations, sequence, etc. to identify the cancer