Molecular Basis of Carcinogenesis Flashcards

1
Q

Properties of Malignant Cancer Cells (8)

A

Altered morphology, contact inhibition, growth without attachment, indefinite proliferation, reduced need of growth factors, high saturation density, increased glucose transport, tumorigenicity

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2
Q

Multi-Step Process of Carcinogenesis

A

Normal -> increased proliferation -> early neoplasia -> progressive neoplasia -> carinoma -> metastasis
Progressive accumulation of many somatic genetic mutations, early mutations tend to be in tumor suppressors

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3
Q

Two types of genes mutated in cancer

A

Oncogenes: Qualitative or quantitative change in protein expression. Increase proliferation.
Tumor Suppressors: reduce mutations through DNA repair, cell cycle control, apoptosis. Decrease proliferation.

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4
Q

Cytogenetic Abnormalities Associated with Malignancy

A

Translocations: activate oncogenes or disrupt tumor suppressors
Loss of Heterozygosity: disruption of tumor suppressors
Aneuploidy: increased aneuploidy has poor prognosis

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5
Q

What causes LOH? (3)

A

Nondisjunction during mitosis, segregation during recombination, chromosomal deletion

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6
Q

Dominant Cancer Syndrome

A

Ex Retinoblastoma, FAP, BRCA1&2. Patient inherits one mutated Rb allele. Remaining Rb allele is sufficient to prevent cancer, but there is a greatly increased risk of cancer through sporadic mutation.

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7
Q

Recessive Cancer Syndrome

A

Xeroderma pigmentosum, Ataxia Telangiectasia, Bloom’s syndrome, fanconi’s congenital aplastic anemia

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8
Q

Retinoblastoma Gene Properties

A

Inhibits proliferation through sequestration of EF2
Attracts HDACs to reduce chromatin access
Hyperphosphorylated in dividing cells, hypo in non-dividing cells

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9
Q

Rb gene in the cell cycle

A

Sequesters EF2 TF so cell cannot move from G1 to S phase. Mitogens can cause expression of cyclin-D which activates dormant CDK-4-6 which causes cyclin-E expression which activates CDK2 which phosphorylates Rb and leads to EF2 release.

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10
Q

Hallmarks of a tumor suppressor gene

A

Reduces cell proliferation. Ex Rb prevents cell movement from G1 to S phase of cell cycle.

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11
Q

APC gene

A

Tumor suppressor. Binds free beta catenin in the cytosol (not bound to PM by E-cadherin) and prevents its translocation to nucleus. This prevents expression of proliferative protein c-myc

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12
Q

BRCA1

A

Tumor suppressor gene that regulates DNA checkpoints through DNA damage sensing. It is a scaffold for many DNA repair proteins including BRCA2 and RAD51. Increased DNA repair limits the proliferation of mutations.

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13
Q

BRCA2

A

Tumor suppressor. Interacts with RAD51 to assist with homologous recombination following DNA damage. Required for RAD51 movement to damage sites.

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14
Q

Why was p53 originally considered an oncogene?

A

Tumor suppressors mutations tend to homozygous in cancer whereas oncogene mutations tend to be heterozygous. p53 mutations can cause cancer with only 1 copy mutation so it was labeled oncogene.
However, this is due to a dominant negative mutation, where one mutated p53 subunit in tetramer negates function and has increased binding strength and affinity.

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15
Q

Why is p53 the guardian of the genome?

A

p53 is a transcription factor for 300+ proteins involved in DNA repair and apoptosis. It is mutated in 50% of cancers.

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16
Q

Cellular function of p53

A

Numerous stressors activate p53 by phosphorylating its N terminus and reducing its degradation. Acts as TF for many important DNA repair and apoptosis proteins. It also upregulates MDM2 which degrades p53

17
Q

HPV pathogenesis

A

Increases E7 expression to inhibit retinoblastoma protein and E6 expression to inhibit p53

18
Q

Discovery of Oncogenes

A

Peyton Rous and the cancer filtrate that caused sarcoma in chickens.

19
Q

v-SRC

A

mutant RTK alters gene expression, causes sarcoma in chickens

20
Q

v-ERB

A

mutant protein similar to EGFR, a RTK. Causes avian erythroblastosis.

21
Q

v-ABL

A

codes for protein kinase (tyrosine).. Causes mouse Abelson Leukemia

22
Q

v-MYC

A

usually fused to gag gene, causes neoplastic transformation

23
Q

HER2

A

EGFR mutation in some breast cancers, over-expression. Treated with Herceptin, a MAB for the receptor.

24
Q

BCR-ABL

A

Philadelphia chromosome (Chr9-22 translocation), creates fusion protein tyrosine kinase. Causes CML. Treated with Gleevec, a TKI that binds ATP site of BCR-ABL

25
Bioinformatics in Cancer treatment
Tumor DNA hybridized to standards of common mutations in specific cancer.
26
Cancer Properties (5)
Uncontrolled proliferation, De-differentiated, Invasive, Metastatic, Clonal Origin
27
P53 Mutations in Cancer
50%
28
Most common P53 mutation type?
75% missense
29
Where is p53 most commonly mutated?
DNA binding domain
30
Dominant Negative mutation
p53 forms as tetramer, one bad p53 in tetramer prevents function Mutatnts tend to be more stable than wt p53
31
Virus Gag gene
Encodes internal virion proteins
32
Viral Env gene
encodes virus membrane glycoproteins
33
Viral Pol gene
encodes viral polymerase
34
EGFR mutation rate in breast cancer?
25%