Molecular Basis of Carcinogenesis

Question 1

Properties of Malignant Cancer Cells (8)

Answer 1

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

Question 2

Multi-Step Process of Carcinogenesis

Answer 2

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

Question 3

Two types of genes mutated in cancer

Answer 3

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

Question 4

Cytogenetic Abnormalities Associated with Malignancy

Answer 4

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

Question 5

What causes LOH? (3)

Answer 5

Nondisjunction during mitosis, segregation during recombination, chromosomal deletion

Question 6

Dominant Cancer Syndrome

Answer 6

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.

Question 7

Recessive Cancer Syndrome

Answer 7

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

Question 8

Retinoblastoma Gene Properties

Answer 8

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

Question 9

Rb gene in the cell cycle

Answer 9

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.

Question 10

Hallmarks of a tumor suppressor gene

Answer 10

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

Question 11

APC gene

Answer 11

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

Question 12

BRCA1

Answer 12

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.

Question 13

BRCA2

Answer 13

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

Question 14

Why was p53 originally considered an oncogene?

Answer 14

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.

Question 15

Why is p53 the guardian of the genome?

Answer 15

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

Question 16

Cellular function of p53

Answer 16

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

Question 17

HPV pathogenesis

Answer 17

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

Question 18

Discovery of Oncogenes

Answer 18

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

Question 19

v-SRC

Answer 19

mutant RTK alters gene expression, causes sarcoma in chickens

Question 20

v-ERB

Answer 20

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

Question 21

v-ABL

Answer 21

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

Question 22

v-MYC

Answer 22

usually fused to gag gene, causes neoplastic transformation

Question 23

HER2

Answer 23

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

Question 24

BCR-ABL

Answer 24

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

Question 25

Bioinformatics in Cancer treatment

Answer 25

Tumor DNA hybridized to standards of common mutations in specific cancer.

Question 26

Cancer Properties (5)

Answer 26

Uncontrolled proliferation, De-differentiated, Invasive, Metastatic, Clonal Origin

Question 27

P53 Mutations in Cancer

Answer 27

50%

Question 28

Most common P53 mutation type?

Answer 28

75% missense

Question 29

Where is p53 most commonly mutated?

Answer 29

DNA binding domain

Question 30

Dominant Negative mutation

Answer 30

p53 forms as tetramer, one bad p53 in tetramer prevents function
Mutatnts tend to be more stable than wt p53

Question 31

Virus Gag gene

Answer 31

Encodes internal virion proteins

Question 32

Viral Env gene

Answer 32

encodes virus membrane glycoproteins

Question 33

Viral Pol gene

Answer 33

encodes viral polymerase

Question 34

EGFR mutation rate in breast cancer?

Answer 34

25%