Path: Molecular Basis of Cancer

Question 1

True/False: Tumors are polyclonal.

Answer 1

FALSE they are monoclonal; meaning a tumor mass results from clonal expansion of a single progenitor cell that has accrued great amounts of damage via environment or germ line causes.

Question 2

What are the 4 principle targets of genetic damage in cancer?

(Also the 4 classes of normal regulatory genes in a cell)

Answer 2

Growth promoting PROTO-ONCOGENES

Growth inhibiting TUMOR SUPPRESSOR GENES

APOPTOSIS REGULATING GENES

DNA REPAIR GENES

Question 3

What gene codes the protein that’s considered the “Guardian of the Genome?”

Answer 3

TP53 codes p53, the tumor suppressor gene.

Question 4

Does mutation of TP53 cause cell transformation into a cancer cell?

Answer 4

NO. Loss of the p53 guardian function has no direct effect on cell proliferation or apoptosis. Instead, it permits and accelerates the acquisition of mutations in oncogenes and other tumor suppressor genes, that collectively cause cancer.

Question 5

What gene type, when mutated, DO produce a transformed cellular phenotype?

Answer 5

Oncogenes –> aka over-expressed versions of normal cell genes called pro to-oncogenes

Question 6

Which genes are called guardians? How about governors?

Answer 6

Guardians are responsible for sensing genomic damage!…… Genes that induce apoptosis or slow the cell cycle to allow DNA repair; and genes involved in DNA repair

Governors: classic Tumor Suppressor genes like RB that, when mutated, lead to transformation of cell phenotype.

Question 7

Genes that normally PREVENT UNCONTROLLED GROWTH and when mutated or lost, allow a cancerous phenotype to happen are called…..

Answer 7

Tumor Suppressor Genes

Question 8

Describe the 2 ways a translocation (detected in a karyotype) can activate a proto-oncogene.

Answer 8

1. Removing proto-oncogene from it snorkel regulatory elements and placing them under the control of an inappropriate, highly active promotor.
2. Fusion genes encoding novel, chimeric proteins that have gene amplification activity.

Question 9

What type of cancer has a translocation between chromosomes 8 and 14? What gene is WAY over expressed as a result?

Answer 9

Burkitt’s Lymphoma has a translocation of chromosome 8 to a spot on chromosome 14 with an IMMUNOGLOBULIN HEAVY CHAIN REGULATORY ELEMENTS!

So in a B cell cancer, a gene in front of an Ig promotor is obviously going to be highly active.

Overexpression of the MYC gene.

Question 10

What kind of fusion gene has tyrosine kinase activity and is seen in more than 90% of cases of MYELOGENOUS LEUKEMIA?

What’s the nickname of the abbreviated chromosome?

Answer 10

BCR-ABL hybrid gene has tyrosine kinase activity.

Chromosome 22 is called the Philadelphia Chromosome. Not sure why.

Question 11

What fusion gene is present in PROSTATE CANCER?

Answer 11

TMPRSS-ETS

“The temptress wants to milk your prostate”

Question 12

Taking a step back…..What are the 3 karyotypic abnormalities that can be found in tumor cells?

Answer 12

1. Balanced translocations (rearrangements and fusion genes)
2. Deletions
3. Cytogenetic manifestations of gene amplification

Question 13

What are the 2 mutations generally involved in the inactivation of a tumor suppressor gene, leading to LOH - Loss of Heterozygosity.

Answer 13

For spontaneous mutations, the first allele is generally mutated via POINT MUTATION, and the second is generally a DELETION.

Question 14

Amplification of a pro to-oncogene will manifest itself in 2 ways within a karyotype. What are they?

Answer 14

Extrachromosomal double minutes

Chromosomally integrated homogenous-staining regions.

Either way, there is a LOT of extra DNA coding for these oncogenes.

Question 15

What gene amplification occurs in 20% of breast cancers?

Answer 15

HER2/NEU

Question 16

What gene amplification occurs in neuroblastoma and manifests itself with the presence of double minutes?

Answer 16

NMYC oncogenes.

Question 17

How can miRNA contribute to cancer?

Answer 17

By down regulating tumor suppressor gene products (increasing miRNA activity) or increasing the expression of oncogenes by lowering the miRNA activity.

Question 18

How do epigenetic changes affect cancer?

Answer 18

Hypomethylation/Hypermethylation of certain parts of the DNA sequence

HYPERmethylation of promotor sequences in front of tumor suppressor genes. The promotor is methylated, therefore not expressed.

HYPOmethylation of the entire genome causes widespread chromosomal instability.

Question 19

Is cancer a one-step process?

Answer 19

NO! Carcinogenesis is a multistep process resulting from the accumulation of multiple genetic alteration that collectively give rise to the transformed phenotype.

Question 20

The concept that tumors become more aggressive and acquire greater malignant potential is called__________.

Answer 20

Tumor Progression

Question 21

Tumors express HETEROGENEITY. What does this mean? How does this happen if tumors are MONOCLONAL?

Answer 21

New sub clones arise from the descendants of the original transformed cell by multiple mutations.

Question 22

Name the 6 hallmarks of cancer.

Answer 22

1. Self-sufficiency in growth signals
2. Insensitivity to growth inhibitory signals
3. Evasion of cell death
4. Unlimited replication potential
5. Sustained angiogenesis
6. Ability to invade and metastasize

Question 23

What are the other 2 characteristics of cancer that aren’t exactly hallmarks yet, but almost?

Answer 23

Evasion of the immune system and reprogramming of energy metabolism.

Question 24

What kind of oxygen requirements do tumors have?

Answer 24

For some reason they switch to AEROBIC GLYCOLYSIS, despite the fact that it makes less ATP than Ox Phos does.

Question 25

Sarcomas express what kind of growth factor and its corresponding receptor?

What about Glioblastomas?

Answer 25

Sarcomas express TGF-aplha and receptor

Glioblastomas express PDGF and receptor

Question 26

What is the most commonly mutated PROTO-ONCOGENE in humans?

Answer 26

RAS

30% of ALL human tumors have mutated RAS.

Mutations of downstream signaling molecules are common as well.

Question 27

Explain how RAS works.

Answer 27

RAS is a small G-protein, active when bound to GTP, inactive when bound to GDP.

Stimulation of the receptor by PDGF and EGF lead to exchange of GTP for GDP and activate RAS.

RAS stimulates downstream regulators of proliferation by 2 pathways that converge in the nucleus.

RAS is inactivated by its own intrinsic kinase activity, that causes hydrolysis of GTP.

Question 28

WTF is BRAF and what does it have to do with RAS?

Answer 28

BRAF is a downstream signal from RAF present in 60% of melanomas.