Molecular Basis of Neoplasia

Question 1

How are benign and malignant neoplasia different?

Answer 1

The key difference is that a benign neoplasm cannot spread to other tissues, hwereas malignant neoplasms can metastasize

Question 2

What are neoplasia classified according to?

Answer 2

the type of parenchymal cells that the neoplastic cells resemble (plus level of differentiation - the extent to which they look like normal cells)

Question 3

What is the key initiating event for carcinogenesis?

Answer 3

a nonlethal genetic mutation.

Question 4

What are the four teyps of genes typically mutated in cancer?

Answer 4

1. growth-promoting proto-oncogenes
2. growth-inhibiting tumor suppressor tgenes
3. genes that regulate apoptosis
4. genes involved in DNA repair

Question 5

What are the 8 essential alterations involved for malignant growth?

Answer 5

1. insensitivity to growth-inhibition
2 .evasion of apoptosis
3. limitless replicative potential
4. sustained angiogenesis
5. ability to invade/metastasize
6. defects in DNA repair - leading to more mutations
7. escape from immune attack. 
8. Self-sufficiency in growth signals

Question 6

Define proto-oncogene, oncogene and oncoprotein .

Answer 6

A proto-oncogene is a normal gene that makes proteins involved in pathways like growth factors, frowth factor receptors, signal transduction, tyrosine kinasea, transcription factros, cyclin, etc.

an oncogene is a mutated form of hte proto-oncogene such that it ubiquitously expresses an oncoprotein from the list above

Question 7

List some of the functional oncogene mutations that can occur.

Answer 7

1. production of growth factors that bind to the same cell that secreted them
2. overexpression or increased activity of a growth factor receptor
3. having signaling transduction proteins always “on’
4. transcription factors
5. cyclins and CDKs

Question 8

Why do we perform Her2/neu testing in breast cancer?

Answer 8

25% of breasta cancers will overexpress Her2/neu, an epidermal growth factor.

Those that are positive for this mutation can be treated with a monoclonal antibody to the her2/neu receptor = trastuzamab (herceptin)

Question 9

Why do we perform KRAS mutation analysis in colon cancer?

Answer 9

mutation results in persistent activation of the RAS signal - present in 40% of colon cancers
We test because people who have this mutation will not respond to the EGFR monoclonal antibody tpically given in treatment

Question 10

What malignancy is associated with a BCR and ABL fusion gene?

Answer 10

CML

Question 11

What’s a tumor suppressor gene?

Answer 11

gene products inhibit cell proliferation, preventing uncontrolled growth

Question 12

What are some examples of tumor suppressor gene functions?

Answer 12

1. regulation of the cell cycle (particularly G1/S and G2/M checkpoints
2. regulation of nuclear transcription
3. regulation of cell differentiation, causing cells to enter postmitotic, differentiated pool without replicative potential

Question 13

For oncogenes, how mnay alleles need to be damaged? For tumor suppressor genes, how many alleles need to be damaged?

Answer 13

oncogenes - only one

tumor suppressor - both

Question 14

Describe the “two hit” hypothesis

Answer 14

It’s the idea that if you inherit one mutation, then it only takes one more “hit’ to get the second mutation and tumor development - this is why inherited occurrences of one cancer are much more common than sporadic cases of the same cancer

Question 15

What malignancy is associated with BRCA1/2 mutation?

Answer 15

Normally regulates DNA repair - associated with breast (60% higher risk!), ovarian and prostate carinomas

Question 16

What malignancy is associated with APC mutations?

Answer 16

APC is a tumor suppressor genes that usually prevents nuclear transcription - associated with familial polyposis colorectal carcinoma 100% RISK!!!! It’s not a matter of if, but when - usually between 35-40 years of age

Question 17

Even though both alleles need to be mutated in a tumor suppressor gene, what’s the inheritance pattern?

Answer 17

autosomal dominant (because you only need to inherit one hit)

Question 18

How can overexpression of BCL-2 lead to follicular lymphoma?

Answer 18

BCL-2 gene products regulate and prevent apoptosis by inhibiting the release of cytochrome C.
85% of B cell lymphomas of the follicular type carry a mutation in the BCL2 protein such that the lymphocytes are protected from apoptosis, allowing them to survive for long periods of time - tend to be slow growing

Question 19

How can the overexpression of telomerase can lead to limitless replication?

Answer 19

As cells replicate, telomeres shorten. When they shorten too much, DNA replication becomes disjointed and unstable. DNA repair pathways are unable to fix the issues, so the cells eventually undergo mitotic catastrophe and death

expression of telomerase allows the cells to escape the bridge-fusion-breakage cycle because their telomeres are maintained - promoting their survival and tumorigenesis.

Question 20

Describe how cancer cells can initiate neoangiogenesis/what cytokine is typically involved?

Answer 20

Cacners need to be vascularized to grow beyon 2 mm. So they need to stimulate neoangiogenesis.
They do this thorugh producing angiogenic facotrs like VEGF that recruit endothelial cells from the bone marrow to form the new vessles (which are leak and dilated)

Question 21

What are the general steps for invasion and metastases?

Answer 21

1. dissociation of tumor cells from one another
2. degradation of the basement membrane and interstitial connective tissue (or ameboid migration thoruh basement membrane)
3. attachment of the tumor cells to ECM proteins
4. migration within the ECM
5. intravasation into blood vessels
6. attachment to the endothelial cells of capillary beds
7. colonization at the site of attachment

Question 22

Describe the defect in hereditary nonpolyposis colon cancer syndrome?

Answer 22

Results from an autosomal dominent inheritance of inactivate genes involved in DNA mismatch repair within the colonic epithelial cell
they develop microsatellite instabilities

Question 23

How many alleles need to be mutated for dysfunction of DNA repair?

Answer 23

both of them (so follows the two hit theory)

Question 24

WHat are some of the ways cancer cells escape immune attack?

Answer 24

cell-mediated immunity is the dominant anti-tumor mechanism, so tumor cells just need to find ways to escape the T cells:

1. selective outgrowth of antigen-negative variants
2. lack of costimulatory molecules (so they may have MCH, but they don’t have CD28 for eample)
3. immunosupression
4. antigen masking with glycocallyx molecules
5. apoptosis of cytotoxic T cells

Question 25

What are the three typical chromosomal alterations seen in malignancies?

Answer 25

1. translocations (swapping regulatory elements for overexpression of protooncogenes or forming fusion hybrids)
2. deletions
3. reducplication and amplification of proto-oncogene DNA sequences