5. Neoplasia II (Principles of Carcinogenesis)

Question 1

what is the nonlethal genetic damage (mutation) that leads to carcinogenesis and what are the 3 types of this?

Answer 1

initiating event: spontanous/random (most common), environmental exposure (viruses, chemicals, endogenous free radicals, etc), or inherited (germline)

Question 2

the initiating mutation for carcinogenesis is also known as what type of mutation?

Answer 2

driver mutation: maintained in all cells of the subsequent cancer (monoclonality)

Question 3

alkylating agents (anticancer drugs) are direct or indirect acting carcinogens?

Answer 3

direct

Question 4

polycyclic and heterocyclic aromatic hydrocarbons, aromatic amines, amides, azo dyes, natural plant and microbial products (aflatoxin B1), and etc are all direct or indirect acting carcinogenic agents?

Answer 4

indirect (require metabolic activation (usu the liver)

Question 5

what are the two general types of radiation carcinogenesis?

Answer 5

UV: squamous cell carcinoma, basal cell carcinoma, melanoma of the skin, pyrimidine dimers in DNA (repaired by nucleotide excision repair pathway but damage if this doesn’t work)

Ionizing radiation: acute and chronic myeloid leukemia (hiroshima), cancer of the thyroid (children and young adults only, hiroshima)

Question 6

microbial carcinogenesis directly vs indirectly

Answer 6

oncogenic RNA/DNA ciruses can casue cancer directly (HPV, HBV), while some microbes cause cancer through inflammation (Hep C and H.pylori)

Question 7

what are the 4 classes of normal regulatory genes that are the principle targets of genetic damage re: carcinogenesis?

Answer 7

1. proto-oncogenes (gain of function - make too much)
2. tumor supressor genes (loss of function, both alleles must be damaged)
3. genes that regulate apoptosis (LOF or GOF whether gene normally promotes or suppresses cell death)
4. genes involved in DNA repair (LOF mutation - affected cells acquire mutations at an accelerated rate = genomic instability = mutator phenotype)

Question 8

what is the significance of stem cell-like properties of tumor cells?

Answer 8

they can persist/lie in hiding/be dormant for decades and cause tumor reappearance

Question 9

how does the acquiision of genomic instability lead to cancer progression

Answer 9

natural selection of “driver mutations” that progress the cancer forward. Acquire more “passenger mutations” that don’t affect cancer progression at all, but are along for the ride when the driver mutation does happen

Question 10

what are the 8 cancer hallmarks and 2 enabling characteristics that lead to the malignant phenotype?

Answer 10

cancer hallmarks:

sustaining proliferative signaling, avoiding immune destruction, evading growth suppressors, enabling replicative immortality, activating invasion and metastasis, inducing angiogenesis, resisting cell death, deregulating cellular energetics

enabling characteristics

tumor-promoting inflammation, and genomic instability (mutator phenotype)

Question 11

oncogenes

Answer 11

promote autonomous growth in cancer cells (come from mutations in protooncogenes, create oncoproteins which are autonomous in that they promote cell growth in the absence of normal growth-promoting signals)

Question 12

into chich hallmark of cancer do oncogenes fit?

Answer 12

sustained proliferative signaling

Question 13

what are the 5 types of oncogenes?

Answer 13

1. growth factors
   
   1. cancer cells can synthesize the same GFs to which they are responsive (autocrine loop)
   2. some have both GFs and excess GFRs
2. growth factor receptors
   
   1. EGFR
   2. HER2/Neu (find with immunostain for oncoproteins)
3. signal-transducers
   
   1. RAS oncogene
      
      1. Most common mutation of proto oncogenes in human tumors
         Pancreas and colon cancers
      2. Mutations in BRAF

Downstream of RAS (RAS/RAF/MAP kinase)
60% melanomas

    3. Nonreceptor tyrosine kinases

c-ABL gene on chromosome 9 is translocated to chrom 22 in chronic myelogenous leukemia where it fuses with the BCR gene (philadelphia chromosome)

Fusion gene with potent tyrosine kinase activity

Inhibited by the drug imatinib (gleebak)= targeted therapy

4. nuclear regulatory proteins/TFs
   
   1. MYC protooncogene

Main txn regulator of cell growth
Upregulates expression of telomerase
May help to convert somatic cells into stem cells (cancer stemness)
Translocated in Burkitt lymphoma where it comes under the influence of immunoglobulin heavy chain gene [t(8;14)]

5. cell cycle components

Question 14

RB gene

Answer 14

first tumor supressor gene discovered

chromosome 13q14

governor of the cell cycle: key negative regulator of the G1/S cell cycle transition

• Normally antiproliferative
• LOF in cancer (2-hit mechanism for retinoblastoma)
• Gene amplifications of CDK4 and cyclin D genes
• Viral oncoproteins can bind and inhibit RB
• HPV

Question 15

p53 gene

Answer 15

Guardian of the genome

Regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis

Most frequently mutated gene in human cancers
Chromosome 17 p13.1

P53 causes cell cycle arrest if there is DNA damage and lets repair of DNA
If not able to repair then it stimulates apoptosis

Mutator phenotype if have a defective p53 = tendency to acquire additional mutations at a high rate

• *Germ-line mutation (Li-Fraumeni Syndrome)**
• *Like RB, p53 is inactivated by viral oncoproteins like the E6 protein of HPV**

Question 16

irradiation and conventional chemotherapy, the two common modalities of cancer treatment, meadiate their effects by inducing DNA damage and subsequent apoptosis. Which tumors are more likely to be killed by such therapy?

1. tumors with wild type TP53 alleles

or

2. Tumors with mutated type TP53 alleles

Answer 16

Tumors with wild type TP53 alleles (if the DNA of the cancer cell is damaged by chemo, p53 will kick and and prevent them from dividing, but tumors with mutated p53 don’t give AF)

Question 17

beta catenin pathway

Answer 17

APC gene - chromosome 5q21
APC protein negatively regulates the WNT pathway in colonic epithelium by promoting the formation of a complex that degrades Beta-catenin
Mutated in 70% of colon carcinomas
Germ line-mutation: FAP (familia adenomatous polyposis)

Question 18

the warburg effect

Answer 18

transition to aerobic glycolysis (rapidly dividing tumor cells have even more energy), used in PET scans

Question 19

follicular B-cell lymphomas and evasion of cell death

Answer 19

anti-apoptotic gene BCL2 is overexpressed due to a 14;18 translocation (LOF)

Question 20

Mechanisms of immune evasion (evasion of host defence as a hallmark of carcinogenesis)

Answer 20

1. Selective outgrowth of antigen-negative variants
2. Loss of reduced expression of MHC molecules

Escape cytotoxic T cells but may trigger NK cells

3. Antigen masking

Tumor cells often express more glycocalyx molecs than normal cells

4. Secretion of immunosuppressive factors by tumor cells

TGF Beta

5. Induction of immunosuppressive regulatory T cells (Tregs)

Question 21

chromosomal alterations in cancer

Answer 21

Point mutations
Rearrangements (BCR-ABL)
Deletions (RB)
Gene amplification (c-ERBB2 in breast cancers)
Chromothyrpsis (chromosome shattering)

Question 22

epigenetic changes in cancer