The Molecular Basis of Cancer

Question 1

Theory of tumorigenesis

Answer 1

Cancer arises from malignant transformation, promotion and progression of neoplastic cells →
Transformation is due to fixed, non-lethal DNA damage

Question 2

Fixed DNA damage

Answer 2

Genetic (translocation, point mutation, etc.)
Epigenetic (change in gene expression- NOT DNA sequence)

Question 3

Main components of epigenetic code

Answer 3

DNA methylation and histone modification

Question 4

DNA methylation

Answer 4

Methyl marks added to certain DNA bases repress gene activity

Question 5

Histone modification

Answer 5

Combo of different molecules can attach to the tails of proteins called histones
Alter the activity of DNA wrapped around them (gene repression)

Question 6

Steps of carcinogenesis

Answer 6

1. Initiation: irreversible alteration of single normal cell
2. Promotion: Reversible clonal expansion of initiated cell
3. Progression: conversion of initiated cell to an invasive, metastasizing cancer cell

Question 7

4 main fates of promoted cells

Answer 7

Progress to lesion with high neoplastic capacity
Grows progressively without qualitative changes
Persist for a long time with no growth
Regress completely

Question 8

Hallmarks of cancer

Answer 8

Self-sufficiency in growth signals
Insensitivity to growth-inhibitory signals
Evasion of apoptosis
Limitless replicative potential
Sustain angiogenesis
Tissue invasion and metastasis

Question 9

Tumor formation

Answer 9

Formed by clonal expansion of a single precursor cells with genetic damage
Inherited in germ line or from chemicals, radiation and viruses

Question 10

Cancer etiopathogenesis

Answer 10

Manifested by alteration of the function of 4 sets of genes:
1. Proto-oncogenes
2. Tumor supressor genes
3. Genes that regulate apoptosis
4. DNA repair genes

Question 11

Proto-oncogenes

Answer 11

Normal cellular genes that regulate cell growth and differentiation (GFs, GFRs, tyrosine kinases, G proteins, etc.)

Question 12

_________ may be altered by carcinogens

Answer 12

Protein activation

Question 12

Oncogenes

Answer 12

When proto-oncogenes are expressed incorrectly, promotes abnorm. cell proliferation
Genes in the ras family

Question 13

Ocogenes alterations

Answer 13

Point mutation, gene amplification, translocation
Promotes autonomous cell growth in cancer cells

Question 14

Effect of mutated RAS

Answer 14

RAS mutation causes the cell to lose the ability to inactivate itself (continuously active)

Question 15

Tumor supressor genes

Answer 15

Function of transcribed protein to regulate growth
Inactivation → growth advantage bc no cells cycle arrest or repair gene

Question 16

Common tumor supression genes

Answer 16

p53
BRCA1 and BRCA2 (DNA repair)

Question 17

Genes regulating apoptosis

Answer 17

Mutations result in accumulation of neoplastic cells
BCL-2 family is a prototype of anti-apoptotic genes

Question 18

Genes that indirectly regulate apoptosis

Answer 18

Tumor suppressor genes and protooncogenes (MYC) by regulating transcription of pro-apoptotic genes (BAX)

Question 19

DNA repair genes

Answer 19

Influence the ability to repair nonlethal damage in other genes
Dysfunction predisposed to mutations in the genome → neoplastic transformation
GADD45, MLH1, MSH2

Question 20

Aberrant gene expression

Answer 20

Leads to abnormal elevation or suppression of normal gene product (protein) or to the production of abnormal gene product (mutation)

Question 21

Specific environmental causes of cancer (carcinogens)

Answer 21

Chemical carcinogens
Radiant energy
Oncogenic viruses

Question 22

Chemical carcinogens

Answer 22

Cause genetic damage to cells which promotes neoplastic transformation

Question 23

2 classes of chemical carcinogens:

Answer 23

Direct acting
Procarcinogens (require chemical or enzymatic activation)
Most are mutagens

Question 24

Chemical carcinogens MOA

Answer 24

Highly reactive electrophiles that bind covalently to nucleophilic residues in DNA to formDNA adducts

Question 24

Radiant energy

Answer 24

Complete carcinogens (initiate and promote)
Directly damages DNA
Associated with reacting O2 species indirectly damages DNA

Question 25

Radiation- associated cancer examples

Answer 25

Melanomas
Squamous cell carcinoma
Basal cell carcinoma
Thyroid cancer
Leukemia
Breast cancer

Question 26

DNA oncogenic virus

Answer 26

Transforming DNA viruses form stable associations with host cell genome

Question 27

Productive infection of DNA virus

Answer 27

Permissive cells
Replication occurs, cytotoxic, not always associated with tumor formation

Question 28

Non-productive infection of DNA virus

Answer 28

Non-permissive cells
Virus can’t replicate
Results in cell transformation and tumor formation

Question 29

DNA oncogenic virus pathogenesis

Answer 29

1. Entry of virus into cell
2. Removal of viral envelope
3. v-DNA incorporated into genome of host cell
4. synthesis of viral coded proteins
5. Replication of genes that code for viral capsid proteins
6. Production of infectious virions (permissive cells)

Question 30

DNA oncogenic viruses examples

Answer 30

Papova viruses
Adenoviruses
Herpesviruses (marek’s)

Question 31

RNA oncogenic viruses

Answer 31

Retroviruses, oncoviruses
Contain RNA dependent DNA polymerase or reverse transcriptase
Uses viral RNA genome to make DNA copy of itself → inserts to host genome

Question 32

RNA oncogenic virus examples

Answer 32

Oncornaviruses: Feline leukemia virus, mouse mammary tumor virus, Jaagsiekte virus