Lec 26: Cancer genetics

Class Topic: Genetics of Cancer
Date: Wednesday, October 29th
Guiding Questions: How can we use our knowledge of genetics to understand cancer?

What do each TALEN protein consist of?

Options:
a) A zinc-finger domain and a DNA polymerase
b) A transcriptional activator like effector and a protease
c) A DNA binding domain and a nuclease domain
d) A guide RNA and a Cas 9 protein

Comparison of ZFNs, TALENs, and CRISPR-Cas9:

Options:
a) ZFNs, TALENs, and CRISPR-Cas9 all require a synthetic RNA guide sequence to target specific DNA sequences.
b) TALENs and CRISPR-Cas9 are less precise than ZFNs in genome editing due to their reliance on RNA molecules for sequence recognition.
c) CRISPR-Cas9 and TALENs both use a single protein for DNA cleavage, whereas ZFNs require two different proteins for DNA recognition and cutting.
d) ZFNs and TALENs use protein-based DNA recognition, while CRISPR-Cas9 uses RNA to direct the Cas9 protein to specific DNA sequences.

Questions for Discussion:
- What do you know about cancer?
- What are the different types of cancer?
- What causes cancer?
- Is cancer heritable?

About the inheritance of cancer mutations:

Scenario: A woman develops breast cancer that does not spread, with the mutation arising in a single breast cell. If she and her husband (who does not have cancer) have children after this diagnosis, which statements are true?
Options:
a) All of the woman’s children will inherit the mutation
b) Half of the woman’s children will inherit the mutation if the mutation is dominant
c) None of the woman’s children will inherit the mutation
d) Some of the woman’s children may inherit the mutation depending on which chromosome they inherit
e) There is not enough information to know for sure

Cell Cycle Definition: The life of a cell from its formation during the division of a parent cell until its own division into two offspring cells.
- Interphase (~90% of the cell cycle):
  - G1 Phase (“first gap”): Metabolic activity and growth.
  - S Phase (“synthesis”): DNA replication (chromosomes are duplicated).
  - G2 Phase (“second gap”): Growth and preparation for cell division.
- Mitotic Phase (cell division):
  - Mitosis: Distribution of chromosomes into identical nuclei.
  - Cytokinesis: Division of the cytoplasm, producing two offspring cells.

Overview: Cancer results from genetic changes that affect cell cycle control.
Key Checkpoints Affected:
- G₁ checkpoint
- G₂ checkpoint
- M checkpoint

Proto-oncogenes: Normal genes that respond to signals stimulating cell division (e.g., Ras).
Transformation to Oncogenes:
- Mechanisms of Conversion:
- (a) Epigenetic changes: Mutation in a chromatin-modifying enzyme causing inappropriate expression of a proto-oncogene.
- (b) Translocation or transposition: Gene moved to a new locus under new controls.
- (c) Gene amplification: Multiple copies of a gene.
- (d) Point mutation within a control element or within the gene itself.
- Consequences: Normal growth-stimulating protein in excess or hyperactive/degradation-resistant proteins.

Function: Normal genes that detect errors in DNA replication and respond by correcting them or initiating cell death.
Example: p53 protein, which plays a critical role in stopping/slowing down cell division.
Mutations in p53: Prevent suppression of the cell cycle, leading to unchecked cell division.

Factors that can lead to DNA damage:
- Replication stress
- Oxygen radicals
- Ionizing radiation
- Chemotherapeutics
- UV light
- Polycyclic aromatic hydrocarbons
Types of DNA Damage:
- Base mismatch
- Single-strand breaks
- Double-strand breaks
- Interstrand crosslinks
- Bulky adducts/intrastrand crosslinks

Multistep Model: More than one mutation is generally needed for cancer to develop, including at least one active oncogene and mutations in several tumor-suppressor genes.
Example: Healthy colon tissue -> Polyposis colon via gradual mutations.

Mitosis occurs in somatic cells, producing identical offspring cells.
Meiosis occurs in germline cells, producing genetically unique (haploid) gametes.
New mutations can occur in both somatic and germline cells.
Only mutations in germline cells and gametes can be inherited.

Mitosis
- Somatic cells: All cells that are not in the germline.
Meiosis
- Produces unique gametes through two rounds of division (Meiosis I and II).
New Mutations can manifest in different cell types including skeletal, blood, organ, fat, and neuron cells.
Inheritance:
- Somatic cell mutations: WILL NOT pass to progeny.
- Germline cell mutations: WILL pass to progeny.

Aflatoxin:
- Produced by Aspergillus, a fungus found in warm, humid environments on nuts and grains.
- Converts to a mutagen in the liver, leading to increased mutation rates.
Exposure Patterns: Areas with high aflatoxin exposure tend to have higher incidences of liver cancer.
Mechanism:
- Enzymes in the liver convert aflatoxin to highly reactive epoxides, which can form adducts with DNA.
- During DNA replication, this can lead to mispairing and mutations.

Plastic Exposure:
- Link between benzyl butyl phthalate (BBP) and increased double-strand break formation, leading to mutations.
- Raises questions about societal responsibility regarding plastic usage and its potential as a carcinogen.

Summary of Genetic Understanding of Cancer:
- Effects of mutations can cause overexpression of proteins (e.g., Ras) or inactivation (e.g., p53), leading to abnormal cell cycle regulation and increased cell division.

Next Class Discussion Topic: How does our body maintain homeostasis?
Homework Due Dates:
- Week 10 Self Assessment by Friday, 10/31 before 11:59 PM
- Dr. Niyogi’s Course Evaluations by Sunday, 11/2 before 11:59 PM