Genetic Mechanisms of Cancer and Mobile DNA Elements - Nov 17

Genetic Basis of Cancer

Normal vs. Cancerous Cells

Genetic mutations drive the transformation of normal cells into cancerous cells. The provided image compares normal colon tissue to colon cancer tissue, highlighting morphological changes due to genetic alterations.

• Normal colon: Organized structure, regulated cell growth.

• Colon cancer: Disorganized, excessive proliferation, loss of normal architecture.

Role of Mutations in Cancer

Mutations are central to cancer development, particularly in somatic cells.

• Somatic mutations: Occur in non-reproductive cells; most cancers arise from these.

• Germline mutations: Inherited mutations; contribute to cancer risk but are less common in actual cancer development.

• Increased mutation rates: Cancer cells often have higher mutation rates, leading to genomic instability.

Oncogenes and Tumor Suppressors

Cancer is driven by two major classes of genes: oncogenes and tumor suppressor genes.

• Oncogenes: Mutated or aberrantly expressed proto-oncogenes that promote tumor formation.

  • Gain-of-function alteration: Only one allele needs to be affected to trigger uncontrolled growth.

  • Dominant phenotype: Oncogenes confer a dominant cancer phenotype.

• Tumor suppressor genes: Genes that normally inhibit tumor formation.

  • Loss-of-function mutations: Both alleles usually need to be inactivated.

  • Recessive phenotype: Tumor suppressor mutations are typically recessive.

Stages of Cancer Development

Cancer progression is multigenic and occurs in stages, with accumulation of mutations over time.

• Pathways: Key genes involved include APC, Kras, and PI3K.

• Stages:

  • Normal colonic epithelium (age 30-50)

  • Small adenoma (age 40-60)

  • Large adenoma (age 50-70)

  • Carcinoma (age 50-70+)

  • Metastasis (invasion of other tissues)

Table: Stages of Colorectal Cancer Progression

Stage	Key Mutation	Age Range
Normal Epithelium	None	30-50
Small Adenoma	APC	40-60
Large Adenoma	Kras	50-70
Carcinoma	PI3K, Cell Cycle/Apoptosis Genes	50-70
Metastasis	Multiple	70+

Evolution/Natural Selection Theory of Cancer

Cancer cells undergo selection pressures similar to natural selection:

• Surveillance mechanisms: Remove mutated cells.

• Escape from surveillance: Mutated cells proliferate, accumulate further mutations, and may invade other tissues (metastasis).

Inheritance and Cancer Risk

Are Cancers Inherited?

Most cancers are not directly inherited, but cancer risk can be inherited due to germline mutations in key genes.

• Somatic mutations: Responsible for most cancers; not passed to offspring.

• Germline mutations: Increase risk but do not guarantee cancer development.

• Direct-to-consumer genetic testing: Tests for specific germline mutations (e.g., BRCA1/2).

Loss of Heterozygosity (LOH) and Tumor Suppressors

LOH is a mechanism by which tumor suppressor gene function is lost, increasing cancer risk.

• Familial recessive inheritance: Both alleles must be mutated for loss of function.

• LOH: Loss of the remaining normal allele in a heterozygous individual leads to tumorigenesis.

Genetic Testing and Counseling

BRCA1 Mutations and Breast Cancer Risk

BRCA1 is involved in DNA repair and genome surveillance. Mutations greatly increase breast cancer risk.

• Loss-of-function mutations: 72% of women heterozygous for a BRCA1 mutation develop breast cancer (vs. 12% of women without the mutation).

• Common pathogenic mutations:

  • 185delAG in BRCA1

  • 5382insC in BRCA1

  • 6174delT in BRCA1

• Direct-to-consumer testing: Limited to specific mutations; negative results do not rule out all risk.

Table: BRCA1 Mutations and Breast Cancer Risk

Mutation	Effect	Risk of Breast Cancer
185delAG	Loss-of-function	72%
5382insC	Loss-of-function	72%
6174delT	Loss-of-function	72%

Genetic Counseling Considerations

• Negative test results: Do not eliminate risk; may miss rare or untested mutations.

• Importance of professional counseling: Interpretation of results and risk assessment require expertise.

Transposons: Mobile DNA Elements

Discovery and Mechanism

Transposons are DNA sequences that can move within the genome, discovered by Barbara McClintock.

• Transposase: Enzyme that recognizes specific motifs and mediates transposon movement.

• Autonomous vs. non-autonomous: Some transposons move independently; others require helper proteins.

• Impact: Can disrupt gene function, cause mutations, and contribute to genetic diversity.

Table: Types of DNA Sequences in the Human Genome

Type	Percentage
Repetitive DNA (transposable elements)	44%
Introns and regulatory sequences	24%
Unique noncoding DNA	15%
Repetitive DNA (unrelated to transposons)	15%
Exons (coding regions)	1.5%

Transposon Genetics in Maize

Transposons can cause visible phenotypic changes, such as color variation in maize kernels.

• Genetic cross: Dominant and recessive alleles for color, with transposon-induced DNA breaks affecting expression.

• Somatic movement: Transposons can move in somatic cells, causing mosaic patterns.

Breaking the Central Dogma

Flow of Genetic Information

Transposons and non-coding RNAs (ncRNAs) can disrupt the traditional flow of genetic information (DNA → RNA → Protein).

• Transcription: DNA is transcribed to mRNA, rRNA, and tRNA.

• Translation: mRNA is translated to protein.

• ncRNA: Can regulate gene expression and interfere with the central dogma.

RNA Interference (RNAi)

Genetic Interference by Double-Stranded RNA

RNAi is a process by which double-stranded RNA silences gene expression, demonstrated in Caenorhabditis elegans.

• Mechanism: Introduction of double-stranded RNA leads to degradation of target mRNA.

• Applications: Used in research and potential therapies to silence disease-causing genes.

Common Features of Cancer Cells

Key Characteristics

• Uncontrolled progression through cell cycle checkpoints

• Chromosomal aneuploidy

• Ability to invade other tissues (metastasis)

• Failure to undergo apoptosis despite extensive DNA damage

• Increased DNA mutation rate (not lower)

Summary Table: Cancer Genetics Concepts

Concept	Definition	Example
Oncogene	Mutated gene promoting tumor growth	Kras
Tumor Suppressor	Gene inhibiting tumor formation	BRCA1
LOH	Loss of normal allele in heterozygote	Retinoblastoma
Transposon	Mobile DNA element	Ac/Ds in maize
RNAi	Gene silencing by double-stranded RNA	Fire & Mello, 1998

Key Equations

• Probability of being heterozygous for an allele: $P_{het} = 2pq$ where $p$ is the frequency of the wild-type allele and $q$ is the frequency of the mutant allele.

Additional info:

• Genetic counseling is essential for interpreting genetic test results and assessing cancer risk.

• Transposons contribute to genome evolution and instability, with implications for disease and diversity.

• RNA interference is a powerful tool for gene function studies and potential therapeutic applications.