Introduction to Genetics: Genetic Fundamentals of Cancer

Genetics is the branch of biology that studies genes, heredity, and variation in organisms. Cancer is fundamentally a genetic disease, as it is caused by changes in genes that control how cells grow and divide.

Genes and Cancer

There are two main types of genes that play a role in cancer development:

Oncogenes

These are mutated versions of normal genes (proto-oncogenes) that can transform a normal cell into a cancer cell. They are usually involved in promoting cell growth and division.

Examples of oncogenes:

• BRAF: Mutations in melanoma and colon cancer
• EGFR: activating mutations in NSCLC, especially exon 19 deletions and L858R; amplification is also described but is not the main clinically defining mechanism
• HER2: Amplification in breast cancer

Activation mechanisms:

• Gene amplification
• Point mutation
• Chromosomal translocation
• Gene fusion

Tumor Suppressor Genes

These are normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (a process known as apoptosis or programmed cell death). When tumor suppressor genes don't work properly, cells can grow out of control, which can lead to cancer.

Important examples:

• TP53: "Guardian of the genome" - mutated in ~50% of cancers Sources: [1]
• BRCA1/BRCA2: DNA repair - mutated in hereditary breast and ovarian cancer syndromes Sources: [2]
• APC: Cell division control - mutated in colon cancer

Genetic Mutations

The genetic mutations that cause cancer can be inherited or acquired.

Inherited Mutations

These are passed from parent to child and are present in all cells of the body. They are responsible for a small percentage of all cancers.

Characteristics:

• Present since birth
• Affect all cells
• Can be detected by genetic testing
• Significantly increase cancer risk

Examples of hereditary syndromes:

• Li-Fraumeni syndrome (TP53)
• Lynch syndrome (DNA repair genes)
• Cowden syndrome (PTEN)

Acquired (Somatic) Mutations

These occur at some point during a person's life and are not passed on to children. They are the cause of most cancers and can be caused by environmental factors.

Environmental causes:

• Ultraviolet (UV) radiation
• Smoking
• Exposure to chemicals
• Viral infections (HPV, HBV, HCV)

Types of Mutations

Point Mutations

Changes in a single DNA base.

Types:

• Missense: Changes one amino acid to another
• Nonsense: Creates a premature stop codon
• Silent: Does not change the protein

Structural Mutations

Larger changes in DNA structure.

Types:

• Deletions: Loss of genetic material
• Duplications: Extra copy of genetic material
• Inversions: Genetic material inverted
• Translocations: Exchange of material between chromosomes

Mutation Detection

Molecular Techniques

• DNA sequencing: Identifies specific mutations
• Real-time PCR: Detects known mutations
• Microarrays: Analysis of multiple genes simultaneously

Bioinformatics Analysis

• Sequence alignment: Compares with reference genome
• Variant annotation: Interprets mutation impact
• Pathway analysis: Identifies affected pathways

Computational Applications

Analysis Tools

• GATK: Toolkit for variant analysis
• VEP: Variant annotation
• ANNOVAR: Functional variant analysis

Databases

• COSMIC: Catalogue of somatic mutations
• ClinVar: Clinical variants
• dbSNP: Single nucleotide polymorphisms

Next Steps

1. Learn about next-generation sequencing (NGS)
2. Explore variant analysis tools
3. Study clinical cases of specific mutations
4. Practice analysis of genomic data

Additional Resources

• COSMIC - Catalogue of somatic mutations
• ClinVar - Clinical variants
• GATK - Toolkit for variant analysis
• VEP - Variant annotation

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This article is part of the fundamentals series for developers and data scientists interested in cancer research.

References

1. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013;339(6127):1546-1558. doi:10.1126/science.1235122.
2. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266(5182):66-71. doi:10.1126/science.7545954.