12. Cancer Genetics

Learning Goals

  1. Explain the difference between tumor and cancer.

    • Tumor: Uncontrolled cell growth; can be benign or metastatic.

    • Cancer: Refers specifically to metastatic tumors.

  2. Describe the ways the environment and genetics contribute to cancer.

    • Environmental: can introduce mutations (ex. carcinogens).

    • Genetic: mutations increase cell replication and additional mutation likelihood.

  3. Tumor Suppressor Genes vs. Oncogenes/Proto-oncogenes.

    • Normal function

      • TSG: Regulate cell growth, repair DNA, initiate apoptosis, act as cell cycle “brakes”

      • OG/POG: Promote cell division and growth, act as cell cycle “accelerators”

    • Mutation types

      • TSG: Loss-of-function mutations, both alleles need to be inactivated (two-hit hypothesis)

      • OG/POG: Gain-of-function mutations, only one allele mutation needed (dominant mutation)

    • Therapeutic approaches

      • TSG: - Reactivate or restore TSG function - Gene therapy - Targeting alternative pathways - Immunotherapy

      • OG/POG: - Inhibit oncogene activity - Targeted therapies (e.g., small molecule inhibitors, monoclonal antibodies) - RNAi or CRISPR to silence oncogenes

    • Inheritance patterns

      • TSG: Recessive at cellular level (but dominant for susceptibility in hereditary cancer syndromes)

      • OG/POG: Dominant at cellular level, typically not inherited (but dominant in some rare hereditary syndromes like MEN2)

  4. Identify features of Retinoblastoma and Rb that make it a typical inherited cancer syndrome.

    • Two-hit hypothesis involving a germline mutation followed by a somatic mutation

    • Autosomal dominant inheritance for cancer susceptibility

    • Early onset of cancer, often in infancy or early childhood

    • Bilateral or multifocal tumors due to predisposition to multiple second hits

    • Increased risk of secondary cancers later in life

    • Involvement of a tumor suppressor gene (RB1) that regulates the cell cycle

    • High penetrance, with most individuals inheriting the mutation developing the disease.

  5. Explain Kudson’s Two Hit Model of cancer formation and explain why a multi-hit model is more accurate.

    • Two-Hit Model: The development of cancer requires losing both copies of a tumor suppressor gene

    • Inherited Cancer

      • First Hit: inherited LOF mutation present in all cells (germline/somatic)

      • Second Hit: acquired mutation in a somatic cell that later forms a tumor

    • Non-Inherited Cancer

      • First Hit: LOF mutation in a somatic cell

      • Second Hit: additional LOF mutation in the same somatic cell

    • Multi-Hit Model: two hits are required to inactive a tumor suppressor gene, but additional mutations are required to generate metastatic cancer

      • This is a better model, because it accurately reflects the reality that cancer typically arises from a series of genetic mutations accumulated over time, not just a single event

  6. Understand the different types of mutations in relation to cancer and cancer pedigrees.

    • Somatic - acquired mutations that drive tumor development, not inherited

    • Germline - increase susceptibility to cancer, inherited from parents, typically autosomal dominant

    • de novo - occur spontaneously, not inherited

  7. Explain how tumor viruses and chromosomal rearrangements helped identify some proto-oncogenes.

    • Tumor Viruses: viruses can hijack normal cellular genes and transform them into cancer-causing oncogenes

    • Chromosomal Rearrangements: bring proto-oncogenes under the control of highly active promoters or fuse them with other genes

  8. Explain genomic instability and how it promotes cancer progression and metastasis.

    • Genomic Instability: increased tendency of cells to acquire genetic mutations.

    • Promotes cancer progression

      • Mutation accumulation

      • Deregulation of cell cycle apoptosis

    • Promotes metastasis

      • Chromosomal rearrangements and mutations in genes regulation cell adhesion, motility, and invasion enable cancer cells to detach from the primary tumor, invade nearby tissues, and spread to distant sites

  9. Explain the relationship between telomerase and senescence in cancer.

    • Telomerase: enzyme that maintains telomere length by adding repeats to the telomeres.

    • Senescence: a state where cells stop dividing

    • In normal cells, telomeres shorten with each cell division, eventually triggering cellular senescence. This acts as a barrier to unlimited cell growth, preventing cancer.

    • In cancer cells, telomerase is reactivated, preventing telomere shortening and bypassing senescence. This allows cancer cells to continue dividing indefinitely, contributing to immortalization and tumor growth.

  10. Compare and contrast p53 vs. Other Tumor Suppressor Genes:

    • p53: Acts as a “guardian of the genome”; regulates DNA repair, apoptosis, and cell cycle arrest in response to cellular stress or DNA damage.

    • Other tumor suppressor genes: generally regulate cell growth, division, and apoptosis; may also be involved in DNA repair and maintaining genomic integrity.

  11. Explain how angiogenesis and metastasis contribute to cancer progression and what basic changes cells undergo as part of metastasis.

    • Angiogenesis: the process by which new blood vessels form to supply nutrients and oxygen to a tumor. This new blood supply supports the rapid growth of the tumor and provides a route for cancer cells to enter the bloodstream, facilitating metastasis.

    • Metastasis: the spread of cancer cells from the primary tumor to distant sites in the body. 

    • Cell changes during metastasis

      • Loss of cell adhesion

      • Increased motility

      • Degradation of the extra cellular matrix

      • Survival in circulation

      • Colonization of distant sites

  12. Explain how chromatin modifications can impact cancer progression.

    • Closing chromatin can lead to shutdown of tumor suppressor genes

    • Opening chromatin can lead to activating oncogenes

    • Changes in chromatin must occur before metastasis

  13. Describe how APC mutations lead to Familial Adenomatous Polyposis (FAP) cancer syndrome and colon cancer.

    • APC: tumor suppressor that regulates the Wnt signaling pathway, controlling cell growth and division.

    • Mutations in the APC gene disrupt its tumor-suppressive role in the Wnt signaling pathway, primarily involved in the colon, leading to the formation of polyps in the colon.

    • Lynch Syndrome: caused by mutations in DNA mismatch repair genes, leads to microsatellite instability and a high risk of colorectal and other cancers, often without polyps.

  14. Use information to determine if a cancer is likely to have an inherited genetic component.

    • Age of Diagnosis - younger age of diagnosis (typically before age 50) is often a sign that a cancer may have a genetic basis, as inherited mutations can lead to earlier onset of cancer.

    • Family History - multiple family members across generations with the same or related types of cancer can indicate an inherited cancer syndrome.

    • Recurrence Risk - a higher recurrence risk for the same or related types of cancer within a family may suggest a genetic mutation is driving cancer susceptibility.

    • Tissue Type - cancers of the breast, ovary, colon, endometrium, pancreas, and prostate are frequently associated with inherited mutations 

Cancer Classification

Tumor vs. Cancer

  • Tumor:

    • Uncontrolled growth; can be benign (without metastasis) or malignant (with metastasis).

  • Cancer:

    • Specifically refers to malignant tumors that interfere with physiological functions.

    • Blood tumors categorized as cancer.

Cancer Genetics

  • Genetic and Environmental Influences:

    • Environmental factors (carcinogens, mutations) influence cancer incidence (e.g., stomach cancer in Japan, colon cancer in US).

  • Genetic Susceptibility:

    • Monogenic: Rare, typically results in early onset and dominant inheritance.

    • Polygenic: Involves risk loci with varying heritability and interactions with environmental exposure.

Cellular Growth Regulation

  • Normal Regulation Mechanisms:

    • Includes growth factor signaling, cell cycle checkpoints, and DNA damage repair mechanisms.

    • Abnormal cellular processes lead to cancer development, resulting in altered proliferation and survival.

Tumor Suppressor Genes and Oncogenes

Tumor Suppressor Genes

  • Function in:

    • DNA damage detection and repair.

    • Regulating cell cycle checkpoints.

    • Inducing apoptosis and inhibiting proliferation.

Oncogenes

  • Promote cell proliferation through:

    • Gain of function mutations, leading to increased activity and expression.

    • Often arise from mutations in proto-oncogenes.

Retinoblastoma Case Study

Importance of Rb Gene

  • Function:

    • Regulates cell cycle transition and maintains genomic stability.

  • Types of Retinoblastoma:

    • Hereditary (bilateral) and sporadic (unilateral) forms.

    • Importance of understanding genetic risks and outcomes.

Multi-Hit Model of Cancer

  • Knudson’s “Two Hit” Model:

    • Requirement of inactivating both copies of the tumor suppressor gene for cancer development.

  • Loss of Heterozygosity:

    • Cells begin as heterozygous and losing the other allele leads to cancer progression.

Clinical Implications

Cancer Types and Genetic Links

  • Familial Adenomatous Polyposis (FAP):

    • Caused by APC mutations; increases colon cancer risk.

  • Lynch Syndrome:

    • Associated with mismatch repair genes (MLH1, MSH2); low polyposis risk.

  • Inherited Breast Cancer:

    • BRCA1 and BRCA2 associated with increased breast and ovarian cancer risk due to disrupted DNA repair.

Cancer and Age of Onset

  • Mutation Accumulation Over Time:

    • Increased risk of developing cancer with age due to mutation accumulation.

Conclusion

  • Understanding genetics and environmental factors is crucial in cancer research and prevention strategies.

  • Early detection and intervention can significantly alter the prognosis and outcomes for cancer patients.