Cancer Genetics: Mechanisms, Mutations, and Inheritance - Nov 14

Cancer Genetics

Introduction to Cancer Genetics

Cancer is a complex genetic disease characterized by uncontrolled cell growth and division. It is not a single disease but a collection of related diseases with common hallmarks, including inappropriate proliferation and failure of cellular surveillance mechanisms. Understanding the genetic basis of cancer is essential for diagnosis, treatment, and genetic counseling.

Learning Objectives

• Identify cellular processes commonly misregulated in cancer (proliferation and surveillance).

• Describe oncogenes, proto-oncogenes, and tumor suppressors, including genetic definitions of mutants.

• Connect genetic and physical mutations to cancer-causing mutations.

• Discuss issues in genetic counseling and cancer risk/inheritance.

Key Concepts

• Mosaicism: The presence of genetically distinct cell populations within an individual, often due to mutations occurring after fertilization.

• Germ line vs Somatic cells: Germ line mutations are inherited and present in every cell, while somatic mutations occur in non-reproductive cells and are not inherited.

• Mutations: Changes in DNA sequence that can affect gene function and contribute to cancer development.

• Properties of cancer: Overgrowth and inhibition in surveillance mechanisms.

• Cancer risk/inheritance: The likelihood of developing cancer based on genetic and environmental factors.

What is Cancer?

General Overview

• Cancer is a leading cause of death in Western countries, with over 1 million cases diagnosed annually in the United States and 500,000 deaths.

• There is no single disease called "the cancer"; rather, cancer encompasses many distinct diseases with common features.

• The central commonality is inappropriate growth, but cancer also involves changes in cell identity and deregulation of control mechanisms.

Hallmarks of Cancer

• Increased proliferation (hyperplasia).

• Loss of cell identity and control over proliferation.

• Failure of surveillance mechanisms that maintain genome integrity.

Cellular Surveillance Mechanisms

DNA Repair Pathways

• Double-strand break repair (DSB): Homologous recombination (HR) and non-homologous end joining (NHEJ).

• Nucleotide excision repair (NER), base excision repair (BER), and mismatch repair (MMR): Pathways that correct various types of DNA damage.

Cell Cycle Control and Checkpoints

• Cell cycle checkpoints (G1/S, G2/M, M) monitor DNA integrity, spindle formation, and attachment to kinetochores.

• Checkpoints prevent progression of cells with damaged DNA, controlling against aneuploidy.

Programmed Cell Death (Apoptosis)

• Apoptosis: Programmed cell death that eliminates cells with severe, irreparable chromosome damage.

• In cancer cells, genes regulating apoptosis are often mutated, allowing survival of damaged cells.

Example: Xeroderma Pigmentosum

• Caused by mutations in nucleotide excision repair genes.

• Leads to extreme sensitivity to UV and a 2000-fold increased risk of skin cancer.

• Does not directly cause cancer, but greatly increases cancer risk.

Types of Genes and Mutations in Cancer

Proto-oncogenes and Oncogenes

• Proto-oncogenes: Genes whose products promote normal cell growth and proliferation.

• Mutation of a proto-oncogene creates an oncogene, which causes increased activity and promotes oncogenesis.

• Oncogenes typically result from gain-of-function mutations and confer a dominant cancer phenotype.

• Only one allele of a proto-oncogene needs to be mutated or misexpressed to trigger uncontrolled growth.

Example: ras Genes

• ras genes are frequently mutated in human tumors and regulate cell growth and division.

• Growth signal pathway: Ras GDP → Ras GTP → Raf → Erk → Cyclins → Proliferation.

Tumor Suppressor Genes

• Tumor suppressor genes: Inhibit oncogenesis and cell growth by regulating cell-cycle checkpoints and initiating apoptosis.

• Mutated tumor suppressor genes cannot respond to checkpoints or undergo apoptosis, leading to more mutations and cancer development.

• Loss-of-function mutations in tumor suppressors are usually recessive and require both alleles to be inactivated.

Example: p53 Tumor Suppressor Gene

• p53 is the most frequently mutated gene in cancer (50% of all cases).

• Acts as a transcription factor regulating genes for cell cycle checkpoints, apoptosis, and DNA repair.

• Normally present at low levels and rapidly degraded; stabilized by DNA damage or mutations.

• Cells lacking p53 cannot arrest at checkpoints or enter apoptosis.

Classifications of Mutations

Physical Mutations

• Insertions

• Deletions

• Point mutations: Missense, nonsense, silent

Genetic Classifications

• Dominant, recessive, co-dominant, incomplete dominant

• Loss-of-function:

  • Amorph (Null): Total loss-of-function

  • Hypomorph: Partial loss-of-function

• Gain-of-function:

  • Hypermorph: Increase in normal function

  • Neomorph: New/novel function

Mutation Types Leading to Cancer

• Oncogenes: Gain-of-function mutations (hypermorph, neomorph, missense mutations).

• Tumor suppressors: Loss-of-function mutations (amorph, hypomorph, frameshift, nonsense mutations).

Stages of Cancer Development

Multigenic and Evolutionary Theory

• Cancers develop in stages, accumulating multiple mutations over time.

• Pathways involved: APC, K-ras, cell cycle/apoptosis genes (e.g., TGF-β).

• Stages: Normal epithelium → Small adenoma → Large adenoma → Carcinoma → Metastasis.

• Evolution/Natural Selection theory: Mutant cells escape surveillance, proliferate, and accumulate further mutations, leading to metastasis.

Inheritance and Cancer Risk

Somatic vs Germline Mutations

• Most cancers develop from somatic mutations (not inherited).

• Germline mutations can predispose individuals to cancer and are detectable by genetic testing (e.g., 23andMe).

Summary Table: Oncogenes vs Tumor Suppressors

Gene Type	Normal Function	Mutation Effect	Inheritance Pattern
Proto-oncogene	Promote cell growth/proliferation	Gain-of-function (oncogene)	Dominant
Tumor suppressor	Inhibit cell growth, promote apoptosis	Loss-of-function	Recessive (usually both alleles)

Recap

• Oncogenes: Mutations in genes that promote tumors.

• Tumor suppressors: Genes that suppress tumors.

• Mutations occur in somatic or germline cells.

• Cancer is a multigenic disease involving accumulation of mutations.

Additional info:

• 23andMe and similar genetic tests screen for germline mutations associated with increased cancer risk (e.g., BRCA1/2).

• Surveillance mechanisms include DNA repair, cell cycle checkpoints, apoptosis, and immune system functions.