Cancer as a Genetic Disease Study Notes

Is Cancer a Genetic Disease?

  • Definition:

    • Cancer is characterized by the uncontrolled growth and reproduction of abnormal cells.

    • These cancerous cells can invade and destroy surrounding healthy tissues and organs.

  • Evidence Supporting Cancer as a Genetic Disease:

    • Carcinogens and Mutagens:

    • Most carcinogens are also mutagens, indicating a link between mutation and cancer.

    • However, not all mutagens are classified as human carcinogens.

    • Transmission and Incidence:

    • Cancer does not exhibit mini-epidemics, hence it is not contagious.

    • The incidence of cancer increases with age, correlating with accumulated DNA damage.

    • Certain cancers show familial segregation and over 50 forms of cancer have some degree of inherited predisposition.

    • Chromosomal Features:

    • Chromosomal instability is common across many cancers, and specific chromosomal changes are observed.

    • DNA Repair Defects:

    • Defects in DNA repair mechanisms increase the probability of developing cancer.

Bert Vogelstein's Perspective

  • Quote:

    • "Cancer is, in essence, a genetic disease… tremendous progress made in understanding tumorigenesis is owing to the discovery of the genes, that when mutated, lead to cancer."

    • Source: Bert Vogelstein, NEJM 1988; 319:525-532.

Types of Mutations

  • Mutation Classification:

    • Substitution (Point Mutations)

    • Insertions

    • Deletions

    • Duplications

    • Inversions

    • Translocations:

    • Example: Philadelphia chromosome, BCR-ABL gene fusion in Chronic Myeloid Leukemia (CML) / Acute Myeloid Leukemia (AML).

Genetic vs. Inherited Cancer

  • Cancer Origin:

    • All cancer originates from mutations in genes, but not all cancer is inherited.

    • Approximately 5-10% of cancers result from inherited mutations.

  • Germline Mutations vs. Somatic Mutations:

    • Germline Mutations:

    • Present in every cell, including reproductive cells (egg and sperm).

    • Passed directly from parent to offspring, leading to inherited cancers.

    • Less common cause of cancer.

    • Somatic Mutations:

    • Also referred to as 'acquired mutations.'

    • Arise from cumulative damage during an individual's lifetime (e.g., from tobacco, UV radiation, aging).

    • Not passed to offspring; most common cause of cancer, termed sporadic cancer.

Detailed Comparison of Germline and Somatic Mutations

  • Characteristics of Somatic Mutations:

    • Occur in non-germline tissues.

    • Cannot be inherited by offspring.

  • Characteristics of Germline Mutations:

    • Present in egg or sperm cells.

    • Can be inherited, leading to cancer family syndromes.

Inheritance of Mutations

  • Diagram Overview:

    • Germ-line to zygote to somatic differentiation and subsequent generations.

'Cancer Genes'

  • Function in Normal Cells:

    • Cancer genes maintain normal functions but act differently when mutated, contributing to cancer development.

  • Types of Cancer Genes:

    • Oncogenes:

    • Normal versions are called proto-oncogenes.

    • Mutations lead to dominant gain of function, promoting cell growth/division.

    • Mutations are usually not inherited.

    • Tumor Suppressor Genes:

    • Function normally to prevent cell growth and division.

    • Mutations cause loss of function; require both copies to be compromised for effect.

    • Many inherited cancers are linked to tumor suppressor genes.

Tumor Suppressor Genes

  • Key Functions:

    • Prevent inappropriate cell growth and division.

    • Mutations lead to functional losses, often requiring mutations in both gene copies to drive cancer.

    • Examples of cancers linked to tumor suppressor genes include:

    • Retinoblastoma: RB1 gene.

    • Familial Adenomatous Polyposis (FAP): APC gene.

    • Li-Fraumeni Syndrome: TP53 gene.

Oncogenes

  • Normal Functions:

    • Promote cell growth/division.

    • Mutations result in dominant gain of function.

    • Examples of family cancers linked to oncogenes include:

    • Multiple Endocrine Neoplasia Type 2 (MEN2): RET gene.

    • Isolated Hereditary Papillary Renal Cell Cancer (HPRCC): MET gene.

Mutation Mechanisms

  • Oncogene Activation:

    • Can occur through:

    • Amplification (e.g., Myc oncogene).

    • Translocation forming BCR-ABL fusion.

    • Point mutations in Ras family genes (Kras, Nras, Hras).

Distribution of Mutations in Genes

  • Oncogenes vs Tumor Suppressor Genes:

    • Oncogenes generally have mutations concentrated in particular codons affecting specific domains.

    • Bias toward missense mutations.

    • Tumor suppressor genes exhibit mutations more evenly distributed across the gene and include both missense and premature termination codon mutations.

Oncogene vs. Tumor Suppressor Analogy

  • Analogy of Car Controls:

    • Oncogenes:

    • Act as the accelerator pedal:

      • Normal Cells: Controlled acceleration (growth).

      • Cancer Cells: Uncontrolled acceleration of cell growth.

    • Tumor Suppressor Genes:

    • Act as the brake pedal:

      • Normal Cells: Brakes functioning to prevent excessive growth.

      • Cancer Cells: Brakes non-functional leading to excessive growth.

Further Classifications of Cancer Genes

  • Caretaker, Gatekeeper, and Landscaper Genes:

    • Gatekeepers:

    • Act directly to restrain cell proliferation (e.g., RB1).

    • Caretakers:

    • Maintain genome integrity; their disruption leads to genomic instability (e.g., BRCA1, BRCA2).

    • Landscapers:

    • Control the microenvironment around cells, aiding in cancer progression.

DNA Repair Genes

  • Functionality:

    • Often regarded as a subclass of tumor suppressor genes that are targeted by loss-of-function mutations.

    • They play a role in maintaining genome integrity indirectly.

    • Inactivation of DNA repair genes leads to uncorrected DNA damage, resulting in accumulating mutations across other critical genes.

Cancer Mechanisms and Evidence

  • DNA Repair Mechanisms:

    • Genetic mechanisms include issues related to specific diseases:

    • Xeroderma Pigmentosum: UV-induced skin cancer.

    • Hereditary Nonpolyposis Colorectal Cancer (HNPCC).

    • BRCA1/BRCA2 linked breast and ovarian cancers.

The Two-Hit Hypothesis

  • An explanation for the genetic complexity of cancers, particularly retinoblastoma.

    • Proposed by Alfred Knudson in 1971.

    • Suggests two independent mutations are necessary for tumor formation; with inherited cases starting with one mutation already present.

Retinoblastoma Overview

  • Characteristics of Retinoblastoma:

    • Most common eye tumor in children, occurring in 1 in 20,000.

    • Symptoms include "white pupil" and eye pain or redness.

    • Treatments vary and include surgery, chemotherapy, and radiation therapy.

    • Can be diagnosed as inherited or sporadic.

Comparison of Sporadic and Inherited Retinoblastoma

  • Key Features of Sporadic (60%) vs. Inherited (40%) Cases:

    • Tumor presentation is usually unilateral for sporadic and bilateral for inherited forms.

    • Family history present in inherited but absent in sporadic cases.

    • Average age at diagnosis is around 2 years old for sporadic and less than a year for inherited cases.

    • Higher incidence of other cancers in individuals diagnosed with inherited retinoblastoma.

Genetics of Inherited Retinoblastoma

  • Genetic Transmission:

    • Autosomal dominant.

    • RB1 gene located on chromosome 13 was cloned in 1986, marking it as the first tumor suppressor gene discovered.

    • The RB1 gene encodes the Rb protein that negatively regulates the cell cycle, with over 100 known mutations.

The Two-Hit Hypothesis Detailed

  • Explanation of how retinoblastoma demonstrates the two-hit model:

    • Inherited cases require just one mutation due to the presence of one inherited mutation.

    • Sporadic cases typically need two somatic mutations.

    • Fast-growing retinal cells increase the likelihood of a second mutation occurring.

Loss of Heterozygosity (LOH) in Retinoblastoma

  • After the first mutation in sporadic cases, the cell remains heterozygous (Rb +/-), exhibiting wild-type phenotype until the second allele is mutated or lost.

Limitations of the Knudson Model

  • Acknowledgment that Knudson's model doesn’t universally apply to all cancers or genes.

Haploinsufficiency

  • Some tumor suppressor genes exhibit abnormal phenotypes with only a single wild-type gene copy, contradicting recessive gene behavior typically seen in cancer.

TP53 Gene and Tumor Suppression

  • Functionality of TP53:

    • Encodes p53, known as the "guardian of the genome."

    • Upon DNA damage, p53 either induces cell cycle arrest or apoptosis.

    • Involved in DNA repair processes.

  • Somatic Mutations:

    • Commonly found in human tumors, breaking down the classic model of tumor suppressor function by exhibiting effects with only one mutated allele.

Multistep Model of Tumorigenesis

  • Cancers typically involve multiple acquired mutations leading towards the final tumor phenotype, commonly known as 'Multi-Step Tumorigenesis'.

    • Formation of tumors progresses over decades, with many mutations accumulated in cancerous cells.

Example of Multistep Tumorigenesis in Colorectal Cancer

  • Reflects changes across a person’s lifetime with the intestinal wall undergoing significant genetic modifications through somatic cells.

    • Estimated that around 5 critical gene mutations are involved leading to cancer development.

Summary

  • Cancer is fundamentally a genetic disease due to mutations in DNA.

  • Though genetic, cancer is usually sporadic; only 5-10% derives from family syndromes.

  • Key genes are primarily classified into tumor suppressor and oncogenes, with specific functions underscoring their role in cancer mechanisms (caretaker, gatekeeper, landscaper).

  • Critical concepts include Loss of Heterozygosity and Haploinsufficiency as they relate to tumor suppression, with implications seen through the p53 pathway.

  • Most sporadic cancers follow a multi-step model, where numerous mutations develop incrementally over time.