Genetics of Cancer

Mr. Arvind Kumar

Introduction

  • Cancer is a genetic disease caused by mutations in genes that control normal cell growth, division, and death.

  • These mutations can be inherited (germline) or acquired (somatic) due to environmental factors like chemicals, radiation, or viruses.

  • Four main gene groups are involved in cancer development — proto-oncogenes, tumor suppressor genes, DNA repair genes, and apoptosis-regulating genes.

  • Accumulation of multiple genetic alterations leads to uncontrolled cell proliferation, loss of apoptosis, and formation of malignant tumors.

  • Understanding the genetic basis of cancer is crucial for early diagnosis, genetic screening, and targeted therapy in modern oncology.

What Is Cancer?

  • Cancer is a condition where cells lose control over growth and division, leading to the formation of a tumor (neoplasm).

  • Normally, cell division is regulated by a balance between growth-promoting genes and growth-suppressing genes.

  • When this balance is disturbed due to genetic mutations, cells begin to divide uncontrollably.

 

Genetic Basis of Cancer

Cancer develops through genetic mutations that can be:

  1. Inherited (Germline mutations):

    • Present in the egg or sperm.

    • Found in every cell of the body.

    • Responsible for hereditary cancers (e.g., BRCA1 mutation in breast cancer).

  2. Acquired (Somatic mutations):

    • Occur during a person’s lifetime due to environmental exposures (radiation, chemicals, viruses) or replication errors.

    • Affect only specific tissues or organs.

    • Account for more than 90% of cancers.

 

Types of Cancer-Related Genes

Cancer arises due to abnormalities in four major classes of genes:

1. Proto-oncogenes

  • These are normal genes that promote cell growth and division.

  • When mutated, they become oncogenes, leading to uncontrolled cell proliferation.

  • Mutation type: Gain-of-function (dominant mutation).

  • Examples:

    • RAS → Colon, lung, pancreatic cancers

    • MYC → Burkitt’s lymphoma

    • HER2/neu → Breast carcinoma

    • ABL → Chronic myeloid leukemia (CML)

2. Tumor Suppressor Genes

  • These genes act as brakes that inhibit abnormal cell growth.

  • When inactivated or deleted, cells lose control over the cell cycle.

  • Mutation type: Loss-of-function (recessive mutation).

  • Key Examples:

    • TP53 → “Guardian of the genome”; mutated in >50% of cancers

    • RB1 → Retinoblastoma, osteosarcoma

    • APC → Familial adenomatous polyposis (colon cancer)

    • BRCA1 and BRCA2 → Breast and ovarian cancers

3. DNA Repair Genes

  • These genes maintain genomic integrity by correcting DNA damage.

  • When defective, DNA mutations accumulate, increasing cancer risk.

  • Examples:

    • MLH1, MSH2 → Hereditary nonpolyposis colon cancer (Lynch syndrome)

    • XPA, XPC → Xeroderma pigmentosum (sensitivity to UV light)

4. Apoptosis-Regulating Genes

  • Control programmed cell death (apoptosis).

  • Mutation can prevent damaged cells from dying.

  • Examples:

    • BCL-2 → Overexpression prevents apoptosis in follicular lymphoma

    • BAX, BAD → Pro-apoptotic genes; loss promotes survival of mutant cells

Mechanisms Leading to Genetic Mutations in Cancer

  1. Point Mutations:
    Alter a single base pair in DNA (e.g., RAS gene mutation).

  2. Chromosomal Translocations:
    Exchange of DNA between chromosomes; produces oncogenic fusion proteins.

    • Example: t(9;22) → BCR-ABL fusion in Chronic Myeloid Leukemia (Philadelphia chromosome)

  3. Gene Amplification:
    Multiple copies of oncogenes cause excessive protein production.

    • Example: HER2/neu amplification in breast cancer.

  4. Deletions or Loss of Heterozygosity:
    Loss of tumor suppressor gene regions (e.g., RB1 in retinoblastoma).

  5. Epigenetic Changes:

    • DNA methylation and histone modification alter gene expression without changing DNA sequence.

    • Hypermethylation → Silencing of tumor suppressor genes.

    • Hypomethylation → Activation of oncogenes.

 

Hallmarks of Cancer

According to Hanahan and Weinberg, cancer cells acquire the following genetic hallmarks:

  1. Sustained proliferative signalling

  2. Evasion of growth suppressors

  3. Resistance to cell death (apoptosis)

  4. Limitless replicative potential

  5. Induction of angiogenesis

  6. Activation of invasion and metastasis

  7. Genome instability and mutation

  8. Deregulated cellular energetics (Warburg effect)

Examples of Specific Genetic Cancers

 

Cancer Type  Gene Involved Mutation Effect
Retinoblastoma RB1 Loss of tumor suppressor control
Breast cancer BRCA1, BRCA2 Defective DNA repair
CML BCR-ABL fusion Constitutive tyrosine kinase activity
Burkitt’s lymphoma MYC Overexpression due to translocation
Colon cancer APC, p53, KRAS Stepwise accumulation of mutations
Melanoma CDKN2A Defective cell cycle regulation

 

Environmental and Viral Causes of Genetic Damage

  1. Chemical Carcinogens:

    • Benzene, aflatoxins, tobacco smoke cause DNA adducts and mutations.

  2. Radiation:

    • UV radiation → thymine dimers

    • Ionizing radiation → double-strand DNA breaks

  3. Oncogenic Viruses:

    • HPV: Cervical cancer (E6, E7 oncogenes inactivate p53, RB)

    • EBV: Burkitt’s lymphoma, nasopharyngeal carcinoma

    • HBV/HCV: Hepatocellular carcinoma

    • HTLV-1: Adult T-cell leukemia

 

Genetic Testing and Molecular Diagnosis

Genetic analysis has revolutionised cancer detection and management.

Modern techniques include:

  • PCR (Polymerase Chain Reaction)

  • FISH (Fluorescence in situ hybridization)

  • DNA sequencing

  • Next-generation sequencing (NGS)

  • Gene expression profiling

These tools help:

  • Detect inherited mutations (e.g., BRCA1/2 testing).

  • Identify therapeutic targets (e.g., HER2 status).

  • Predict treatment response and prognosis.

 

Targeted and Genetic Therapies

Modern cancer treatment now includes genetic and molecular-based approaches:

  • Imatinib (Gleevec): Inhibits BCR-ABL in CML

  • Trastuzumab (Herceptin): Targets HER2 receptor in breast cancer

  • PARP inhibitors: Exploit DNA repair defects in BRCA-mutated cancers

  • Checkpoint inhibitors: Block PD-1/PD-L1 to enhance immune response

  • CAR-T cell therapy: Uses genetically modified T-cells to attack tumor cells

 

MCQs

  1. Cancer is primarily considered a disease of:
    A. Blood circulation
    B. Genetic mutations
    C. Immune deficiency
    D. Hormonal imbalance

  2. Which of the following best describes the genetic nature of cancer?
    A. Metabolic disorder
    B. Infectious disease
    C. Genetic disease of somatic cells
    D. Autoimmune disorder

  3. Mutations in which genes promote uncontrolled cell growth?
    A. Tumor suppressor genes
    B. Proto-oncogenes
    C. DNA repair genes
    D. Housekeeping genes

  4. When a proto-oncogene is mutated, it becomes a/an:
    A. Enzyme
    B. Oncogene
    C. Tumor suppressor
    D. Hormone

  5. The p53 gene is classified as a:
    A. Proto-oncogene
    B. Tumor suppressor gene
    C. DNA repair gene
    D. Oncogene

  6. The “Guardian of the Genome” refers to which gene?
    A. RB1
    B. BRCA1
    C. TP53
    D. MYC

  7. Mutation in the RB1 gene leads to which type of cancer?
    A. Lung cancer
    B. Retinoblastoma
    C. Breast cancer
    D. Leukemia

  8. BRCA1 and BRCA2 genes are associated with:
    A. Brain cancer
    B. Breast and ovarian cancers
    C. Lung cancer
    D. Skin cancer

  9. The BCR-ABL fusion gene is produced by:
    A. Gene duplication
    B. Point mutation
    C. Chromosomal translocation
    D. Gene deletion

  10. The Philadelphia chromosome is found in:
    A. Chronic myeloid leukemia (CML)
    B. Retinoblastoma
    C. Colon cancer
    D. Melanoma

  11. The HER2/neu gene is associated with which cancer?
    A. Breast cancer
    B. Cervical cancer
    C. Thyroid cancer
    D. Brain tumor

  12. The MYC gene is an example of a/an:
    A. Oncogene
    B. Tumor suppressor gene
    C. DNA repair gene
    D. Enzyme gene

  13. Tumor suppressor genes are inactivated by:
    A. Point mutations
    B. Gene deletions
    C. Promoter methylation
    D. All of the above

  14. Which of the following genes controls apoptosis?
    A. BCL-2
    B. BRCA1
    C. RB1
    D. KRAS

  15. Overexpression of BCL-2 leads to:
    A. Increased apoptosis
    B. Decreased apoptosis
    C. Increased DNA repair
    D. Enhanced immune response

  16. Which of the following is a DNA repair gene?
    A. MLH1
    B. KRAS
    C. TP53
    D. HER2

  17. Defects in mismatch repair genes lead to which condition?
    A. Xeroderma pigmentosum
    B. Lynch syndrome (HNPCC)
    C. Leukemia
    D. Melanoma

  18. The APC gene is associated with which cancer?
    A. Colon cancer
    B. Lung cancer
    C. Pancreatic cancer
    D. Prostate cancer

  19. The transformation of a normal cell into a cancer cell is known as:
    A. Mutation
    B. Oncogenesis
    C. Apoptosis
    D. Differentiation

  20. Gene amplification results in:
    A. Reduced gene expression
    B. Multiple copies of an oncogene
    C. Deletion of a gene
    D. Normal gene activity

  21. Which virus is associated with cervical cancer?
    A. Epstein-Barr virus (EBV)
    B. Hepatitis B virus (HBV)
    C. Human papillomavirus (HPV)
    D. Human T-cell leukemia virus (HTLV-1)

  22. The viral oncogenes E6 and E7 inactivate which cellular genes?
    A. p53 and RB1
    B. MYC and KRAS
    C. APC and MLH1
    D. BRCA1 and BRCA2

  23. The main cause of cancer at the molecular level is:
    A. Abnormal gene expression
    B. Hormonal imbalance
    C. Vitamin deficiency
    D. Protein denaturation

  24. Loss of heterozygosity is commonly seen in:
    A. Tumor suppressor genes
    B. Oncogenes
    C. DNA repair genes
    D. Structural genes

  25. Which of the following is NOT a hallmark of cancer?
    A. Uncontrolled proliferation
    B. Evasion of apoptosis
    C. Limited replicative potential
    D. Metastasis

  26. The term “multi-step carcinogenesis” means:
    A. One mutation causes cancer
    B. Cancer develops after accumulation of multiple mutations
    C. Cancer spreads rapidly
    D. Genetic repair is enhanced

  27. The gene product of p53 acts as a:
    A. Transcription factor
    B. Kinase enzyme
    C. Cell surface receptor
    D. Growth factor

  28. RAS oncogene causes cancer by:
    A. Activating cell proliferation pathways
    B. Inhibiting apoptosis
    C. Blocking DNA repair
    D. Preventing cell adhesion

  29. Which chemical agent causes DNA adduct formation leading to mutations?
    A. Benzene
    B. Aflatoxin B1
    C. Nicotine
    D. Methanol

  30. UV radiation mainly causes which type of DNA damage?
    A. Double-strand break
    B. Thymine dimer formation
    C. Cross-linking of proteins
    D. Frameshift mutation

  31. Which virus is associated with Burkitt’s lymphoma?
    A. EBV (Epstein–Barr virus)
    B. HPV
    C. HBV
    D. HCV

  32. Which of the following tests can detect specific gene mutations in cancer?
    A. ELISA
    B. PCR
    C. ESR
    D. CBC

  33. Targeted therapy for HER2-positive breast cancer uses which drug?
    A. Trastuzumab (Herceptin)
    B. Imatinib (Gleevec)
    C. Tamoxifen
    D. Methotrexate

  34. The BCR-ABL fusion protein in CML acts as a:
    A. Tyrosine kinase
    B. DNA polymerase
    C. Protease
    D. Transcription factor

  35. The future of cancer treatment focuses mainly on:
    A. Chemotherapy only
    B. Gene therapy and personalized medicine
    C. Herbal medicine
    D. Radiation alone

Answer Key

  1. B — Genetic mutations

  2. C — Genetic disease of somatic cells

  3. B — Proto-oncogenes

  4. B — Oncogene

  5. B — Tumor suppressor gene

  6. C — TP53

  7. B — Retinoblastoma

  8. B — Breast and ovarian cancers

  9. C — Chromosomal translocation

  10. A — Chronic myeloid leukemia (CML)

  11. A — Breast cancer

  12. A — Oncogene

  13. D — All of the above

  14. A — BCL-2

  15. B — Decreased apoptosis

  16. A — MLH1

  17. B — Lynch syndrome (HNPCC)

  18. A — Colon cancer

  19. B — Oncogenesis

  20. B — Multiple copies of an oncogene

  21. C — Human papillomavirus (HPV)

  22. A — p53 and RB1

  23. A — Abnormal gene expression

  24. A — Tumor suppressor genes

  25. C — Limited replicative potential

  26. B — Cancer develops after accumulation of multiple mutations

  27. A — Transcription factor

  28. A — Activating cell proliferation pathways

  29. B — Aflatoxin B1

  30. B — Thymine dimer formation

  31. A — EBV (Epstein–Barr virus)

  32. B — PCR

  33. A — Trastuzumab (Herceptin)

  34. A — Tyrosine kinase

  35. B — Gene therapy and personalized medicine