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Describe the genetic and molecular mechanisms involved in carcinogenesis. [5] b) Describe the role of oncogenes and tumor suppressor genes with suitable examples. [5]

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NCI genetic changes cancer oncogenes tumor suppressor genes

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a) Genetic and molecular mechanisms in carcinogenesis [5]

Carcinogenesis is a multistep process in which a normal cell accumulates non-lethal genetic and epigenetic alterations, giving rise to a clone with progressively greater growth advantage.
  1. Activation of growth-promoting genes
    Proto-oncogenes, which normally promote controlled proliferation, are converted to oncogenes by mutation, gene amplification, or chromosomal translocation. This produces persistent growth signaling.
  2. Inactivation of growth-inhibitory genes
    Loss of tumor suppressor genes removes cell-cycle checkpoints and growth restraint. Usually both alleles must be inactivated, often by mutation plus deletion, loss of heterozygosity, or promoter hypermethylation.
  3. Defective DNA repair and genomic instability
    Mutations of DNA repair genes, such as BRCA1/BRCA2 or mismatch-repair genes, allow DNA damage to persist. The resulting genomic instability accelerates accumulation of mutations in oncogenes and tumor suppressor genes.
  4. Evasion of apoptosis and cellular senescence
    Cancer cells avoid programmed cell death, commonly through loss of TP53, increased anti-apoptotic BCL2, and reactivation of telomerase. They therefore survive despite DNA damage and can divide indefinitely.
  5. Clonal evolution and tumor progression
    Successive mutations generate subclones. Natural selection favors clones that proliferate faster, induce angiogenesis, evade immune destruction, invade tissues, and metastasize. Epigenetic changes, such as abnormal DNA methylation, may also silence tumor suppressor genes without altering the DNA sequence.
Thus, carcinogenesis results from accumulated alterations affecting growth signaling, cell-cycle control, apoptosis, DNA repair, and genome integrity. Thompson & Thompson Genetics and Genomics in Medicine, p. 364. The NCI overview of cancer genetics similarly groups key cancer-driver alterations into proto-oncogenes, tumor suppressor genes, and DNA-repair genes.

b) Oncogenes and tumor suppressor genes, with examples [5]

FeatureOncogenesTumor suppressor genes
Normal counterpartProto-oncogeneGrowth-regulating / DNA-repair gene
Effect of alterationGain of functionLoss of function
Genetic behaviorDominant at cellular level: one altered allele is usually sufficientRecessive at cellular level: usually both alleles are lost or inactivated
Main role in cancerAct as the accelerator of cell proliferation and survivalLoss removes the brakes on proliferation, repair, and apoptosis

Oncogenes

Oncogenes encode proteins involved in growth-factor signaling, signal transduction, transcription, and cell-cycle progression. Activation occurs by:
  • Point mutation: RAS mutation locks RAS in its active GTP-bound state.
  • Chromosomal translocation: BCR-ABL, t(9;22), produces a constitutively active tyrosine kinase in chronic myeloid leukemia.
  • Gene amplification: HER2/ERBB2 amplification in breast carcinoma; N-MYC amplification in neuroblastoma.
  • Overexpression: MYC activation, including t(8;14) in Burkitt lymphoma.

Tumor suppressor genes

These genes normally inhibit proliferation, promote DNA repair, or induce apoptosis when damage is irreparable. Their loss promotes malignancy.
  • TP53: “guardian of the genome”; induces cell-cycle arrest, DNA repair, senescence, or apoptosis after DNA damage. It is commonly mutated in human cancers.
  • RB1: regulates the G1-to-S checkpoint; loss causes retinoblastoma and contributes to several cancers.
  • APC: restrains WNT/β-catenin signaling; loss is an early event in colorectal adenoma-carcinoma sequence.
  • BRCA1 and BRCA2: participate in homologous-recombination DNA repair; inherited pathogenic variants predispose to breast and ovarian cancers.
  • CDKN2A (p16): inhibits cyclin D-CDK4/6 and prevents inappropriate G1-to-S progression.
In short, cancer commonly requires both activation of oncogenes and loss of tumor suppressor genes. Thompson & Thompson Genetics and Genomics in Medicine, p. 364.
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