Mechanisms of Oncogenesis: Introduction , FAQS

Introduction

• TSG suppresses cell growth and proliferation.
• Proto-oncogenes are necessary for certain group cells to proliferate and maintain homeostasis via growth factors.
• Proto-oncogenes mutations can be inherited in MEN syndrome - RET (Receptor tyrosine kinase) on chromosome 10.
• TSG mutations follow KNUDSON Hypothesis (Two hits), recessive.
  • The first TSG discovered is the retinoblastoma gene.
• TSG - Tissue preference;
  • APC gene mutations are seen only in colon cancers.
  • RB gene mutations are seen only in eye cancer - Retinoblastoma.

Mechanisms of Oncogenesis

• Mutations can be of the following types:
  • Substitutions (Ex., JAK V617F, BRAFV600E) 
  • Deletions (Ex., EGFR exon 9 del, 5q del)
    • 5q deletion examples: Myelodysplastic syndrome, 5q deletion syndrome.
  • Insertion (Ex., EGFR exon 20 insertion)
    • Non-small cell lung cancer, especially adenocarcinoma.

• Substitution: substitution is a Single gene mutation. Substitutions are point mutations. Where G is replaced by T and the amino acid is changed from Glu to Lys. The Best example of missense mutation is also substitution.
• Insertion: Insertions are frame-shift mutations. Complete changeover of the amino acids is seen during insertion
• Deletion: Deletion is a frame-shift mutations. Complete new amino acids are produced.

Also Read: Cancer Therapies - Types And Basic Principles

Large Chromosomal Changes

• Duplication - A particular region of the chromosome is duplicated twice or thrice.
  • The normal function of the gene is amplified as the number of times the chromosomes are duplicated.
  • Ex., HER2/ERBB2 amplification.
• Translocation - Fusion of one part of a chromosome to the other.
  • It may render some additional properties as per the gene in that area.
  • Ex., BCR-ABL1 - Chronic Myeloid leukemia.
• Inversion - Part of the chromosome that flips by 180⁰.
  • Translocation within chromosomes.
  • Ex., CBFB-MYH11 - Acute Myeloid leukaemia.
• Deletions - Part of the chromosome is deleted.
  • Ex., FIP1L1-PDGFRA because of deletion of 4q12 deletion on chromosome 4 causes myeloproliferative variant of hypereosinophilic syndrome.

The changes made in the chromosomes may result in abnormal function causing cancer or render the function of TSG nullified and can lead to the development of cancer.

Also Read: Etiology Screening of Cancer

Other Mechanisms of Oncogenesis

Apart from mutations and chromosome abnormalities, the other causes of oncogenesis are;

1. Infections (e.g., HPV and H. pylori).

• Virulence factors of H.pylori is CAG-A causes alteration in the gastric epithelial cells that can lead to gastric cancer or lead to the development of extra nodal marginal zone lymphoma, maltoma.
  • HPV produces two proteins E6/E7 inhibits P56 protein and RB proteins.
• Hormone receptors: Breast cancer (ER) and prostate cancer (AR).
  • SERMs like Tamoxifen and Raloxifene are given to block ER.
  • Aromatase inhibitors like Anastrozole, Ezimestran in postmenopausal women can be given.
  • Flutamide, Bicalutamide, Nilutamide are AR inhibitors.
• Epigenetic changes (Myelodysplastic syndrome) (DNA methylation and histone modification.
  • The way of gene expression is altered.
  • DNA methylation without altering the sequence renders a gene inactive.
  • Demethylation increases the activity or increases the particular expression of genes.
  • Histones acetylation increases the activity.
  • Histone deacetylation represses the activity of genes.

• DNA methylation without altering the sequence renders a gene inactive or suppresses the transcription of that particular gene.
• De novo DNMTs
  • DNMT1 - Maintenance of methylation during replication.
• Once the particular gene is demethylated, regions activate of transcription of a particular gene.
• Demethylation can be passive, where DNMT1 is inhibited. Tet proteins are involved in the active demethylation.
• In some cancers, methylation of tumour suppressor gene occurs and its activity is reduced.
  • Ex: Various cases of myelodysplastic syndrome.
  • DNMT1 inhibitors are like Azacitidine, and Decitabine can be used.
• Methylation occurs at CPG sites of DNA.
• IDH - IDH1, IDH2 mutant forms produce 2-hydroxyglutarate that inhibit the Tet enzyme.
  • Once blocked, TSG methylation can be maintained, responsible for gliomas, acute myeloid leukaemia.
• IDH inhibitors are used like Ivosidenib and Enasidenib
• Histone acetylation increases the activity.
• Histone deacetylation represses the activity of genes.
• Some cancers can actively cause histone deacetylation, repressing the activity of certain TSG.
• HDACC inhibitors are useful.
  • Romidepsin
  • Panobinostat
    • Used in advanced cases of multiple myeloma.
  • Belinostat

DNA Methylation affecting Cancer

• In normal cells, TSG promoter is not methylated and the TSG is actively transcribing, suppressing the growth of the cell.
• In a cancer cell, the TSG promoter area is methylated, making the gene completely inactive, which leads to uncontrolled proliferation and subsequently to cancer.

Frequently Asked Questions

Q: What type of mutations are substitutions?

Answer: Point Mutation

Q: What doesthe TSG suppresses?

Answer: Tsg suppresses cell growth and proliferation.

Q: Which hypothesis is followed by the TSG?

Answer: TSG munitions follow the Knudson Hypothesis.

Question: Which protiens are involved in active demethylation?

Answer: Tet Proteins