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Epigenetic changes in neoplasia / cancer Robbins based md pathology 10 marks question give easy answer with flowcharts

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Robbins Basic Pathology epigenetic changes cancer promoter hypermethylation histone modifications microRNA

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Epigenetic changes in neoplasia / cancer

Definition:
Epigenetic changes are reversible and heritable alterations in gene expression without a change in the DNA nucleotide sequence. They are important in cancer because they can switch off tumor-suppressor genes or promote genomic instability.
Robbins & Kumar Basic Pathology, 11th ed., p. 228.

Main epigenetic mechanisms in cancer

Epigenetic abnormality
        ↓
Altered gene expression
        ↓
Loss of growth control / reduced apoptosis / genomic instability
        ↓
Neoplastic transformation and tumor progression

1. DNA methylation abnormalities

Normally, methyl groups are added to cytosine residues in CpG islands, especially in promoter regions. Methylation generally suppresses gene transcription.

A. Promoter hypermethylation

In cancers, there is selective hypermethylation of promoter regions of tumor-suppressor genes.

Promoter CpG island hypermethylation
                ↓
Transcription of tumor-suppressor gene is switched off
                ↓
Loss of tumor-suppressor protein
                ↓
Uncontrolled cell proliferation / decreased DNA repair / reduced apoptosis
                ↓
Cancer

Important point: This causes functional loss of tumor-suppressor genes without mutation or deletion.

Examples:

Gene silenced	Normal function	Result
CDKN2A / p16	Inhibits cell-cycle progression	Uncontrolled cell division
MLH1	DNA mismatch repair	Microsatellite instability, especially colorectal carcinoma
BRCA1	DNA repair	Genomic instability
VHL	Controls hypoxia signaling	Seen in some renal cancers

B. Global DNA hypomethylation

Cancer cells also show genome-wide hypomethylation.

Global DNA hypomethylation
            ↓
Activation of normally silent DNA sequences
            ↓
Chromosomal instability + abnormal gene expression
            ↓
Increased mutations and oncogene activity
            ↓
Tumor development and progression

Effects:

Causes chromosomal instability
May activate proto-oncogenes
May activate transposable/repetitive DNA sequences
Helps tumor progression

High-yield contrast

Cancer cell DNA methylation pattern

Global hypomethylation
        +
Selective promoter hypermethylation
        ↓
Genomic instability     Tumor-suppressor gene silencing
        ↓                         ↓
        └────────── Promotes cancer ──────────┘

2. Histone modifications

DNA is wrapped around histone proteins. Histone modification changes chromatin structure and therefore gene transcription.

Histone modification
        ↓
Chromatin structure changes
        ↓
Gene becomes accessible or inaccessible to transcription machinery
        ↓
Altered expression of genes controlling growth, apoptosis, and differentiation
        ↓
Cancer

Common changes

Change	Effect on chromatin	Effect on gene expression
Histone acetylation	Open chromatin	Increased transcription
Histone deacetylation	Condensed chromatin	Reduced transcription
Abnormal histone methylation	Depends on site modified	May activate oncogenes or silence tumor suppressors

In cancer, abnormal histone modification can silence tumor-suppressor genes even when their DNA sequence is normal.

3. Mutations in epigenetic regulator genes

Some cancers have mutations in genes that normally regulate DNA methylation or histone modification.

Mutation in epigenetic regulatory gene
                  ↓
Abnormal methylation / histone modification
                  ↓
Abnormal expression of many genes
                  ↓
Growth advantage and survival of cancer cells

Thus, a genetic mutation may promote cancer indirectly by producing an abnormal epigenetic state.
Robbins & Kumar Basic Pathology, 11th ed., p. 228.

4. MicroRNAs and cancer

MicroRNAs are short non-coding RNAs that reduce gene expression by inhibiting translation or degrading mRNA.

Abnormal microRNA expression
            ↓
Abnormal regulation of target mRNA
            ↓
↓ Tumor-suppressor proteins OR ↑ Oncogene proteins
            ↓
Carcinogenesis

Two patterns

A. Excess miRNA targeting a tumor-suppressor gene
        ↓
Tumor suppressor ↓
        ↓
Cancer promotion

B. Loss of miRNA that normally inhibits an oncogene
        ↓
Oncogene protein ↑
        ↓
Cancer promotion

Examples:

Increased oncomiRs can suppress tumor-suppressor genes.
Loss of certain miRNAs in leukemias and lymphomas can increase BCL2, an anti-apoptotic protein.
Abnormal miRNAs may also affect RAS and MYC oncogenes.
Robbins & Kumar Basic Pathology, 11th ed., p. 228.

Summary flowchart for exam

EPIGENETIC CHANGES IN CANCER
             ↓
1. DNA methylation abnormalities
   ├─ Promoter hypermethylation
   │       ↓
   │   Tumor-suppressor gene silencing
   │       ↓
   │   Cancer
   │
   └─ Global hypomethylation
           ↓
       Chromosomal instability
           ↓
       Cancer

2. Histone modifications
        ↓
   Altered chromatin structure
        ↓
   Abnormal gene transcription
        ↓
   Cancer

3. Defective epigenetic regulators
        ↓
   Widespread abnormal gene expression
        ↓
   Cancer

4. MicroRNA dysregulation
        ↓
   ↑ Oncogenes / ↓ tumor suppressors
        ↓
   Cancer

Conclusion

Epigenetic alterations are major contributors to carcinogenesis. The two hallmark DNA methylation changes are:

Global hypomethylation → chromosomal instability
Promoter hypermethylation → tumor-suppressor gene silencing

Unlike DNA mutations, epigenetic alterations are potentially reversible, which is why they are relevant targets for cancer therapy. A supporting review also describes the combination of global hypomethylation and CpG-promoter hypermethylation in tumors in this cancer epigenetics review.

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