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Explain me this

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These pages are from a General Pathology textbook (Chapter 7: Neoplasia) and cover Tumour Suppressor Genes, Oncogenes, and Cell Cycle Regulation. Here is a full breakdown:

Tumour Suppressor Genes (Anti-Oncogenes) - Complete Explanation

The Core Concept

Think of cell division like a car: oncogenes are the accelerator, and tumour suppressor genes are the brakes. In cancer, the accelerator gets stuck down (oncogene mutation) OR the brakes fail (tumour suppressor gene mutation) - either way, the car crashes (uncontrolled growth).

The main checkpoint where both types act is the G1 → S phase transition of the cell cycle.

Part 1: Oncogenes (Brief Recap from Image 1)

MYC Oncogene (Nuclear Transcription Factor)

Normally on chromosome 8; regulates entry into S phase
When mutated or overexpressed → autonomous cell proliferation
Three types:
- C-MYC: translocation t(8;14) → Burkitt lymphoma
- N-MYC: amplification → neuroblastoma, small cell lung Ca
- L-MYC: amplification → small cell lung Ca

Cell Cycle Regulatory Proteins (Cyclins/CDKs)

Cyclins (A, B, D, E) + CDKs drive the cell cycle forward
Gain-of-function mutations in these = oncogenes
- Mutated Cyclin D → mantle cell lymphoma, myeloma
- Mutated Cyclin E (overexpression) → breast cancer
- Mutated CDK4 (amplification) → melanoma, glioblastoma, sarcomas

Part 2: Tumour Suppressor Genes - The Main Focus

How They Work

Normal function: push the cell into G0 (rest) or the post-mitotic pool
Mutation type: loss-of-function (deletions, point mutations)
Inheritance pattern: Recessive - both alleles must be lost (unlike oncogenes which are dominant)

i) RB Gene - "Master Brake of the Cell Cycle"

Location: Long arm (q) of chromosome 13

Product: pRB protein (nuclear transcription protein)

State	What Happens
Active pRB	Binds transcription factor E2F → blocks cell cycle genes → cell arrested at G1
Inactive pRB	Hyperphosphorylated by CDKs + growth factor signals → releases E2F → cell crosses G1→S → proliferates

Key regulator: TGF-β activates p16 protein which inhibits CDKs → keeps pRB active → brakes ON

Cancers: Retinoblastoma, osteosarcoma

ii) p53 Gene - "Guardian of the Genome"

Location: Short arm (p) of chromosome 17 (also called TP53, 53 kDa protein)

Normal function: Present in tiny amounts; accumulates only after DNA damage

Two major roles:

Blocking mitotic activity - inhibits cyclins and CDKs → temporary arrest at G1 → gives time to repair DNA
Promoting apoptosis - works with RB gene; identifies irreparably damaged DNA → activates BAX gene → apoptosis (operates at G1 and G2 phases)

Mutated p53:

Stops acting as brake → acts like an oncogene
Homozygous loss → damaged cells survive and proliferate → malignant transformation
Found in >70% of all human cancers (lung, head & neck, colon, breast)
Also seen in stepwise cancer progression: hyperplasia → carcinoma in situ → invasive carcinoma

Li-Fraumeni Syndrome: Germline p53 mutation → predisposes to cancers of breast, bone, brain, sarcomas

iii) TGF-β and Its Receptor

Normally a strong inhibitor of cell proliferation (especially in epithelial, endothelial, haematopoietic cells)
Acts at G1 phase by:
- a) Activating CDK inhibitors (growth inhibitory)
- b) Suppressing MYC, CDKs, and cyclins
Mutant TGF-β → loses inhibitory effect → cancer of pancreas, colon, stomach, endometrium

iv) APC and β-catenin Proteins

APC gene normally inhibits mitosis via β-catenin degradation
β-catenin normally binds E-cadherin (intercellular adhesion) in cytoplasm
Also activates cell proliferation via WNT signalling pathway (frizzled cell surface receptors)
When APC is lost → β-catenin accumulates → uncontrolled mitosis
Cancer: Colon cancer (patients with one mutant APC allele develop polyps by age 20; 85% develop colon cancer)

v) Other Tumour Suppressor Genes

Gene	Function	Cancer
BRCA1 (chr 17q21) / BRCA2 (chr 13q12)	Repair of damaged DNA	Breast Ca (85% risk), Ovarian Ca (40%)
VHL (chr 3p)	Ubiquitinates HIF-1α; prevents angiogenesis	Renal cell carcinoma
WT1 / WT2 (chr 11)	Transcription factor in embryonic kidney	Wilms tumour
NF1 (neurofibromin, a GTPase) / NF2 (merlin, cytoskeletal)	Prevent Schwann cell proliferation	Neurofibromatosis type 1 and 2
PTEN	Phosphatase; inhibits PI3K/AKT signalling	Breast cancer, epithelial cancers
PTCH1	Inhibits Hedgehog signalling (PTCH = PATCHED-1)	Naevoid basal cell carcinoma (Gorlin syndrome)
CDKN2A	Encodes p16/INK4 - inhibits CDK4/Cyclin D	Bladder Ca, Ca cervix

Part 3: Knudson's Two-Hit Hypothesis (Key Concept!)

This explains why tumour suppressor genes need BOTH alleles inactivated:

Sporadic Retinoblastoma (~60% of cases, unilateral)

Born with two normal RB alleles
Two separate somatic mutations must hit both alleles in the same retinal cell → tumour
Occurs in one eye, later in life

Familial/Inherited Retinoblastoma (~40%, bilateral)

Born with one mutant RB allele (germline) already in every cell
Only needs one more somatic "hit" in the other allele
Occurs earlier, often bilateral, higher risk of other cancers (osteosarcoma, breast, colon - 200x increased risk)

Analogy: You need to knock out both copies (both "hits") of the gene for the brake to completely fail.

Part 4: Oncogenes vs Tumour Suppressor Genes - Comparison Table

Feature	Oncogenes	Tumour Suppressor Genes
Derived from	Mutated proto-oncogenes	Mutated growth-suppressor genes
Inheritance	Dominant (one mutation enough)	Recessive (both alleles needed)
Common mutations	Point mutation, translocation, amplification, overexpression	Deletion, point mutation, loss-of-function
Major action	Allows proliferation by increased growth promotion	Allows proliferation by removing brakes; passive loss of normal function
Level of action	Cell surface, cytoplasm, nucleus	Cell surface, cytoplasm, nucleus
Major types	GFs, GF receptors, RAS, MYC, Cyclin D, CDK4	RB, p53, TGF-β receptor, APC/β-catenin, BRCA, VHL, WT, NF, PTEN, PTCH1, CDKN2A

Summary: How It All Connects

Growth Factor → Receptor → RAS signal → MYC / Cyclin D / CDK4
                                                  ↓
                                        G1 → S phase entry
                                                  ↑ (brakes here)
                              pRB (active) ← p16/CDKN2A ← TGF-β
                              p53 ← DNA damage sensor
                              APC → degrades β-catenin

When oncogenes mutate (gain-of-function) OR tumour suppressors mutate (loss-of-function), the balance tips toward uncontrolled cell division → Cancer.

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