1. General Genetic Changes in Cancer

Cancer cells acquire a range of genetic alterations:

Small-scale changes

• Point mutations = single-nucleotide substitutions

Large-scale chromosomal abnormalities

• Translocations
• Inversions
• Deletions
• Amplifications

Nonrandom chromosomal patterns

• Especially seen in:
• leukemias
• lymphomas

These recurrent changes target:

• oncogenes
• tumor suppressor genes
• DNA repair genes

→ promote:

• malignant transformation
• selective growth advantage
• support the hallmarks of cancer

Analogy: point mutations = small chips; chromosome rearrangements = big structural moves.

2. Driver vs Passenger Mutations

Driver mutations

• Directly promote cancer progression
• Act by altering cancer genes
• Usually acquired during life, but can be inherited
• Cluster in key pathways

Passenger mutations

• Random, neutral, do not change tumor behavior
• Scattered across genome

Why passengers still matter

• Reveal carcinogen footprints
• e.g., melanoma carries thousands of UV-signature mutations showing UV exposure
• Can seed therapy resistance if a previously neutral passenger becomes advantageous under drug pressure

Hooks:

• Drivers steer the cancer
• Passengers ride along
• UV fingerprints in melanoma
• Some passengers “speak up” during treatment → resistance

3. Point Mutations in Cancer

• Definition: change in one DNA base

Gain-of-function → proto-oncogene activation

• A point mutation can convert proto-oncogene → oncogene
• Often by changing amino acids in a regulatory domain
• Produces overactive signaling

Classic example: RAS

• Normal RAS cycles:
• ON when bound to GTP
• OFF when bound to GDP
• Mutated RAS:
• Locked ON (GTP-bound)
• Continuous proliferation signaling

Hook:

• Proto-oncogene activation = green light
• RAS = gas pedal stuck down

Loss-of-function → tumor suppressor inactivation

• Point mutations or small insertions/deletions (indels)
• Remove checkpoint control

Most common suppressor hit: TP53

• Normal TP53:
• After DNA damage → induces cell-cycle arrest or apoptosis
• Mutant TP53:
• Checkpoint fails → genomic instability

Hook:

• TP53 = tumor police

4. Gene Rearrangements (Structural Changes)

Definition

Chromosomal reshuffling such as:

• translocations
• inversions

These cause cancer by:

• overexpression of oncogenes OR
• formation of fusion genes (chimeric oncoproteins)

Seen mainly in:

• hematopoietic tumors
• sarcomas
• some carcinomas

Mechanism A — Overexpression (enhancer hijacking)

A proto-oncogene moves next to a strong promoter/enhancer → excess protein.

Examples:

• t(8;14) Burkitt lymphoma
• MYC under Ig heavy-chain enhancer → MYC overexpression
• t(14;18) follicular lymphoma
• BCL2 overexpressed → anti-apoptotic

Mechanism B — Fusion Genes

Two genes fuse → abnormal oncoprotein with novel function.

Examples:

• t(9;22) Philadelphia chromosome in CML
• BCR-ABL fusion → constitutively active tyrosine kinase
• t(11;22) Ewing sarcoma
• EWS-FLI1 fusion transcription factor

Why lymphoid tumors are prone

• B and T cells intentionally break and join DNA during:
• Ig recombination
• TCR recombination
• Errors can activate oncogenes

Myeloid neoplasms & sarcomas

• Often have:
• fusion kinases (e.g., BCR-ABL)
• fusion transcription factors (e.g., EWS-FLI1)

Why carcinomas seemed genetically quiet initially

• Large cytogenetic rearrangements were hard to detect using microscopy

Later, sequencing revealed cryptic rearrangements:

• e.g., EML-ALK fusion in lung cancer

Summary Comparison Table

Key memory anchors

• Tiny changes (points) + big changes (chromosome moves)
• Drivers steer, passengers ride
• RAS stuck ON
• TP53 lost = checkpoints failed
• MYC, BCL2, BCR-ABL = classic rearrangement targets
• EWS-FLI1 + EML-ALK = fusion oncogenes revealed by advanced sequencing