Mutation Sources and Genomic Instability

Some mutations come from outside — UV light creates C→T changes at pyrimidine dimers (melanoma); tobacco smoke causes C→A changes (lung). Others are internal: replication errors, spontaneous deamination, and enzymes like APOBEC. Each leaves a recognizable mutational signature in the genome.

Sequencing a tumor can therefore reveal its history — like reading fingerprints at a crime scene.

Chromosomal instability (CIN) — frequent gains, losses and rearrangements of whole chromosomes or arms — is common in most solid tumors. Microsatellite instability (MSI) comes from defective mismatch repair (MLH1, MSH2), causing slippage in short repeats. Inherited MMR defects cause Lynch syndrome (colon, endometrial cancer).

Some tumors show chromothripsis: one chromosome shattered and stitched back randomly in a single catastrophic event.

Most mutations in a tumor are passengers with no effect. Drivers give a growth advantage. A typical solid tumor has a handful of driver mutations among thousands of passengers.