Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively increases for several years before turning into a lethal condition.

Mutations in the genome can arise due to errors during DNA replication or DNA damage caused by carcinogens - agents that can trigger cancer-causing mutations in the gene. Such mutations can either be a point mutation; for example, exposure to carcinogen aristolochic acid causes A to T base substitutions. The mutations can also be indels, large-scale chromosomal deletions, and translocation, as seen in breast cancer BRCA1 and BRCA2 gene mutations. The CML cells have the Philadelphia chromosome, where a part of the chromosomal segment is translocated between chromosomes 9 and 22.

The evolution of cancer cells from normal cells is described as an example of Darwinian evolution, where each cancer-critical mutation is naturally selected and fixed in the population. The development of cancer typically requires a substantial number of independent, rare genetic mutations and epigenetic changes in a single cell's lineage. This may be the reason for the increased incidence of cancer as a function of age. For instance, the median age for breast cancer diagnosis in patients is 61 years; for colorectal cancer, it is 68 years, and for lung cancer, it is 70 years.