Bert Vogelstein at the Johns Hopkins Oncology Center analyzed changes that occur during the development of colon cancer from small polyps that can be easily and safely removed to full-blown colorectal cancer that is invasive and metastatic. He proposed a multistep model of cancer and showed that the evolution from a benign polyp to a malignant cancer involved activation of at least one oncogene and inac­tivation of at least three tumor suppressor genes (23). Subsequent studies showed that there are dozens of different mutations in most cancers, and on average about 13 different pathways are affected (16). These multiple, independent genetic muta­tions explain why there is such a long latency period for cancer to develop after an initiating event. The probability of a single cell getting four or more independent mutations is extremely small. In fact, it would appear to be vanishingly small, to the point that cancer would seem to be very unlikely to ever occur, and yet it does!

One explanation for this conundrum is that some alterations can cause the chromosomes to become unstable and accumulate a large number of mutations and aberrations very rapidly, a condition known as genetic (or genomic) instabil­ity. This might occur, for example, if DNA repair genes are mutated so that DNA damage cannot be repaired effectively. There are many genetic syndromes such as Ataxia telangiectasia, Fanconis anemia, Nijmegan breakage syndrome, Xeroderma pigmentosum, and Werner’s syndrome that involve mutations in DNA repair genes and often cause genetic instability. Individuals with these syndromes have a high probability of getting various kinds of cancer.

Another mutation that can cause genetic instability is the deletion of the ends of chromosomes—the telomeres (24). Telomeres have six bases that are repeated hundreds of times and serve to preserve the ends of the chromosomes when cells divide. Every time cells copy their DNA in the synthesis phase, a short piece at the end of each chromosome is lost, but it doesn’t matter because the ends have identical copies of the telomere sequence. But when the cells have divided a large number of times, the telomeres become short and the cells can no longer con­tinue to divide—they become senescent. That is true for normal cells, but cancer cells often activate an enzyme called telomerase that adds more telomere units to the ends of chromosomes so they can continue to divide. Under certain condi­tions, the ends of telomeres can look like DSBs to cell repair machinery and can be fused with actual DSBs, leading to chromosome fusions and causing genetic instability (25).