Summary

Cancer is a genetic disease characterized by abnormal cell proliferation. It is caused by somatic mutations in tumor suppressor genes and proto-oncogenes.

Many of these mutations accumulate through failure of DNA repair pathways, and many DNA repair proteins are tumor suppressors, involved in genomic caretaker roles. Tumor suppressors like Rb and p53, on the other hand, serve as gatekeepers to the cell cycle, blocking the cell cycle unless conditions are appropriate for cell division. A loss of function in tumor suppressors leads to abnormal proliferation and/or an increase in mutation rate.  Cancer-associated mutations in tumor suppressor genes are recessive on a cellular level.

In contrast, mutations in proto-oncogenes are dominant on a cellular level. Proto-oncogenes normally promote cell cycle progression, but only when conditions are right.  Gain of function mutations in proto-oncogenes convert them to oncogenes, driving the cell cycle forward regardless of whether the timing is appropriate.

Most cells require an accumulation of 5-6 distinct mutations in both proto-oncogenes and tumor suppressors, although there are examples of so-called “one-hit” and “two-hit” cancers. With each subsequent mutation, cells acquire a growth advantage over their neighboring cells. This advantage results in a genetically heterogeneous tumor. Familial cancers essentially have a head start on this process, beginning with a germline tumor suppressor mutation.

The accumulation of mutations leads to characteristic hallmarks of cancer, many of which have been targeted for cancer therapeutics in recent years.

Although we might expect that large-bodied or long-lived organisms would have a greater incidence of cancer than small short-lived organisms, this is not the case. Our understanding of cancer and its physiology has been enhanced by studying cancer in other organisms, where the rate of cancer is higher or lower than would be expected by body size or lifespan.