Kidney Cancer Genome Sequencing

Cancer is caused by alterations in the genetic information inside cells. This genetic information, which makes up the genome, is stored in the form of DNA (deoxyribonucleic acid).

The DNA consists of a string of four chemicals. These chemicals, which are called bases, are referred to by the first letter of their names: A, T, G, and C. These bases are arranged into different sequences. Not all sequences are believed to carry information. Sequences that carry information are referred to as genes. Many genes carry instructions to make proteins. Proteins serve as the scaffold for the cell and are also responsible for specific activities of cells.

Every cell in the body has a natural life span. New cells are made by duplicating their contents and dividing into two. It is essential that DNA be copied without introducing errors. But errors do occur. In fact, errors build up as part of the natural aging process (that is why cancer tends to occur more frequently as we age). Errors may also be introduced by radiation and chemicals (such as those in tobacco). These errors (referred to as mutations) may affect genes encoding proteins that regulate cell growth and division. As a consequence, cells may start growing and dividing uncontrollably— this is cancer. When these tumor cells gain the ability to leave the tissue and invade blood vessels, they circulate throughout the body and may settle at distant sites causing metastases.

Technology now allows us to “read” the entire sequence of bases that makes up the DNA or human genome. By comparing the sequence of healthy tissue and tumors, we can pinpoint mutations that cells have acquired as they became cancerous. These mutations tell us the history of the tumor and account for its behavior.

A typical kidney tumor has several thousand mutations. However, it is estimated that 5 to 20 mutations in critical genes are enough for a cell to become a cancer cell. These mutations are referred to as “driver mutations” as they fuel the growth of cancer cells within the tumor. However, most mutations are considered "passenger" mutations and are believed to contribute little to the behavior of cancer cells.

Genome sequencing of tumors is now available to patients at UT Southwestern. The first patient to have had his kidney cancer genome sequenced in a clinical laboratory may have been a patient at UT Southwestern (Cold Spring Harbor Laboratories, Personal Genome Conference, 2010). Among the mutations identified, one was found that may explain why the tumor was very responsive to everolimus, a drug used for kidney cancer treatment.

The significance of most mutations however, remains unknown. In rare cases, a mutation may be found in a gene that is known to drive cancer, and a drug may be available that counteracts the effects. Thus, although it is not often useful at present, cancer genome sequencing may open up new treatment opportunities when standard treatments have been exhausted.