WHAT HAS BEEN LEARNED FROM GENOME SEQUENCING OF CANCER?
With the ability to sequence whole genomes and exomes, attention has quickly turned to trying to understand the full spectrum of genetic mutations that underlie cancer. Now the genomes or exomes of tens of thousands of cancers have been sequenced and a number of important new insights into cancer biology have been revealed:
- Every tumor is different and has a different genomic
- Certain mutations are common in specific cancers. For example, many cancers have mutations in the tumor suppressor gene, TP53; many colon and ovarian cancers have mutations in the RAS pathway; and 40%–60% of melanomas have a very specific mutation in the BRAF proto-oncogene. Although the genetic basis of certain cancers was known prior to whole genome sequencing, our knowledge of the genes and biological pathways commonly mutated in many different types of cancers has been greatly
- Different types of cancers can have mutations in the same proto- oncogene. For example, mutations in the BRAF gene commonly occur in melanoma but also appear in many other cancers such as colon cancer and thyroid
- Although there are many different types of cancer, the underlying molecular defects typically affect just a dozen or so processes or “pathways” (Figure b). The pathways are often involved in cell growth and proliferation or in repair of DNA For example, breast cancers often have mutations in the pTEN pathway and Rb pathways, which affect cell growth as well as in the BRCA genes, which affect DNA repair pathways. Mutations in genes in DNA repair pathways (e.g., MLH and BRCA genes) can lead to accumulation of mutations in tumor suppressor genes and oncogenes, giving rise to the cancer indirectly.
- Overall, it is very clear that cancers are best classified not only by tissue of origin (i.e., the conventional classification system), but also by their underlying molecular
Figure . (b) Examples of biochemical pathways that are mutated (or altered in expression in the case of Notch) in four common cancers. These pathways participate in the biological processes shown at the top.