Understanding Cancer at the Molecular Level
Cancer is a complex disease driven by multiple genomic alterations. Affected pathways lead to multiple cancer subtypes that vary from patient to patient.
Cancer genomics research efforts, such as The Cancer Genome Atlas, are helping scientists and physicians understand cancer at the molecular level. This research has been moving at an increasingly rapid pace due to new technologies that allow for faster and more accurate genome analysis. Next-generation sequencing is a method of sequencing large amounts of DNA in a very short period of time.
Genomic alterations in cancer
Somatic alterations, genomic alterations present in the cancer but not in the germ-line, are the major causes of cancer. Hundreds of somatic alterations have been causally linked to human oncogenesis. These include point mutations, insertions, deletions, translocations or genomic rearrangements, and copy number alterations.
Various genes are altered in any individual tumor, and cancer cells often contain combinations of somatic alterations resulting in uncontrolled growth and the other hallmarks of cancer. To understand cancer at the molecular level, scientists are assembling a pathway view of cancer. One aim is to understand the distribution of alterations that can occur within any cancer type.
The Cancer Genome Atlas (TCGA) pilot project
The foundation laid by researchers is being leveraged in a 3-year project sponsored by NIH’s National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI).
The Cancer Genome Atlas (TCGA) Pilot Project, and other similar projects, are systematically identifying and cataloging all somatic alterations in cancer. The outcome is forming a comprehensive “atlas”, which will provide the basis for further understanding the molecular mechanisms responsible for the uncontrolled growth of cancer cells and their spread throughout the body. Additionally, the project will identify new targets for cancer therapeutics, and allow clinical trials to focus on patients who are most likely to respond to specific treatments.
Next-generation sequencing is a method of sequencing large amounts of DNA accurately in a very short period of time. Using this technology, results from projects such as the TCGA and other scientific discoveries are occurring at speeds never before possible.
Sequencing technologies continue to improve, making large-scale DNA sequencing even faster and less costly. These advances are making the use of massively parallel sequencing for molecular diagnostics possible and practical.
New model for drug development
As a direct result of new sequencing technology and projects such as TCGA, identification of somatic alterations that occur in cancer is providing potential new therapeutic targets on an almost daily basis.
This rapid identification and classification of these alterations is permitting the development of drugs and biologic therapies that more precisely target the molecular mechanism causing or contributing to individual cancers. Because somatic alterations are present only in the tumor, there can be a large “therapeutic window” where toxicity to cancer vastly exceeds toxicity to normal cells.
There are already many targeted therapies in routine clinical use, several currently in clinical trials, and hundreds more in development across many tumor types. However, unlike past efforts where targeted therapies were commonly tested without knowledge of the presence or absence of a given target, massively parallel sequencing will allow a true assessment of an agent’s efficacy – applying it in patients whose tumors possess the target in question.