Decoding the complete DNA of cancer patients is giving scientists at Washington University School of Medicine and Siteman Cancer Center a clearer picture of the complexity of the disease and allowing them to see intriguing and unexpected genetic relationships among patients.
Reporting in the New England Journal of Medicine, the scientists have sequenced the genome of another patient with acute myeloid leukemia (AML), discovering a suite of genetic changes in the cancer cells completely different from those uncovered following analysis of their first patient in 2008.
One mutation was also found in samples taken from 15 other patients with AML, making it one of the most common mutations linked to date to the disease. It additionally is thought to play a role in the development of glioma brain tumors. A second new mutation in the noncoding region of the genome also occurred in another AML patient, suggesting it is of importance. Neither mutation had been previously linked to leukemia.
“Only by sequencing thousands of cancer genomes are we going to find and make sense of the complex web of genetic mutations and the altered molecular pathways in this disease,” says lead author Elaine Mardis, PhD, co-director of Washington University’s Genome Center.
A large majority of the mutations were found in the long noncoding stretches of DNA between genes.
Although this information does not yet point to better treatment options, it highlights the strong potential
of sequencing many cancer genomes to unravel the genetic basis of cancer.
In all, the scientists defined 64 mutations that were the most likely to be important for the patient’s cancer. Twelve were found in genes that code for proteins, including a mutation in the IDH1 gene that has only recently been linked to gliomas, and 52 mutations were in long stretches of DNA that do not contain genes at all but potentially affect when and how neighboring genes are expressed.
“Other than the two mutations the patient was known to have before his genome was sequenced, we never would have guessed any of these mutations—they were a huge surprise,” says co-author Richard K. Wilson, PhD, director of the Genome Center. “That so many of the mutations were found outside of protein-coding genes also underscores the need to sequence whole genomes to find all the mutations that occur in cancer. If we only look at genes with known or suspected links to cancer, we’ll miss many mutations that are potentially relevant.”
The Washington University researchers are now sequencing additional genomes of patients with AML and have expanded the approach to breast, lung and ovarian cancers and glioblastomas. Mardis ER, et al. Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome. New England Journal of Medicine online August 5, 2009.