By Allison Proffitt
August 7, 2009 | Researchers at Washington University in St. Louis have sequenced the second acute myloid leukemia (AML) cancer genome with whole genome sequencing, and have identified two mutations previously unassociated with AML. The results were published online in the New England Journal of Medicine on Wednesday.
The sequencing occurred on Illumina instruments and compared leukemia cancer cells to normal skin cells from a 39 year old male patient. “The tumor sample required just 16.5 runs… to reach 98% diploid coverage. That’s a dramatic improvement over our first cancer genome, AML1 [completed in November 2008], which took 98 runs… to achieve 91% diploid coverage,” said Dan Koboldt with Washington University Genome Center and an author on the AML1 paper, on his MassGenomics blog on Thursday.
The group identified 12 acquired mutations within the coding sequence of genes and 52 point mutations in conserved or regulatory portions of the genome. Of those 64 mutations, four were found in one of the 187 other AML samples tested. Two of these four were newly identified mutations.
The first was a noncoding conserved mutation on chromosome 10, found in one other AML sample. The study authors stress that this is “unlikely to be a random event. It falls in a conserved region with regulatory potential, and its detection in a second patient with AML suggests that this region may contribute to pathogenesis through a novel mechanism that remains to be defined.”
The second newly identified mutation was a nonsynonymous mutation in the IDH1 gene. “Sixteen of 187 other leukemia samples carried mutations at the same residue in IDH1,” writes Koboldt, “suggesting an important role for this gene in the development of AML.” Mutations in IDH1 have been seen in gliomas, a type of brain tumor, but the authors note that “there are significant differences between the IDH1 mutations found in gliomas and those in AML.”
Revealing Genome-Wide
“This study opens a clear window into the rapid advancements that are being made in cancer-genome sequencing,” writes James Downing of St. Jude Children’s Research Hospital in an editorial in the same issue of the Journal.
“Only by sequencing complete genomes of cancer patients are we going to find unexpected, recurring genetic mutations that are highly likely to be important for cancer to develop and grow," said hematologist and senior author Timothy Ley, in a University of Washington press release. "Gaining a genome-wide understanding of cancer lays the foundation for developing more powerful ways to diagnose, classify, and treat patients."
Koboldt credits much of the group’s progress with the technical advances in sequencing. He points out that current capacities allow for sequencing an entire human genome (though not data analysis) within a week. He writes: “With the ever-growing throughput of the Illumina platform and our automated pipelines for whole-cancer-genome analysis, we hope to sequence at least a hundred more cancers in the coming year.”