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Wash U Researchers Use Whole-Genome Sequencing to ID Relapse-Specific Mutations in AML Tumor

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by Monica Heger

This story was originally published May 12

Researchers from Washington University's Genome Center have sequenced the genome of a tumor that developed in a patient with acute myeloid leukemia during disease relapse, and have identified relapse-specific mutations by comparing the relapse-tumor genome to the primary tumor and normal genome from the same patient.

The researchers, who presented the unpublished data last week at the Biology of Genomes meeting at Cold Spring Harbor Laboratory, originally sequenced the primary AML tumor in 2008 (IS 11/11/2008). The relapse tumor that the team is currently analyzing developed 11 months after the primary tumor, and after the patient had received chemotherapy.

Elaine Mardis, co-director of the Genome Center, who led the research, said the team sequenced the relapse tumor on Illumina's Genome Analyzer using a paired-end sequencing approach with read lengths of 75 base pairs and achieved a 28.9-fold coverage of 99.3 percent of the diploid genome.

Aside from the 10 somatic mutations found in coding regions, or "tier 1" mutations, originally identified in the primary tumor, the team found three tier 1 mutations that they had missed in that study because of lower coverage. The original study was also done on the Illumina platform, but using a combination of fragment reads and paired-end reads that were only 32 or 35 base pairs long, achieving 32.7-fold coverage.

In the current sequencing study, they found 47 relapse-specific mutations, including three tier 1 point mutations and one tier 1 translocation, and 14 "tier 2" mutations, which are in regulatory regions, as well as 30 "tier 3" mutations in the rest of the genome. Mardis said her team used targeted capture arrays to help identify and characterize the lower tier mutations.

The relapse-specific tier 1 mutations included an 11 base pair insertion and a missense mutation in two genes that are thought to be tumor suppressors. However, when an additional 21 AML relapse tumors were screened for the mutations using targeted resequencing of the specific genes, those mutations were not found. The third relapse-specific point mutation was detected in a de novo AML genome from a different patient.

Mardis said the translocation, which was a fusion of two genes, is of particular interest and that she and her team are studying the fusion in cell cultures to determine how chemotherapy affects its expression. "In particular, for this fusion, we're pursuing the potential of a drug-resistant phenotype," said Mardis. One of the genes involved in the fusion could affect drug transport in and out of the cell, she added.

Mardis said that while the results are preliminary, along with a study the Wash U researchers published in April that found metastatic-specific mutations in breast cancer (IS 4/20/2010), they show how sequencing cancer genomes at different stages of disease progression can reveal important insights into cancer evolution.

"Whole-genome sequencing and analysis of cancer progression samples is providing a compelling picture of genome evolution," said Mardis.

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