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Washington University Team Sequences AML Relapse Tumor

By Andrea Anderson

COLD SPRING HARBOR, NY (GenomeWeb News) – By sequencing the genome of a relapse tumor isolated from an individual with acute myeloid leukemia and comparing it to primary tumor and normal skin genomes from the same individual, researchers from Washington University have identified relapse-specific mutations that offer clues to the cancer's evolution.

"I personally am as excited as I can be about the prospect of studying this progression," said Elaine Mardis, co-director of Washington University's Genome Center. Mardis presented the work at the Biology of Genomes meeting here last night.

The relapse tumor sample came from the same individual as the tumor used to generate the first sequenced cancer genome, which was published in Nature in 2008. The patient, a 57-year-old Caucasian woman, was diagnosed with de novo M1 AML and was treated with standard chemotherapy and stem cell therapy. Despite these treatments, she relapsed at 11 months and again at 18 months and died about two years after diagnosis.

In an effort to better understand the genetic changes underlying cancer relapse, the team used paired-end sequencing to get 28.8 times haploid coverage and 99.3 percent diploid coverage of the genome of the 11-month relapse tumor. They then compared this genome with the previously sequenced primary tumor and matched normal skin genomes.

Along with the 10 somatic mutations originally identified in the primary tumor, the researchers also found three additional mutations present in both the primary and relapse tumors, as well as four mutations — one translocation and three somatic mutations — found only in the relapse tumor.

The relapse-specific somatic mutations identified in coding regions so far include missense mutations affecting the ETV6 and MYO18B genes, respectively, an insertion in the STK4 gene, and a translocation involving the WNK1 gene on chromosome 10 and WAC on chromosome 12.

Mardis noted that the team is using custom capture arrays to characterize additional mutations in the genome, including so-called tier 2 and tier 3 mutations that affect non-coding regulatory, conserved, and poorly characterized parts of the genome.

Meanwhile, she explained, collaborators are also currently doing a series of cell culture experiments aimed at characterizing the effects that the chemotherapy drugs AraC and daunorubicin have on cells containing full-length Wnk1 protein or a Wnk1-Wac fusion.

The presentation comes on the heels of a Nature paper published last month in which Mardis and her colleagues at Washington University and elsewhere reported on their effort to sequence and analyze a quartet of breast cancer-related genomes, including genomes from the primary tumor, metastasis, xenograft, and a matched normal sample from the same individual.

Together, Mardis said, such whole-genome sequencing data and analyses of cancer progression samples are not only providing a compelling view of cancer evolution but also expanding researchers' overall understanding of cancer genomes.

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