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WashU Scientists, Collaborators Use Whole-Genome Sequencing to Uncover New Cancer Mutations

NEW YORK (GenomeWeb News) – A team of researchers reported today that they have sequenced the complete tumor and normal genomes of a cancer patient for the first time.
 
Researchers from the Washington University Genome Sequencing Center and elsewhere used the Illumina Genome Analyzer to unravel the tumor and normal skin genomes of a woman who was diagnosed with acute myeloid leukemia in her mid-50s and eventually died of the disease. The work, appearing online today in Nature, reveals ten mutations that were present in her tumor genome alone. As such, the work not only provides new insights into AML, but also opens the door for additional cancer-genome sequencing efforts.
 
Calling it a “true landmark in cancer research,” geneticist Francis Collins, former director of the National Human Genome Research Institute, said in a statement, “This achievement ushers in a new era of comprehensive understanding of the fundamental nature of cancer, and offers great promise for the development of powerful new approaches to diagnosis, prevention, and treatment.”
 
Acute myeloid leukemia, or AML, is a cancer of blood-forming cells in the bone marrow that affects about 13,000 Americans annually. Just 21 percent of those diagnosed with AML survive for five years or more and about 8,800 people are expected to die from the disease this year.
 
“This was a disease that we had been working on for some time,” co-lead author Elaine Mardis, co-director of Washington University’s Genome Sequencing Center, told GenomeWeb Daily News, adding that the team received a National Cancer Institute grant to study AML back in 2002. That project involved looking at a panel of 94 AML tumor genomes and matched, normal samples, surveying candidate genes with ABI 3730s.
 
Those studies didn’t turn up anything all that new, Mardis said. But as the team gained more and more experience and capacity with next-generation sequencing, they began turning their focus to larger-scale projects.
 
For the latest paper, they used Illumina Genome Analyzers to sequence the AML tumor genome to 90 percent diploid coverage and a control, skin genome from the same patient to 82.6 percent diploid coverage.
 
The tumor and skin samples came from a woman belonging to the group of 94 AML patients, Mardis explained. She was a good candidate for whole-genome sequencing because she had a high percentage of tumor cells in her tumor sample, allowing researchers to sequence as much tumor DNA as possible.
 
Her chromosomes were also relatively unperturbed by obvious amplifications or deletions, as shown by cytogenetics and, later, by array-CGH, Mardis added. Finally, the patient had one of the most common AML subtypes, M1, and array data suggested that her tumor was genetically similar to those of other AML patients.
 
The researchers detected almost 2.7 million single nucleotide variants in the tumor genome. Nearly 98 percent of these were also present in the skin genome and most of the remaining 63,277 variants were present in dbSNP and/or the Watson and Venter genomes.
 
The team eventually focused in on ten mutations in the tumor that appear to be disease specific: eight new non-synonymous, somatic small nucleotide variants and two previously identified insertions in FLT3 and NTM1.
 
The findings speak to the power of whole-genome sequencing versus the candidate gene approach, Mardis emphasized: of the ten genes identified in the tumor genome, just the FLT3 and NTM1 mutations had been previously linked to AML.
 
The remaining mutations were single-base mutations in eight genes: CDH24, PCLKC, GPR123, EBI2, PTPRT, KNDC1, SLC15A1, and GRINL1B. Although several of these genes are suspected tumor suppressors and/or are linked to other types of cancer, they had not been previously implicated in AML. “They were not genes that were on our candidate list at all,” Mardis said.
 
So far, the researchers haven’t found recurrences of the eight new mutations found in the 187 other AML samples tested. Nor have they detected other mutations in the same genes. But that’s not all that surprising, Mardis said, since only a couple of the other genomes tested are from patients with the M1 AML subtype.
 
“We need to look at more M1 subtype genomes,” she said, noting that the glioblastoma and lung adenocarcinoma studies published recently also suggest that even in much larger sample sizes only certain genes are highly mutated.
 
Subsequent research involving consented family members indicated that the patient had a genetic predisposition to cancer, Mardis noted. And some of these inherited mutations were also present in the woman’s normal skin sample, including mutations in two key cancer associated genes: TP53 and BRCA2.
 
The team is primarily using the Illumina platform for such sequencing efforts, though Mardis noted that Roche’s 454 technology also played a key role in the latest paper by helping the researchers characterize the prevalence of mutations in the tumor cells that were sequenced.
 
The team has secured funding to sequence more AML genomes, Mardis said, and is close to completing the “AML2” genome. She said they expect the primary data production for that genome to wrap up this week.
 
The team reportedly plans to sequence lung and breast tumors as well. And Mardis noted that Washington University researchers have gotten tumor-normal pairs from glioblastoma to use in whole-genome sequencing projects, as have collaborators at the Broad Institute and Baylor College of Medicine.
 
Such studies will likely become more common as the cost and time of genome sequencing continue dropping. Still, Mardis added, challenges remain, such as getting tumor samples with enough material for sequencing or, alternatively, finding a way to decrease the amount of tumor material you need to put in to do sequencing.
 
Ultimately, Mardis noted, it is also going to be important to come up with strategies for going beyond sequencing, looking also at structural variants and at how the methylation and transcriptional profiles change during cancer.

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