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Taking Stab at Cancer Genome Sequencing, Illumina and Sanger Institute Analyze Melanoma Genome

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By Julia Karow

This article was originally published Sept. 16.

COLD SPRING HARBOR, NY — In an effort to evaluate its in-house cancer genome sequencing capabilities, Illumina has collaborated with the Wellcome Trust Sanger Institute to sequence a human melanoma genome and catalog all its somatic mutations using the Genome Analyzer platform.

At the Personal Genomes conference at Cold Spring Harbor Laboratory last week, Illumina chief scientist David Bentley presented initial results from the study, which the company conducted in collaboration with Mike Stratton, who heads the Sanger Institute's Cancer Genome Project.

Cancer genomes present particular challenges, according to Bentley, since tumors tend to be heterogeneous, and their genomes are often polyploid and harbor many rearrangements. The project served as a pilot to see what Illumina could achieve with its technology.

The scientists sequenced a cell line derived from a metastatic melanoma to about 40-fold coverage, and a normal control from the same patient to about 30-fold coverage, using 75-base paired-end reads and short-insert as well as long-insert libraries. The data was generated at Illumina's sequencing facility in the fall of 2008 and was extensively validated by the Sanger group. Producing the data required — in the case of the melanoma — eight runs, each generating about 15 gigabases of data.

The reads covered approximately 90 percent of the reference genome, and the scientists estimated they were able to determine somatic substitutions with more than 95 percent specificity and 90 percent sensitivity. The spectrum of substitutions they found reflects the mutational mechanisms that accompany UV exposure, Bentley noted, as expected in tumors of this type.

The scientists also detected other types of mutations, including insertions, deletions, translocations, and copy number variants. Further validation of the results and refinement of the analysis are in progress, Bentley said, particularly regarding algorithms to analyze the sequence data, such as indel callers.

In the meantime, he told In Sequence, Illumina has been sequencing other human genomes with high depth. In all, the company has sequenced 28 human genomes in house with coverage greater than 30-fold to date, including a HapMap trio, which it has sequenced twice; four samples sequenced as pilot samples for its personal genome sequencing service; several HapMap samples that are part of the 1,000 Genomes Project; and a number of cancer samples and their normal controls. Last year, the company published one genome from the HapMap trio (see In Sequence 11/11/2008).

The company currently uses technology that allows it to achieve 30 gigabases of data per run with 100-base pair reads, thus requiring only four runs per genome. In the near future, Illumina expects to incorporate further improvements to the GA, currently in R&D, that will allow scientists to generate up to 50 gigabases per run with 100-base pair reads. This throughput would enable researchers to sequence a human genome in two to three runs.

Illumina has said previously that it plans to sequence approximately 50 cancer genomes and their controls in house — including transcriptome and methylation analyses — as part of its diagnostic strategy. During the company's second-quarter earnings call in July, Jay Flatley, president and CEO, said that Illumina expects to begin analyzing the first sets of sequenced samples from an ovarian and gastric cancer sequencing program during the third quarter (see In Sequence 7/28/2009).

The melanoma genome, which the company and its collaborators intend to publish shortly, is not the first human cancer genome analyzed on Illumina's platform. Last year, researchers at Washington University published an acute myelogenous leukemia genome, sequenced to 32-fold depth in 98 runs on the GA, using unpaired reads (see In Sequence 10/14/2008). This year, the group published a second AML genome with paired-end reads and plans to sequence about 150 cancer and their normal controls within the next year or so (see In Sequence 5/12/2009).

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