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Genentech Group Validates Complete Genomics' Methodology in Lung Tumor Study

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This article has been corrected to reflect that the Lee et al. paper was published in Nature in May.

It was a mutually beneficial partnership from the start. Genentech, the Roche subsidiary, was looking for ways to cut whole-genome sequencing costs. Thirty miles south along the San Francisco Bay a sequencing-as-a-service startup was searching for collaborators to bring its proprietary approach to market.

Zemin Zhang, a senior scientist in the bioinformatics and computational biology division at Genentech, says that his team's decision to collaborate with Complete Genomics was partially driven by the potential for symbiosis between the firms — and by Bay Area biotech camaraderie.

"We realized this technology had a lot of potential, and we wanted to do a small pilot project with them," Zhang says. He says that the two companies worked jointly how to go about the projects. "Our motivation was that, if it work[ed] out well, we can expand this, because they have the best potential to sequence whole human genome[s] at a very reasonable cost," he adds.

The Genentech-Complete Genomics pilot project, which reports the full genome sequences of non-small cell lung cancer tumor and normal tissue samples from a single patient, was published in Nature in May. Zhang calls the collaborative study, which identified 50,000 somatic point mutations, representing approximately 17.7 mutations per megabase throughout the tumor genome — more than was previously estimated or detectable using less sensitive sequencing methods — a proof-of-concept that the Complete Genomics sequencing service "provides reliable results."

The Complete Genomics team used its combinatorial probe anchor ligation — or cPAL — chemistry on arrays of self-assembling DNA nanoballs as a whole-genome sequencing method to map the cancer genome of the patient to a 60-fold depth of coverage. Zhang says that their analyses revealed several transversions, copy-number alterations, and G-to-T changes — mutational signatures resulting from cigarette smoke — in the NSCLC genome. William Lee, a postdoc in Zhang's lab, says that sequencing tumor and normal samples from the same patient allowed them to "essentially filter out germline changes" and "focus on the somatic changes that occurred" as a result of the disease itself.

Another advantage of working with the sequencing firm, Lee says, is that Complete Genomics maps and assembles the sequence reads, and even performs some of the initial bionformatic analyses. "We dug a little deeper," he says, "and worked with them to develop novel methods with their sequencing technology for detecting structural variation."

Zhang says that outsourcing sequencing projects is a "very cost-effective way" to interrogate cancer genomes, and that Genentech is continuing to work with Complete Genomics on an extended collection of samples. "We do have our own Illumina machines here," which they use for small-scale analyses, like ChIP-seq, he says. "But when it comes to full-genome sequencing, it doesn't quite make economic sense for us to do this on our own."

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