Dana Farber and 454 Life Sciences announce breakthrough in DNA sequencing for cancer research.

454 Life Sciences Corporation (Branford, CT), a majority-owned subsidiary of CuraGen Corporation , in collaboration with scientists at Dana Farber Cancer Center and Broad Institute, reported a new method for the detection of cancer gene mutations present at extremely low levels. The research, published online (ahead of print) in the journal Nature Medicine, describes how the 454 Sequencing method identifies rare cancer-associated genetic variations at the molecular level, potentially enabling the personalization of targeted therapies. The title of the article is: 'Sensitive mutation detection in heterogeneous cancer specimens by massively parallel picoliter reactor sequencing.'

454 Sequencing technology was used to analyze mutations in five exons of the Epidermal Growth Factor Receptor (EGFR) gene in tumor samples from 22 patients with lung cancer. The EGFR gene is the target for several new anti- cancer drugs called EGFR inhibitors. This research proposes that 454 Sequencing may help to validate the ability of EGFR mutations to predict patient responsiveness to treatment with an EGFR inhibitor.

It has been realized that genetic mutations are responsible for sensitizing some tumor cells to chemotherapy, while other mutations render tumor cells completely resistant to drug treatments. Historically, research progress has been slowed by the complex mix of cells in a tumor sample, compounded by cost-prohibitive, conventional low-resolution sequencing methods that lack sufficient accuracy to characterize the DNA in cancerous cells. 454 Sequencing is the first advanced sequencing technology that can generate hundreds of thousands of DNA sequences in one run, rapidly and comprehensively conducting high-throughput nucleotide sequencing, with specific application to sequencing of whole genomes and ultra-deep sequencing of target genes. By enabling a method of sequencing that is more comprehensive and less expensive than conventional sequencing methods, 454 Sequencing may be used in medical research settings to detect cancer-associated genetic mutations.

"Analysis of DNA from tumors is complicated by varying amounts of tumor cells in patient samples. Furthermore, the heterogeneous nature of many tumors makes it difficult to accurately sequence the tumor DNA, which is required in order to personalize treatment," explained senior author of the study, Matthew Meyerson, M.D. Ph.D., of Dana Farber Cancer Center and Broad Institute. "454 Sequencing may facilitate accurate molecular diagnosis of heterogeneous cancer specimens and enable patient selection for targeted cancer therapies," added Meyerson.

The technology is already being explored at other institutions. "We have validated 454 Sequencing for medical sequencing on a gene target of interest," stated Robert Strausberg, Ph.D. Deputy Director and Vice President of Human Genomic Medicine at The J. Craig Venter Institute. "The method is not only very sensitive, but it is also quantitative and provides a digital display of gene variation within tumors. We have already identified a mutation missed by our previous sequencing approach," said Strausberg. "The publication of this paper demonstrates the versatility of our system and its ability to enable medical research that has been considered impractical until now," stated co-author Michael Egholm, Ph.D., Vice President of Molecular Biology at 454 Life Sciences. "454 Sequencing can open new research opportunities through its low cost, high throughput, and superior sensitivity. The ability to sequence entire exons in a single read is unique to 454 Sequencing among the commercially available, next generation sequencing technologies. Ultimately, we hope our system will enable personalized medicine, such as identifying the early stages of drug resistance and facilitating a change in treatment that is tailored to a patient's unique genetic response," added Egholm.

454 Life Sciences, a 66% majority-owned subsidiary of CuraGen Corporation , is commercializing novel instrumentation and measurement services for rapidly and comprehensively conducting high-throughput nucleotide sequencing, with specific application to sequencing of whole genomes and ultra-deep sequencing of target genes. 454 Life Sciences' Genome Sequencer 20 System enables one individual to prepare and sequence an entire genome after performing a single sample preparation, irrespective of the size of the genome being studied. The hallmark of 454 Life Sciences' technology is the PicoTiterPlate, which allows a single instrument using patented light emitting sequencing chemistries to produce over 20 million nucleotide bases per five- hour run, totaling more than 60 times the capacity of instruments using the current macro-scale technology.

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