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Researchers Test Integrated Sequencing Strategy for Personalized Cancer Dx

NEW YORK (GenomeWeb News) – A team of researchers primarily affiliated with the University of Michigan has conducted a pilot study to explore the challenges associated with using high-throughput sequencing for clinical oncology applications.

The researchers, led by Arul Chinnaiyan of the Michigan Center for Translational Pathology and the Center for Computational Medicine and Biology at the University of Michigan, hypothesized that the clinical management of cancer may be suited to personalized medicine approaches. They believe that the results of their study, published in this week's issue of Science Translational Medicine, "provides an early road map for translating high-throughput sequencing into biomarker-driven clinical trials in oncology."

For the pilot study, the team enrolled four patients with advanced or refractory cancer who were eligible for clinical trials. They performed whole-genome sequencing of tumors for each of the patients, whole-exome sequencing of tumor and normal DNA, and transcriptome sequencing of the tumors to identify potentially informative mutations within a clinically relevant time frame of three to four weeks. Among the tools used by the researchers were the Illumina HiSeq 2000 platform, Agilent's SureSelect Human Exon Target Enrichment kit, and Roche's NimbleGen Sequence Capture kits.

The study, called the Michigan Oncology Sequencing Project, sought to address a variety of challenges associated with biomarker-driven clinical trials for personalized oncology. Among those challenges are identifying patients who could benefit, developing an informed consent process that includes a way to deal with incidental findings, implementing efficient and integrative computational pipelines for data analysis, selecting results that should be disclosed to patients, and completing the sequencing and analysis in a cost-effective and clinically relevant time frame.

In addition to recruiting the four patients for the pilot study and conducting the sequencing and analysis, the researchers instituted a Sequencing Tumor Board (STB), which included experts in clinical oncology, pathology, cancer biology, bioethics, bioinformatics, and clinical genetics. The STB acted as an expanded version of a traditional tumor board.

The researchers first performed a "test" study that evaluated tumor xenografts from two patients with metastatic prostate cancer. Genomic events from the analysis conducted on their cancers were chosen for presentation to a "mock" STB on the basis of predetermined criteria for a potential role in cancer. These included amplification of the androgen receptor and homozygous deletion of the PTEN tumor suppressor.

Two patients were then studied for the clinical sequencing study, including a 46-year-old male with colorectal cancer that had spread to the liver. Tumor analysis of this third patient turned up 160 nonsynonymous somatic point mutations, 49 copy number alterations, 20 rearrangements, and two gene fusions.

The researchers conducted whole-genome and exome sequencing to produce a global landscape of copy number alterations. The analysis of this integrative approach revealed a large region of chromosome 13 containing CDK8 that was prominently amplified. They noted that CDK8 also was overexpressed in the RNA-seq outlier analysis.

The STB deliberated the findings from the third patient and concluded that although most of the findings were deemed biologically interesting, they were not clinically significant.

Sequencing and analysis of a fourth subject, a 48-year-old woman with metastatic melanoma, identified 36 nonsynonymous point mutations, 269 CNAs, 24 rearrangements, and four gene fusions. Among the findings was an activating mutation of HRAS, but no mutations were observed in the prevalent melanoma oncogenes BRAF, CKIT, or NRAS. However, the patient's tumor harbored wild-type BRAF.

Based on the analysis, the STB nominated the HRAS gene as a potential target for clinical trials. "The HRAS activating mutation was surprising, because HRAS mutations have not been described in malignant melanoma, whereas NRAS mutations are common," they wrote.

"Findings that inhibitors of mutant BRAF can paradoxically activate MAPK signaling suggest that [the genotype combination of wild-type BRAF and mutant HRAS] could predict outcomes for BRAF or MEK inhibitors in a clinical trial," the researchers wrote. "This patient could potentially qualify for an upcoming trial of combined treatment with PI3K and MEK inhibitors for specified solid tumor malignancies with KRAS, NRAS, and BRAF mutations."

The researchers concluded that although their efforts provide an early road map for using integrative sequencing approaches for clinical oncology, "we anticipate the need for improvements and modifications to the process and procedures used here." They said that as high-throughput sequencing technologies move toward CLIA certification, the costs and turnaround time will be reduced.

"Moving forward, we anticipate that incorporation of global epigenetic and small RNA analyses, as well as evolving bioinformatics algorithms, will provide complementary information and enable cross-validation," they concluded.

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