Personalized Oncology Through Integrative High-Throughput Sequencing: A Pilot Study

By S. Roychowdhury, Matthew K. Iyer, D. Robinson, R. Lonigro, Yi Mi Wu, Xuhong Cao, Shanker Kalyana-Sundaram, L. Sam, O. A. Balbin, M. Quist and 17 more. Science Translational Medicine, 2011

625 citations recorded by the source corpus.

The mutations present in advanced cancers can be identified by integrative high-throughput sequencing to enable biomarker-driven clinical trials and, ultimately, treatment. First Steps to Personalized Cancer Treatment In an optimistic vision of personalized medicine, each cancer patient is treated with drugs tailored for their particular tumor. This sounds appealing, but is it even possible? Roychowdhury and his colleagues tested this approach by extensively characterizing cancers in several patients and then convening a Sequencing Tumor Board of experts to determine the appropriate treatment. With a combination of whole genome and exome sequencing plus sequencing of transcribed RNA, the authors were able to find informative mutations within 3 to 4 weeks, a short enough time to be useful clinically. To verify that their sequencing strategy would work before testing it on actual patients, they assessed two xenografts established from patients with metastatic prostate cancer. They found that one of these carried the common prostate cancer–specific gene fusion of TMPRSS2 and ERG and another, previously undescribed, gene fusion. Also, the androgen receptor gene was amplified and two tumor suppressors were inactivated. The Board concluded that this pattern of mutations could in theory be treated by combined block of the PI3K and androgen receptor signaling pathways. The authors then turned to an actual patient, a 46 year old with colorectal cancer, who had been unsuccessfully treated. Characterization of his metastatic tumor showed mutations in the oncogene NRAS, the tumor suppressor TP53, aurora kinase A, a myosin heavy chain and the FAS death receptor, plus amplification of CDK8. Of these, the Sequencing Tumor Board concluded that the NRAS and CDK8 aberrations could potentially be matched to clinical trials, although none were available at the time. Similar analysis of another patient with metastatic melanoma revealed a structural rearrangement in CDKN2C and HRas. Although the HRAS mutation has not been described before in melanoma, the Sequencing Tumor Board suggested that combined treatment with PI3K and MEK inhibitors would be suitable for this patient. The good news resulting from these studies was that the patients’ tumors were analyzed with in 24 days for ~$3600, well within the cost of routine clinical tests. But aspects need improvement: Additional testing for epigenetic and small RNA variants will allow more informative characterization. Sequencing at higher depth or enrichment methods will be needed for tumors of lower purity. And perhaps most important, we need a broader array of clinical trials, as highlighted by the fact that none was available for these two patients. Individual cancers harbor a set of genetic aberrations that can be informative for identifying rational therapies currently available or in clinical trials. We implemented a pilot study to explore the practical challenges of applying high-throughput sequencing in clinical oncology. We enrolled patients with advanced or refractory cancer who were eligible for clinical trials. For each patient, we performed whole-genome sequencing of the tumor, targeted whole-exome sequencing of tumor and normal DNA, and transcriptome sequencing (RNA-Seq) of the tumor to identify potentially informative mutations in a clinically relevant time frame of 3 to 4 weeks. With this approach, we detected several classes of cancer mutations including structural rearrangements, copy number alterations, point mutations, and gene expression alterations. A multidisciplinary Sequencing Tumor Board (STB) deliberated on the clinical interpretation of the sequencing results obtained. We tested our sequencing strategy on human prostate cancer xenografts. Next, we enrolled two patients into the clinical protocol and were able to review the results at our STB within 24 days of biopsy. The first patient had metastatic colorectal cancer in which we identified somatic point mutations in NRAS, TP53, AURKA, FAS, and MYH11, plus amplification and overexpression of cyclin-dependent kinase 8 (CDK8). The second patient had malignant melanoma, in which we identified a somatic point mutation in HRAS and a structural rearrangement affecting CDKN2C. The STB identified the CDK8 amplification and Ras mutation as providing a rationale for clinical trials with CDK inhibitors or MEK (mitogen-activated or extracellular signal–regulated protein kinase kinase) and PI3K (phosphatidylinositol 3-kinase) inhibitors, respectively. Integrative high-throughput sequencing of patients with advanced cancer generates a comprehensive, individual mutational landscape to facilitate biomarker-driven clinical trials in oncology.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/2431af9d4d6842bc3679f5e6ee0349a8e15c483d

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Citations in the corpus

Integrative clinical genomics of advanced prostate cancer (2015, positive): “Interestingly, even when AR was not considered, 65% of cases harbored a putatively clinically actionable alteration (defined as predicting response or resistance to a therapy, having diagnostic or prognostic utility across tumor types) (Table S8) (Roychowdhury et al., 2011; Van Allen et al., 2014c).”
Accurate and efficient detection of gene fusions from RNA sequencing data (2021, background): “tional pipelines, because the overall workflow allocates only a few days for bioinformatics processing (Roychowdhury et al. 2011; Worst et al. 2016).”
Sailfish enables alignment-free isoform quantification from RNA-seq reads using lightweight algorithms (2013, background): “[11]) of RNAseq measurements of transcript abundance will only serve to magnify the divide between our data acquisition and data analysis capabilities.”
Identification of Targetable FGFR Gene Fusions in Diverse Cancers (2013, neutral): “The set of candidates used for estimation consisted of coding variants that (1) exhibited at least 3 variant fragments in the tumor sample, (2) exhibited zero variant fragments in the matched benign sample with at least 16 fragments of coverage, (3) were not present in dbSNP, (4) were within a targe”
Integrative Clinical Genomics of Metastatic Cancer (2017, positive): “…Oncology Sequencing (Mi-Oncoseq) Program, an IRB-approved protocol to carry out prospective, integrative exome and transcriptome sequencing of advanced cancer patients 7 , mirroring the efforts of the TCGA project which focused on generating exome and transcriptome sequence 11 in primary cancers.”