Biomarker Studies for Precision Oncology

All biomarker studies were prospectively planned. Whole-exome sequencing and transcriptome studies were performed on DNA from fresh-frozen tumor-biopsy samples obtained before treatment; germline whole-exome sequencing was performed on DNA from saliva samples. These studies were conducted at the University of Michigan as previously described.^{3 (link),17 (link)} Targeted next-generation sequencing studies were conducted at the Institute of Cancer Research^{18 (link),19}; libraries were constructed with the use of the GeneRead DNAseq Panel (Qiagen) and run on a MiSeq sequencer (Illumina). Copy-number data were validated by means of droplet digital polymerase-chain-reaction (PCR) testing with the use of the QX100 Droplet Digital PCR System (Bio-Rad).¹⁹ Circulating tumor-cell counts were performed with the use of CellSearch (Janssen Diagnostics).^{20 (link)} For the purpose of correlating the results of next-generation sequencing with the response to treatment, patients were classified as positive or negative for genomic defects in DNA-repair genes. A patient was considered to be biomarker-positive if a homozygous deletion or deleterious mutation was identified in a gene reported to be involved either in DNA damage repair or sensitivity to PARP inhibition.^{21 (link)–23 (link)} PTEN and ERG protein expression was determined by means of immunohistochemical assessment^{24 (link)} (for details, see the Supplementary Appendix).

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Mateo J., Carreira S., Sandhu S., Miranda S., Mossop H., Perez-Lopez R., Nava Rodrigues D., Robinson D., Omlin A., Tunariu N., Boysen G., Porta N., Flohr P., Gillman A., Figueiredo I., Paulding C., Seed G., Jain S., Ralph C., Protheroe A., Hussain S., Jones R., Elliott T., McGovern U., Bianchini D., Goodall J., Zafeiriou Z., Williamson C.T., Ferraldeschi R., Riisnaes R., Ebbs B., Fowler G., Roda D., Yuan W., Wu Y.M., Cao X., Brough R., Pemberton H., A’Hern R., Swain A., Kunju L.P., Eeles R., Attard G., Lord C.J., Ashworth A., Rubin M.A., Knudsen K.E., Feng F.Y., Chinnaiyan A.M., Hall E, & de Bono J.S. (2015). DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. The New England journal of medicine, 373(18), 1697-1708.

Publication 2015

Biomarker Biopsy Cancer Deletion Diagnostics Dna damage repair Frozen Gene Genomic Germline Homozygous Inhibition Mutation Patient Polymerase chain reaction Protein Pten Saliva Sensitivity Transcriptome Tumor

Corresponding Organization :

Other organizations : Royal Marsden NHS Foundation Trust, University of Michigan–Ann Arbor, Queen's University Belfast, University of Leeds, Churchill Hospital, University of Liverpool, Beatson West of Scotland Cancer Centre, The Christie Hospital, University College Hospital, University College London, Cornell University, Thomas Jefferson University

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Protocol cited in 13 other protocols

Variable analysis

independent variables

Biomarker status (positive or negative for genomic defects in DNA-repair genes)

dependent variables

Response to treatment

control variables

Whole-exome sequencing and transcriptome studies were performed on DNA from fresh-frozen tumor-biopsy samples obtained before treatment
Germline whole-exome sequencing was performed on DNA from saliva samples
Targeted next-generation sequencing studies were conducted using the GeneRead DNAseq Panel (Qiagen) and run on a MiSeq sequencer (Illumina)
Copy-number data were validated by means of droplet digital polymerase-chain-reaction (PCR) testing with the use of the QX100 Droplet Digital PCR System (Bio-Rad)
Circulating tumor-cell counts were performed with the use of CellSearch (Janssen Diagnostics)
PTEN and ERG protein expression was determined by means of immunohistochemical assessment

positive controls

None specified

negative controls

None specified

Annotations

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