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- Study Description
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Most prostate cancer deaths are caused by metastatic, castration resistant disease (mCRPC). To develop a precision medicine framework for mCRPC, we established a multi-institutional, international clinical sequencing infrastructure to enroll and carry out prospective whole exome and transcriptome sequencing of tumors from a cohort of mCRPC patients. We obtained high quality DNA and RNA sequence data from 150 bone or soft tissue biopsies. Central pathology revealed high-grade adenocarcinoma with only four cases (3.6%) showing neuroendocrine differentiation. Aberrations of AR, ETS genes, TP53 and PTEN were frequent (40-60% of cases), with TP53 and AR alterations being the most enriched in mCRPC compared to primary prostate cancer. We identified novel genomic alterations in PIK3CA/B (fusions and mutations); R-spondin, BRAF and RAF1 (fusions); APC (inactivating mutations); delta-catenin (missense mutations); and ZBTB16/PLZF (homozygous deletions). Aberrations of BRCA2, BRCA1 and ATM were observed at substantially higher frequencies (19.3% overall) than seen in primary prostate cancers, with 56% of these being exclusively somatic. Putative driver gene alterations were identified in nearly all patients, and over half also harbored driver gene fusions, homozygous deletions and/or amplifications. Moreover, 89% of patients harbored a clinically actionable aberration including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. Overall, integrative clinical sequencing analysis can be safely and efficiently performed in mCRPC, yields findings that may be actionable for enrolling patients in clinical trials of targeted therapies, and may inform the basis of individual clinical responses.
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- Study Design:
- Case Set
- Study Type:
- Case Set
- Longitudinal
- Total number of consented subjects: 60
- Subject Sample Telemetry Report (SSTR)
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- Publicly Available Data
- Molecular Data
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Type Source Platform Number of Oligos/SNPs SNP Batch Id Comment Whole Exome Sequencing Illumina HiSeq 2500 N/A N/A Transcriptome Sequencing Illumina HiSeq 2500 N/A N/A - Selected Publications
- Diseases/Traits Related to Study (MeSH terms)
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- Primary Phenotype: Prostatic Neoplasms
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- Study Attribution
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Principal Investigator
- Arul Chinnaiyan. University of Michigan, MI, USA.
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Institute
- University of Michigan, MI, USA.
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Funding Source
- Stand up to Cancer.
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Principal Investigator