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Integrative Clinical Sequencing Analysis of Metastatic Castration Resistant Prostate Cancer Reveals a High Frequency of Clinical Actionability

ABSTRACT: Integrative Clinical Sequencing Analysis of Metastatic Castration Resistant Prostate Cancer Reveals a High Frequency of Clinical Actionability

PROVIDER: PRJNA283922 | ENA |

REPOSITORIES: ENA

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Project description:Integrative Clinical Sequencing Analysis of Metastatic Castration Resistant Prostate Cancer Reveals a High Frequency of Clinical Actionability

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Integrative Clinical Sequencing Analysis of Metastatic Castration Resistant Prostate Cancer Reveals a High Frequency of Clinical Actionability

Project description:<p>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.</p>

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Integrative Somatic and Germline Computational Biology to Redefine Clinical Actionability in Solid Tumors

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Whole Transcriptomic Sequencing of Metastatic Castration Resistant Prostate Cancer Samples

Project description:We report the gene expression profile of 8 metastatic castration resisistant prostate cancer samples analyzed by paired-end RNA-seq. We found evidence of extensive abnormal splicing as well as several novel fusion genes. Finally, we also observed several recurrent high-confidence somatic mutations. Paired-end RNA-seq by rRNA depletion

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Integrative sequencing reveals alterations in untreated and castration-resistant prostate cancer

Project description:We conducted an integrative sequencing of genomic, transcriptomic and DNA methylation changes in 28 untreated (PC) and 13 castration-resistant prostate cancers (CRPC). We wanted to search for previously unannotated transcripts from the RNA-sequencing data. Transcriptome assembly uncovered 128 previously unannotated prostate cancer-associated transcripts. Trans-acting correlation analysis associated the expression of several TPCATs with prostate cancer-associated transcriptional regulators, such as ERG or AR. The strongest positive correlation was observed between ERG and transcript TPCAT-10-36067 that was expressed in a subset of PCs and CRPCs as well as ETV4-positive PC-3 and ERG-positive VCaP cells. We suppressed the expression of TPCAT-10-36067 with three different siRNAs in PC-3 cells, and studied the changes in the genome-wide expression patterns of the cell line using expression arrays. Gene Ontology enrichment analysis indicated that cell cycle, mitosis and Aurora signaling were the most extensively affected processes. Experimental assay showed that the siRNA suppression of TPCAT-10-36067 had a dramatic effect on the growth, invasiveness, and rate of apoptosis of prostate cancer cells.

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Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma

Project description:Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma

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Prognostic implication of blood immune cell composition in Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Project description:The prognosis of patients with metastatic castration-resistant prostate cancer (mCRPC) is variable. Several blood-related prognostic factors have been reported, including transcriptional profiling of whole blood and neutrophil to lymphocyte ratio. We aimed to address the contribution of distinct whole blood immune cell components to the prognosis of these patients. Subjects/Patients and Methods: Pre-treatment whole blood samples from chemotherapy-naïve mCRPC patients were prospectively collected before treatment with enzalutamide. The study consisted of a training cohort including 98 patients treated with enzalutamide in a phase 2 biomarker clinical trial (NCT02288936)

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Whole Transcriptomic Sequencing of Metastatic Castration Resistant Prostate Cancer Samples

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Epigenetic Activation and alteration of chromatin structure regulated by NSD2 in metastatic castration-resistant prostate cancer (Hi-C)

Project description:To elucidate the regulation of NSD2 in metastatic castration-resistant prostate cancer(CRPC), we performed Hi-C against castration-sensitive prostate cancer cell line LNCaP and metastatic castration-resistant prostate cancer cell lines, PC3 respectively. In metastatic CRPC, we found specific regions of activation with epigenetic changes.

2024-09-04 | GSE248627 | GEO

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