Integrative clinical genomics of advanced prostate cancer

By D. Robinson, E. Allen, Yi-Mi Wu, Nikolaus Schultz, R. Lonigro, J. Mosquera, B. Montgomery, M. Taplin, C. Pritchard, G. Attard and 63 more. Cell, 2015

3,214 citations recorded by the source corpus.

SUMMARY Toward development of a precision medicine framework for metastatic, castration resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53 and PTEN were frequent (40–60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified novel genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin and ZBTB16/PLZF. Aberrations of BRCA2, BRCA1 and ATM were observed at substantially higher frequencies (19.3% overall) than seen in primary prostate cancers. 89% of affected individuals 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. This cohort study provides evidence that clinical sequencing in mCRPC is feasible and could impact treatment decisions in significant numbers of affected individuals.

Subfields: Cancer Research, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/6737283079ab2751abeca6941f821bc829f2a1d9

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Citations in the corpus

Olaparib for Metastatic Castration-Resistant Prostate Cancer. (2020, neutral): “Adverse event Any 244 (95) 130 (51) 114 (88) 49 (38) Anemia† 119 (46) 55 (21) 20 (15) 7 (5) Nausea 106 (41) 3 (1) 25 (19) 0 Fatigue or asthenia 105 (41) 7 (3) 42 (32) 7 (5) Decreased appetite 77 (30) 3 (1) 23 (18) 1 (<1) Diarrhea 54 (21) 2 (<1) 9 (7) 0 Vomiting 47 (18) 6 (2) 16 (12) 1 (<1) Constipat”
RNA-Seq of Single Prostate CTCs Implicates Noncanonical Wnt Signaling in Antiandrogen Resistance (2015, positive): “Thus, in our study, point mutations in AR known to be associated with altered signalingwere uncommon in patients with CRPC, consistent with other reports (4, 21).”
Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer (2016, background): “Inspection of extended pedigree information of probands with DNA-repair gene mutations revealed affected relatives with breast cancer (24 probands), ovarian cancer (10), leukemia and lymphoma (6), pancreatic cancer (7), or other gastrointestinal cancers (18).”
Translating RNA sequencing into clinical diagnostics: opportunities and challenges (2016, background): “Recent clinical sequencing reports from various groups point to the value of incorporating RNA sequencing (RNA-seq) with DNA sequencing to evaluate the expression of mutant alleles, to detect both known and novel gene fusions, and to detect splice variants 127, 138, 139 .”
ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. (2022, background): “74 CHIP may cause false-positive results, however, and additionally ctDNA assays cannot robustly detect homozygous deletions (a common feature in BRCA1/2 and other tumour-suppressor genes).”
The Need for Multi-Omics Biomarker Signatures in Precision Medicine (2019, methodology): “The TCGA initiative has also used transcriptomics to provide detailed gene expression characterization of individual tumors and tissues from over 11,000 patients [41], and together with other initiatives such as the Stand Up To Cancer-Prostate Center Foundation Project [42], has helped in the detail”
Genomic correlates of clinical outcome in advanced prostate cancer (2019, methodology): “Flash-frozen needle biopsies and matched normal samples underwent nucleic acid extraction as previously described (5).”
Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling (2017, background): “13) in an independent dataset of 150 metastatic CRPC tumors from the SU2C/PCF dataset (data not shown) (Robinson et al., 2015).”
Precision Oncology: The Road Ahead (2017, background): “notable example is that of BRCA-associated signatures [73], where tumors (such as breast, ovarian or prostate tumors among others [66, 73]) sharing similar molecular signatures to BRCA-mutant tumors may also respond to similar therapeutic approaches, even when lacking specific BRCA mutations [73–75]”