Molecular Clues Assist in the Cancer Clinic

Tomlins, Scott A.

doi:10.1126/scitranslmed.3006642

Cited by 3 publications

(8 citation statements)

References 10 publications

(9 reference statements)

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“…Approximately 40% to 60% of prostate cancers harbor recurrent gene fusions, typically involving 5′ androgen–regulated genes fused to 3′ ETS transcription factor family members, with the most common fusion being TMPRSS2 ( T2 ) :ERG [36,37] . The RNA component of the OCP is designed to detect recurrent gene fusions in prostate cancer through inclusion of forward primers in known 5′ fusion partners (including TMPRSS2 , SLC45A3 , and C150RF21 ) and reverse primers in known 3′ fusion partners (including ERG , ETV1 , ETV4 , and BRAF ).…”

Section: Resultsmentioning

confidence: 99%

“…Likewise, ATM alteration frequency varied across treatment subtypes, with 7 of 22 (32%) of samples treated with ADT + XRT and/or chemotherapy [ADT +] harboring ATM alterations compared to 0 of 8 (0%) of SCCs (Table S15, P = .14). Robust prostate cancer molecular subtypes have been identified, including those defined by ETS gene fusions, SPOP hotspot mutations, and rare alterations (i.e., fibroblast growth factor receptor [FGFR] or RAF family fusions) [36] . Of interest, PR-122 harbored an IDH1 R132 hotspot mutation (at 18% variant allele frequency) but lacked ETS gene fusions, SPOP mutations, or other prioritized alterations ( Figures 4 A and S6 A ).…”

Section: Resultsmentioning

confidence: 99%

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Development and Validation of a Scalable Next-Generation Sequencing System for Assessing Relevant Somatic Variants in Solid Tumors

et al. 2015

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Next-generation sequencing (NGS) has enabled genome-wide personalized oncology efforts at centers and companies with the specialty expertise and infrastructure required to identify and prioritize actionable variants. Such approaches are not scalable, preventing widespread adoption. Likewise, most targeted NGS approaches fail to assess key relevant genomic alteration classes. To address these challenges, we predefined the catalog of relevant solid tumor somatic genome variants (gain-of-function or loss-of-function mutations, high-level copy number alterations, and gene fusions) through comprehensive bioinformatics analysis of >700,000 samples. To detect these variants, we developed the Oncomine Comprehensive Panel (OCP), an integrative NGS-based assay [compatible with < 20 ng of DNA/RNA from formalin-fixed paraffin-embedded (FFPE) tissues], coupled with an informatics pipeline to specifically identify relevant predefined variants and created a knowledge base of related potential treatments, current practice guidelines, and open clinical trials. We validated OCP using molecular standards and more than 300 FFPE tumor samples, achieving >95% accuracy for KRAS, epidermal growth factor receptor, and BRAF mutation detection as well as for ALK and TMPRSS2:ERG gene fusions. Associating positive variants with potential targeted treatments demonstrated that 6% to 42% of profiled samples (depending on cancer type) harbored alterations beyond routine molecular testing that were associated with approved or guideline-referenced therapies. As a translational research tool, OCP identified adaptive CTNNB1 amplifications/mutations in treated prostate cancers. Through predefining somatic variants in solid tumors and compiling associated potential treatment strategies, OCP represents a simplified, broadly applicable targeted NGS system with the potential to advance precision oncology efforts.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Development and Validation of a Scalable Next-Generation Sequencing System for Assessing Relevant Somatic Variants in Solid Tumors

et al. 2015

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“…NGS has made a major impact on our understanding of the types and frequency of somatic mutations in PCa 13,49,53–61 . Many of the NGS genomic studies have confirmed genomic events in PCa such as PTEN loss, TP53 mutation/loss, and ETS gene fusions.…”

Section: Ngs Reveals Distinct Subclasses Of Pca; Recurrent Spop Mutat...mentioning

confidence: 99%

The evolving landscape of prostate cancer somatic mutations

Cotter

Rubin

2022

The Prostate

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Background: The landscape of somatic mutations in prostate cancer (PCa) has quickly evolved over the past years.Results: This evolution was in part due to the improved quality and lower cost of genomic sequencing platforms available to an ever-larger group of clinicians and researchers. The result of these efforts is a better understanding of early and late mutations that are enriched or nearly exclusive to treated PCa. There are, however, some important limitations to the current knowledge. The expanding variety of next-generation sequencing (NGS) assays either capture a wide spectrum of mutations but at low coverage or are focused panels that cover a select number of genes, most often cancer-related, at a deep coverage. Both of these approaches have their advantages, but ultimately miss low-frequency mutations or fail to cover the spectrum of potential mutations. Additionally, some alterations, such as the common ETS gene fusions, require a mixture of DNA and RNA analysis to capture the true frequency. Finally, almost all studies rely on bulk PCa tumor samples, which fail to consider tumor heterogeneity. Given all these caveats, the true picture of the somatic landscape of PCa continues to develop.Summary: In this review, the focus will be on how the landscape of mutations evolves during disease progression considering therapy. It will focus on a select group of early and late mutations and utilize SPOP mutations to illustrate recurrent alterations that may have clinical implications.

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“…Advances in high-throughput technologies, such as NGS, have provided extraordinary insight into the PCA genome/transcriptome Taylor et al 2010;Berger et al 2011;Rubin et al 2011;Barbieri et al 2012;Grasso et al 2012b;Baca et al 2013;Beltran and Rubin 2013;Lindberg et al 2013;Tomlins 2013;Weischenfeldt et al 2013). There have been numerous recent NGS genomic studies that largely confirm many of the known genomic events in PCA such as PTEN loss, TP53 mutation/loss, and ETS gene fusions.…”

Section: Molecular Landscape Of Prostate Cancer In the Next-generatiomentioning

confidence: 99%

“…There have been numerous recent NGS genomic studies that largely confirm many of the known genomic events in PCA such as PTEN loss, TP53 mutation/loss, and ETS gene fusions. One important observation is that some events such as ETS gene fusions and SPOP mutation (the most common point mutation in primary PCA, see below) are mutually exclusive, leading to the view that PCA represent a collection of potentially definable molecular subclasses (Rubin et al 2011;Beltran and Rubin 2013;Tomlins 2013). Such subtyping is largely based on the presence or absence of recurrent gene fusions between the androgen regulated gene TMPRSS2, and ETS family members (most commonly ERG).…”

Section: Molecular Landscape Of Prostate Cancer In the Next-generatiomentioning

confidence: 99%

The Genomics of Prostate Cancer: A Historic Perspective

Rubin

Demichelis

2018

Cold Spring Harb Perspect Med

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The genomics of prostate cancer (PCA) has been difficult to study compared with some other cancer types for a multitude of reasons, despite significant efforts since the early 1980s. Overcoming some of these obstacles has paved the way for greater insight into the genomics of PCA. The advent of high-throughput technologies coming from the initial use of microsatellite and oligonucleotide probes gave rise to techniques like comparative genomic hybridization (CGH). With the introduction of massively parallel genomic sequencing, referred to as next-generation sequencing (NGS), a deeper understanding of cancer genomics in general has occurred. Along with these technologic advances, there has been the development of computational biology and statistical approaches to address novel large data sets characterized by single base resolution. This review will provide a historic perspective of PCA genomics with an emphasis on the cardinal mutations and alterations observed to be consistently seen in PCA for both hormone-naïve localized PCA and castration-resistant prostate cancer (CRPC). There will be a focus on alterations that have the greatest potential to play a role in disease progression and therapy management.

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Molecular Clues Assist in the Cancer Clinic

Abstract: The winner of the Wachtel prize navigates a journey from the prostate cancer genome to the clinic.

Cited by 3 publications

References 10 publications

Development and Validation of a Scalable Next-Generation Sequencing System for Assessing Relevant Somatic Variants in Solid Tumors

Development and Validation of a Scalable Next-Generation Sequencing System for Assessing Relevant Somatic Variants in Solid Tumors

The evolving landscape of prostate cancer somatic mutations

The Genomics of Prostate Cancer: A Historic Perspective

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