Tissue- and Blood-derived Genomic Biomarkers for Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review

Eecken, Kim Van der; Vanwelkenhuyzen, Jan; Deek, Matthew P.; Tran, Phuoc T.; Warner, Evan W.; Wyatt, Alexander W.; Kwan, Edmond M.; Verbeke, Sofie; Dorpe, Jo Van; Fonteyne, Valérie; Lumen, Nicolaas; Laere, Bram De; Ost, Piet

doi:10.1016/j.euo.2021.10.005

Cited by 31 publications

(19 citation statements)

References 46 publications

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“…Numerous mutations in PTEN and TP53 , and modifications in DNA repair genes and in the Wnt pathway were also disclosed [ 42 , 43 ]. A review of 11 studies comprising 1682 mHSPC patients shows changes in TP53 , DNA damage repair and the Wnt pathway to be frequent [ 44 ]. A less favorable clinical outcome is observed in the case of alterations in AR , Myc , TP53 or cell cycle signaling [ 44 ].…”

Section: Genome Analysismentioning

confidence: 99%

“…A review of 11 studies comprising 1682 mHSPC patients shows changes in TP53 , DNA damage repair and the Wnt pathway to be frequent [ 44 ]. A less favorable clinical outcome is observed in the case of alterations in AR , Myc , TP53 or cell cycle signaling [ 44 ]. Dominant-negative TP53 mutations are associated with a negative outcome and SPOP mutations with a favorable outcome in mHSPC patients [ 45 ].…”

Section: Genome Analysismentioning

confidence: 99%

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From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer

Nevedomskaya

Haendler

2022

IJMS

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Cancer arises following alterations at different cellular levels, including genetic and epigenetic modifications, transcription and translation dysregulation, as well as metabolic variations. High-throughput omics technologies that allow one to identify and quantify processes involved in these changes are now available and have been instrumental in generating a wealth of steadily increasing data from patient tumors, liquid biopsies, and from tumor models. Extensive investigation and integration of these data have led to new biological insights into the origin and development of multiple cancer types and helped to unravel the molecular networks underlying this complex pathology. The comprehensive and quantitative analysis of a molecule class in a biological sample is named omics and large-scale omics studies addressing different prostate cancer stages have been performed in recent years. Prostate tumors represent the second leading cancer type and a prevalent cause of cancer death in men worldwide. It is a very heterogenous disease so that evaluating inter- and intra-tumor differences will be essential for a precise insight into disease development and plasticity, but also for the development of personalized therapies. There is ample evidence for the key role of the androgen receptor, a steroid hormone-activated transcription factor, in driving early and late stages of the disease, and this led to the development and approval of drugs addressing diverse targets along this pathway. Early genomic and transcriptomic studies have allowed one to determine the genes involved in prostate cancer and regulated by androgen signaling or other tumor-relevant signaling pathways. More recently, they have been supplemented by epigenomic, cistromic, proteomic and metabolomic analyses, thus, increasing our knowledge on the intricate mechanisms involved, the various levels of regulation and their interplay. The comprehensive investigation of these omics approaches and their integration into multi-omics analyses have led to a much deeper understanding of the molecular pathways involved in prostate cancer progression, and in response and resistance to therapies. This brings the hope that novel vulnerabilities will be identified, that existing therapies will be more beneficial by targeting the patient population likely to respond best, and that bespoke treatments with increased efficacy will be available soon.

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Section: Genome Analysismentioning

confidence: 99%

Section: Genome Analysismentioning

confidence: 99%

From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer

Nevedomskaya

Haendler

2022

IJMS

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“…Mutations in DDR genes (incidence rate ratio [IRR] 1.61; p < 0.001), and TP53 (IRR 1.45; p = 0.004) were associated with increasing number of metastatic lesions. Along with the specific high‐risk mutations detailed above, additional work in this space may hold potential in further classifying omCSPC patients 111–124 …”

Section: Metastatic Castration‐sensitive Prostate Cancer (Mcspc)mentioning

confidence: 99%

Genomic biomarkers to guide precision radiotherapy in prostate cancer

et al. 2022

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Our ability to prognosticate the clinical course of patients with cancer has historically been limited to clinical, histopathological, and radiographic features. It has long been clear however, that these data alone do not adequately capture the heterogeneity and breadth of disease trajectories experienced by patients. The advent of efficient genomic sequencing has led to a revolution in cancer care as we try to understand and personalize treatment specific to patient clinico-genomic phenotypes. Within prostate cancer, emerging evidence suggests that tumor genomics (e.g., DNA, RNA, and epigenetics) can be utilized to inform clinical decision making. In addition to providing discriminatory information about prognosis, it is likely tumor genomics also hold a key in predicting response to oncologic therapies which could be used to further tailor treatment recommendations. Herein we review select literature surrounding the use of tumor genomics within the management of prostate cancer, specifically leaning toward analyticallyThe Prostate.

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“…The genetic landscapes of primary prostate cancer, 12 metastatic hormone sensitive prostate cancer (mHSPC), 13 and mCRPC 14 have been characterized, and have nominated oncogenic drivers and mechanisms of treatment resistance, as well as potential therapeutic targets. For example, genetic alterations in the AR gene locus (including amplifications, point mutations, or structural variants 15 ) and the presence of ligand‐independent splice variants (such as AR‐v7 16 ) seen in mCRPC have been implicated in resistance to ADT.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, at the posttranslational level, PTEN function is regulated by various modifications including phosphorylation, oxidation and ubiquitination, 28,29 so alterations in these posttranslational modifications could also diminish PTEN function. The frequency of PTEN loss in prostate cancer reported in the literature is highly variable and dependent on the source of tissue tested and assay used, 30 but homozygous loss or truncating mutation in the PTEN gene by next generation sequencing (NGS) is seen in ~16%–20% of metastatic cases 13,17,21 . The estimate of frequency of PTEN loss by NGS is likely an underestimate when compared with studies using highly validated immunohistochemistry (IHC) assays (or FISH) that correlate with genomic alterations, 30 as NGS analysis of bulk tissues can easily underestimate homozygous deletions for PTEN because of normal cell contamination, and may not detect certain structural alterations detectable through linked‐read genome sequencing 31 …”

Section: Introductionmentioning

confidence: 99%

PTEN‐PI3K pathway alterations in advanced prostate cancer and clinical implications

Choudhury

2022

The Prostate

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Background: Despite significant advances in molecular characterization and therapeutic targeting of advanced prostate cancer, it remains the second most common cause of cancer death in men in the United States. The PI3K (Phosphatidylinositol 3-kinase)/AKT (AKT serine/threonine kinase)/mTOR (mammalian target of rapamycin) signaling pathway is commonly altered in prostate cancer, most frequently through loss of the PTEN (Phosphatase and Tensin Homolog) tumor suppressor, and is critical for cancer cell proliferation, migration, and survival.Methods: This study summarizes signaling through the PTEN/PI3K pathway, alterations in pathway components commonly seen in advanced prostate cancer, and results of clinical trials of pathway inhibitors reported to date with a focus on more recently reported studies. It also reviews rationale for combination approaches currently under study, including with taxanes, immune checkpoint inhibitors and poly (ADP-ribose) polymerase inhibitors, and discusses future directions in biomarker testing and therapeutic targeting of this pathway.Results: Clinical trials studying pharmacologic inhibitors of PI3K, AKT or mTOR kinases have demonstrated modest activity of specific agents, with several trials of pathway inhibitors currently in progress. A key challenge is the importance of PI3K/AKT/mTOR signaling in noncancerous tissues, leading to predictable but often severe toxicities at therapeutic doses.Conclusions: Further advances in selective pharmacologic inhibition of the PI3K/AKT/ mTOR pathway in tumors, development of rational combinations, and appropriate biomarker selection to identify the appropriate tumor-and patient-specific vulnerabilities will be required to optimize clinical benefit from therapeutic targeting of this pathway.

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Tissue- and Blood-derived Genomic Biomarkers for Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review

Cited by 31 publications

References 46 publications

From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer

From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer

Genomic biomarkers to guide precision radiotherapy in prostate cancer

PTEN‐PI3K pathway alterations in advanced prostate cancer and clinical implications

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