Intratumor heterogeneity and clonal evolution revealed in castration-resistant prostate cancer by longitudinal genomic analysis

Zhang, Wenhui; Wang, Tao; Wang, Yan; Zhu, Feng; Shi, Haoqing; Zhang, Jili; Wang, Ziwei; Qu, Min; Zhang, Huaru; Wang, Tianyi; Qian, Yuping; Yang, Jinjian; Gao, Xu; Li, Jing

doi:10.1016/j.tranon.2021.101311

Cited by 9 publications

(3 citation statements)

References 49 publications

(68 reference statements)

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“…Of the somatic CNVs in Figure S2, the most frequent CNVs included losses at 17q21.31, 16q22.1, and 6q15 regions and gains at 8q24.3 and 12q13.2 regions. These results were consistent with the analyses conducted in previous studies (Figure S3) [25-28]. The analyses confirmed the reliability of our pipeline.…”

Section: Resultssupporting

confidence: 92%

Heterogeneity and genomic evolution of metastatic prostate cancer

Wu,

Lu,

Wang

et al. 2023

Preprint

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BackgroundMetastasis is the primary cause of prostate cancer-related deaths. However, the underlying molecular mechanisms and evolutionary patterns remain largely uncharacterized.MethodsWe evaluate the heterogeneity and genomic evolution of prostate cancer with multi-organ metastases. The samples include 32 primary samples, 23 lymph node metastases, 22 bone metastases, 16 liver metastases, and four pelvic mess metastases. They are analyzed to identify the mutated genes enriched in metastatic samples, selected by metastases, and leading to different long-distance migrations. These metastasis-related alterations constitute a Mscore for evaluating the metastatic risk of primary prostate tumors.ResultsOur analysis discovers 21 metastasis-related mutated genes in total. Of them, 14 genes are finally selected for metastatic risk prognosis, including the mutations ofARandKMT2Cwith high prediction ability. A Mscore established with these 14 characteristics by the xgboost model displays its ability to classify primary tumors and metastases. This score can further divide primary prostate tumors from the TCGA cohort into two groups. The two subsets present significantly differential survival risks. This score can also identify metastasis-featured primary tumors for breast cancer, bladder cancer, liver cancer, and uterine corpus endometrial carcinoma.ConclusionOur research proposes 14 molecular features potentially driving prostate cancer metastasis. The Mscore established on them can estimate the metastatic risk of primary tumors.

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Section: Resultssupporting

confidence: 92%

Heterogeneity and genomic evolution of metastatic prostate cancer

Wu,

Lu,

Wang

et al. 2023

Preprint

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“…Although PCa is a multifocal disease, it is not clear to what extent molecular heterogeneity in these foci is a determining factor in the natural history of the disease or its role as a prognostic molecular biomarker for this disease. 32 , 33 The novelty of this work lies in the infrequency of molecular analyses of many foci in the same PCa with different lesion degrees (HGPIN, GL3, GL4, GL5, and LN). This approach allowed contributing to a better understanding of the molecular heterogeneity of a multifocal disease.…”

Section: Discussionmentioning

confidence: 99%

Determination of ERG(+), EZH2, NKX3.1, and SPINK‐1 subtypes to evaluate their association with clonal origin and disease progression in multifocal prostate cancer

et al. 2022

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cause death. The criteria to establish PCa prognosis include PSA level, Gleason score, and clinical TNM stage, but these criteria still do not establish the prognosis with su cient certainty (2).Many studies have established different classi cations of PCa in molecular subtypes that can contribute to determining the prognosis, among them ETS(+) subtypes, characterized by chromosomal fusions, which cause the overexpression of ETS transcription factors. The most prevalent ETS fusion in PCa is TMPRSS2-ERG, which leads to ERG overexpression (3-5). ERG overexpression leads to an increase in the expression of EZH2, which acts as a histone methyltransferase enzyme, as well as to a decrease in the expression of the tumor suppressor gene NKX3.1, which is an androgen-regulated prostate-speci c homeobox gene and a transcription factor. NKX3.1 also binds to TMPRSS2 upstream sequences, and in TMPRSS2-ERG cases, it negatively regulates ERG expression and constitutes a negative feedback control since ERG in turn directly represses NKX3.1 (6,7). EZH2 and NKX3.1 had also been described as PCa subtypes. Another subtype reported in PCa is characterized by SPINK-1 overexpression, which is speci cally overexpressed in a subset of ETS(-) and is associated with another subtype, the SPOP subtype, characterized by a mutation in this gene (3). SPINK-1 protein is a trypsin inhibitor, which can function as an autocrine growth factor (8,9), and SPOP is an E3 ubiquitin ligase substrate-binding subunit of the proteasome complex that mediates the ubiquitination of target proteins, leading more frequently to their proteasomal degradation (10).The prognostic relevance of PCa molecular subtypes remains controversial (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). The presence of multiple foci -with the possibility of different subtypes-in the same patient with PCa could contribute to the di culty of predicting the clinical behavior of a speci c PCa subtype (21-23). It is not well known whether these foci have a monoclonal origin that expands through the prostate, giving rise to new foci, and share some molecular characteristics by origin, which begins to acquire changes in subclonal events; or whether each focus appears independently, so they have a multiclonal origin and they are expected to be very heterogeneous at the molecular level (22,24,25).To help elucidate the origin of heterogeneity in PCa and its association with disease progression, ERG(+), SPOP, EZH2, SPINK-1, and NKX3.1 subtypes were analyzed in 83 samples from prostatic foci and regional metastasis to lymph nodes (LN) from 20 PCa patients with poor prognosis. We also established molecular patterns in samples and patients, combining the presence of all subtypes analyzed. Methods SamplesSamples from formalin-xed para n-embedded (FFPE) tissues obtained from radical prostatectomy (RP) of 20 PCa patients with poor prognosis (regional metastases and/or biochemical recurrence (BCR)) and 5-years of follow-up were included. Cases were selected from the project "Exploration of potential predictor b...

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“…CHD6 has been identified as a driver gene of CRPC. 66 CHD6 also acts as an oxidative DNA damage response factor. 67 Since oxidative DNA damage enhances prostate cancer progression, 68 CHD6 may act as a prostate cancer driver gene through the DNA damage response.…”

Section: The Role Of Chd Proteins In Prostate Cancermentioning

confidence: 99%

Recent advances in prostate cancer: WNT signaling, chromatin regulation, and transcriptional coregulators

Takahashi

Takada

2023

Asian J Androl

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Prostate cancer is one of the most common diseases in men worldwide. Surgery, radiation therapy, and hormonal therapy are effective treatments for early-stage prostate cancer. However, the development of castration-resistant prostate cancer has increased the mortality rate of prostate cancer. To develop novel drugs for castration-resistant prostate cancer, the molecular mechanisms of prostate cancer progression must be elucidated. Among the signaling pathways regulating prostate cancer development, recent studies have revealed the importance of noncanonical wingless-type MMTV integration site family (WNT) signaling pathways, mainly that involving WNT5A, in prostate cancer progression and metastasis; however, its role remains controversial. Moreover, chromatin remodelers such as the switch/sucrose nonfermentable (SWI/SNF) complex and chromodomain helicase DNA-binding proteins 1 also play important roles in prostate cancer progression through genome-wide gene expression changes. Here, we review the roles of noncanonical WNT signaling pathways, chromatin remodelers, and epigenetic enzymes in the development and progression of prostate cancer.

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Intratumor heterogeneity and clonal evolution revealed in castration-resistant prostate cancer by longitudinal genomic analysis

Cited by 9 publications

References 49 publications

Heterogeneity and genomic evolution of metastatic prostate cancer

Heterogeneity and genomic evolution of metastatic prostate cancer

Determination of ERG(+), EZH2, NKX3.1, and SPINK‐1 subtypes to evaluate their association with clonal origin and disease progression in multifocal prostate cancer

Recent advances in prostate cancer: WNT signaling, chromatin regulation, and transcriptional coregulators

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