Abstract:The outcome of prostate cancer (PCa) patients is highly variable and depends on whether or not distant metastases occur. Multiple chromosomal deletions have been linked to early tumor marker PSA recurrence (biochemical relapse, BCR) after radical prostatectomy (RP), but their potential role for distant metastasis formation is largely unknown. Here, we specifically analyzed whether deletion of the tumor suppressor CHD1 (5q21) influences the post-surgical risk of distant metastasis and whether CHD1 loss directly… Show more
“…Of note, early states of each subtype had similar favorable prognosis, while both late states showed similar unfavorable prognosis (Supplemental Figure 16). Endpoints of biochemical recurrence-free survival and PCa-specific mortality-free survival rates followed similar patterns (Supplemental Figure 17), consistent with previous findings (7,43). These results show that genomic alterations defined as late progression events at the molecular level also show clear evidence of more aggressive disease, consistent with clinical progression.…”
BACKGROUND. Molecular characterization of prostate cancer (PCa) has revealed distinct subclasses based on underlying genomic alterations occurring early in the natural history of the disease. However, how these early alterations influence subsequent molecular events and the course of the disease over its long natural history remains unclear.
METHODS.We explored the molecular and clinical progression of different genomic subtypes of PCa using distinct tumor lineage models based on human genomic and transcriptomic data. We developed transcriptional classifiers, and defined "early" and "late" categories of molecular subclasses from 8,158 PCa patients. Molecular subclasses were correlated with clinical outcomes and pathologic characteristics using Kaplan-Meier and logistic regression analyses.
RESULTS.We identified PTEN and CHD1 alterations as subtype-specific late progression events specifically in ERGoverexpressing (ERG+) and SPOP-mutant tumors, respectively, and 2 distinct progression models consisting of ERG/PTEN (normal to ERG+ to PTEN-deleted) and SPOP/CHD1 (normal to SPOP-mutated to CHD1-deleted) with shared early tumorigenesis but distinct pathways toward progression. We found that within ERG+ and SPOP-mutant subtypes, late events were associated with worse prognosis. Importantly, the clinical and pathologic features associated with distinct late events at radical prostatectomy were strikingly different; PTEN deletions were associated with increased locoregional stage, while CHD1 deletions were only associated with increased grade, despite equivalent metastatic potential.CONCLUSION. These findings suggest a paradigm in which specific subtypes of PCa follow distinct pathways of progression, at both the molecular and clinical levels. Therefore, the interpretation of common clinical parameters such as locoregional tumor stage may be influenced by the underlying tumor lineage, and potentially influence management decisions.
“…Of note, early states of each subtype had similar favorable prognosis, while both late states showed similar unfavorable prognosis (Supplemental Figure 16). Endpoints of biochemical recurrence-free survival and PCa-specific mortality-free survival rates followed similar patterns (Supplemental Figure 17), consistent with previous findings (7,43). These results show that genomic alterations defined as late progression events at the molecular level also show clear evidence of more aggressive disease, consistent with clinical progression.…”
BACKGROUND. Molecular characterization of prostate cancer (PCa) has revealed distinct subclasses based on underlying genomic alterations occurring early in the natural history of the disease. However, how these early alterations influence subsequent molecular events and the course of the disease over its long natural history remains unclear.
METHODS.We explored the molecular and clinical progression of different genomic subtypes of PCa using distinct tumor lineage models based on human genomic and transcriptomic data. We developed transcriptional classifiers, and defined "early" and "late" categories of molecular subclasses from 8,158 PCa patients. Molecular subclasses were correlated with clinical outcomes and pathologic characteristics using Kaplan-Meier and logistic regression analyses.
RESULTS.We identified PTEN and CHD1 alterations as subtype-specific late progression events specifically in ERGoverexpressing (ERG+) and SPOP-mutant tumors, respectively, and 2 distinct progression models consisting of ERG/PTEN (normal to ERG+ to PTEN-deleted) and SPOP/CHD1 (normal to SPOP-mutated to CHD1-deleted) with shared early tumorigenesis but distinct pathways toward progression. We found that within ERG+ and SPOP-mutant subtypes, late events were associated with worse prognosis. Importantly, the clinical and pathologic features associated with distinct late events at radical prostatectomy were strikingly different; PTEN deletions were associated with increased locoregional stage, while CHD1 deletions were only associated with increased grade, despite equivalent metastatic potential.CONCLUSION. These findings suggest a paradigm in which specific subtypes of PCa follow distinct pathways of progression, at both the molecular and clinical levels. Therefore, the interpretation of common clinical parameters such as locoregional tumor stage may be influenced by the underlying tumor lineage, and potentially influence management decisions.
“…Among the chromatin regulators/transcription factors, BACH1, CTBP2, HDAC2, KDM4A, MYC, RAD21, and SUZ12 have been known to play roles in cancer proliferation, whereas CHD1, CHD2, and ZBTB7A have been reported as tumor suppressors exemplified in Ref. 27 , 28 , 29 , 30 , 31 , 32 . Fig.…”
“…For instance, the deletion of CHD1 has been associated with cancer and postoperative biochemical relapse (BCR) in a cohort of prostate cancer (PCa) patients, suggesting it is a poor prognosis marker [36]. Recent research by Oh-Hohenhorst et al revealed that CHD1 loss increases the risk of postoperative metastasis in R0-resected PCa patients and promotes spontaneous metastasis formation in vivo [37]. In a study investigating CHD1's potential roles in breast cancer, researchers introduced shRNA-mediated depletion of CHD1 into both PTEN-deficient and PTEN-intact breast cancer cell lines.…”
Background: Several recent studies suggest that chromodomain-helicase -DNA-binding domains (CHDs) are linked with cancers. We explored the association between chromodomain-Helicase-DNA-binding domain proteins and breast cancer (BrCa) and introduced potential prognostic markers using various databases. Materials and Methods: We analyzed the expression of the CHD family and their prognostic value in BrCa by mining UALCAN, TIMER, and Kaplan-Meier plotter databases. The association of CHD expression and immune infiltrating abundance was studied via the TIMER database. In addition, microRNAs related to the CHD family were identified by using the MirTarBase online database. Results: The present study indicated that compared to normal tissues, BrCa tissues showed increased mRNA levels of CHD3/4/7 but decreased CHD2/5/9 expression. Interestingly, We also found a positive correlation between CHD gene expression and the infiltration of macrophage, neutrophil, and dendritic cells in BrCa, except CHD3/5. The Kaplan-Meier Plotter analysis suggested that high expression levels of CHD1/2/3/4/6/8/9 were significantly related to shorter relapse-free survival (RFS), while higher mRNA expression of CHD1, CHD2, CHD8, and CHD9 was significantly associated with longer overall survival of BrCa patients. The miRNAs of hsa-miR-615-3p and hsa-let-7b-5p were identified as being more correlated with the CHD family. Conclusion: The altered expression of some CHD members was significantly related to clinical cancer outcomes, and CHD1/2/8/9 could serve as potential prognostic biomarkers to improve the survival of BrCa patients. However, to evaluate the studied CHD members in detail are needed further investigations including experimental validation.
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