Differential impact of RB status on E2F1 reprogramming in human cancer

McNair, Christopher; Xu, Kexin; Mandigo, Amy C.; Benelli, Matteo; Leiby, Benjamin E.; Rodrigues, Daniel Nava; Lindberg, Johan; Grönberg, Henrik; Crespo, Mateus; Laere, Bram De; Dirix, Luc; Visakorpi, Tapio; Li, Fugen; Feng, Felix Y.; Bono, Johann S. de; Demichelis, Francesca; Rubin, Mark A.; Brown, Myles; Knudsen, Karen E.

doi:10.1172/jci93566

Cited by 90 publications

(105 citation statements)

References 83 publications

(100 reference statements)

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“…The topmost overexpressed genes were transcriptional targets of E2F Transcription Factor 1 (E2F1; negatively regulated by Retinoblastoma 1 [RB1]). RB1 loss signature 25 scores were higher in the t-SCNC-enriched cluster (Data Supplement). To further characterize the transcriptional hallmarks of cluster 2, we used the MR Inference algorithm and visualized results using TumorMap.…”

Section: Transcriptional Profile Of T-scncmentioning

confidence: 97%

Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study

Aggarwal

Huang

Alumkal

et al. 2018

JCO

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580

701

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The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)-targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. MethodsPatients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. Metastatic biopsy specimens underwent independent, blinded pathology review along with RNA/DNA sequencing. ResultsA total of 202 consecutive patients were enrolled. One hundred forty-eight (73%) had prior disease progression on abiraterone and/or enzalutamide. The biopsy evaluable rate was 79%. The overall incidence of t-SCNC detection was 17%. AR amplification and protein expression were present in 67% and 75%, respectively, of t-SCNC biopsy specimens. t-SCNC was detected at similar proportions in bone, node, and visceral organ biopsy specimens. Genomic alterations in the DNA repair pathway were nearly mutually exclusive with t-SCNC differentiation (P = .035). Detection of t-SCNC was associated with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95% CI, 1.07 to 3.82). Unsupervised hierarchical clustering of the transcriptome identified a small-cell-like cluster that further enriched for adverse survival outcomes (hazard ratio, 3.00; 95% CI, 1.25 to 7.19). A t-SCNC transcriptional signature was developed and validated in multiple external data sets with . 90% accuracy. Multiple transcriptional regulators of t-SCNC were identified, including the pancreatic neuroendocrine marker PDX1.Conclusion t-SCNC is present in nearly one fifth of patients with mCRPC and is associated with shortened survival. The near-mutual exclusivity with DNA repair alterations suggests t-SCNC may be a distinct subset of mCRPC. Transcriptional profiling facilitates the identification of t-SCNC and novel therapeutic targets.J Clin Oncol 36.

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Section: Transcriptional Profile Of T-scncmentioning

confidence: 97%

Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study

Aggarwal

Huang

Alumkal

et al. 2018

JCO

Self Cite

580

701

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“…Therefore, partially defective RB1 can contribute to the early stages of cancer through a distinct set of effects. However, a number of studies have highlighted that RB1 loss is statistically enriched in advanced stages of cancer progression (Beltran et al, 2016;McNair et al, 2017;Robinson et al, 2017). In addition, analysis of the landscape of cancer alterations in TCGA consortia reveals so called 'shallow deletions' of RB1 as relatively commonplace (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that RB-pathway mutations are not necessarily equivalent. Second, a number of studies have suggested that RB1 gene loss is more prevalent in advanced cancers, or mechanistically contribute to progression or dissemination (Beltran et al, 2016;McNair et al, 2017;Robinson et al, 2017;Thangavel et al, 2017), a stage where cell autonomous proliferative control is presumably already deregulated.…”

Section: Introductionmentioning

confidence: 99%

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RB1 deletion in RB-pathway disrupted cells results in DNA damage and cancer progression

Marshall

Roes

Passos

et al. 2019

Preprint

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Proliferative control in cancer cells is frequently disrupted by mutations in the RB-pathway.Intriguingly, RB1 mutations can arise late in tumorigenesis in cancer cells whose RB-pathway is already compromised by another mutation. In this study, we present evidence for increased DNA damage and instability in CDKN2A silenced cancer cells when RB1 mutations are induced.We generated isogenic RB1 mutant genotypes with CRISPR in a number of cell lines. Cells with even one mutant copy of RB1 have increased basal levels of DNA damage and increased mitotic errors. Elevated levels of reactive oxygen species as well as impaired homologous recombination repair underlie this DNA damage. When xenografted into immune compromised mice RB1 mutant cells exhibit an elevated propensity to seed new tumors in recipient lungs. This study offers evidence that late arising RB1 mutations can facilitate genome instability and cancer progression that are beyond the pre-existing proliferative control deficit.

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“…18 Direct RB loss in CRPC has been associated with reprogramming of E2F1 to support its role in tumor propagation. 19 In 2 series, 14 a deleterious change in at least one of the RB1, PTEN, or p53 genes was found in 92% to 99.6% of cases of AVPCa, and at least 2 of those genes contained variants in 48.2% of cases. However, not all studies of NEPC have found the same results because only 38 of 77 patients (49.3%) classified as having NEPC in a study from the Broad Institute (Cambridge, Massachusetts) had a mutation or deletion in 1 of these 3 genes, and only 8 of 77 patients (10.3%) had at least 2 of these variants.…”

Section: Pathophysiology Of and Predictivementioning

confidence: 98%

Clinicopathologic Diagnostic Approach to Aggressive Variant Prostate Cancer

Manucha

Henegan

2019

Archives of Pathology &Amp; Laboratory Medicine

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Context.-Aggressive variant prostate cancer (AVPCa) develops in a subset of patients with metastatic castrationresistant prostate cancer. The clinical and histologic overlap of AVPCa with other neuroendocrine carcinomas of the prostate has resulted in a lack of consensus on its terminology and treatment.Objective.-To review AVPCa to familiarize pathologists with this entity so they can actively participate in the detection, ongoing research, and evolving management of AVPCa.Data Sources.-The English language literature was reviewed.

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Differential impact of RB status on E2F1 reprogramming in human cancer

Cited by 90 publications

References 83 publications

Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study

Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study

RB1 deletion in RB-pathway disrupted cells results in DNA damage and cancer progression

Clinicopathologic Diagnostic Approach to Aggressive Variant Prostate Cancer

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