Spatial Intratumor Genomic Heterogeneity within Localized Prostate Cancer Revealed by Single-nucleus Sequencing

Su, Fei; Zhang, Wei; Zhang, Dalei; Zhang, Yaqun; Pang, Cheng; Huang, Yingying; Wang, Miao; Cui, Luwei; He, Lei; Zhang, Jinsong; Zou, Lihui; Zhang, Junhua; Li, Wenqinq; Li, Lin; Shao, Jian Yong; Ma, Jie; Xiao, Fei; Liu, Ming

doi:10.1016/j.eururo.2018.06.005

Cited by 42 publications

(43 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1c, d). Moreover, few ERG family gene fusions in our cohort were detected, which is consistent with previous studies based on the Chinese population 12,16 .…”

Section: Resultssupporting

confidence: 92%

Immune signature driven by ADT-induced immune microenvironment remodeling in prostate cancer is correlated with recurrence-free survival and immune infiltration

et al. 2020

Self Cite

View full text Add to dashboard Cite

Androgen deprivation therapy (ADT) is a cornerstone treatment for locally advanced or metastatic prostate cancer (PCa). However, its potential effects on the tumor immune microenvironment (TIM) of PCa patients and the underlying mechanism remain largely unclear. To explore the effects of ADT on PCa TIM, RNA sequencing was performed on six paired pre-ADT biopsy and post-ADT PCa lesions, and five paired paracancerous benign tissues from patients receiving neoadjuvant ADT with locally advanced PCa. Bioinformatics methods including ESTIMATE and ssGSEA were used to evaluate the stromal immune score and immune cell infiltration in PCa and paracancerous tissues. Weighted correlation network analysis was used to screen hub genes in the ADT-induced immune remodeling process. The results showed differences exist between PCa and paracancerous tissues in response to ADT. Compared with paracancerous tissues, the immune remodeling effect of ADT in PCa was more intense. ZFP36, JUNB, and SOCS3 served as hub genes in the ADT-induced immune remodeling process and were associated with PSA recurrent-free survival in the TCGA and our neoadjuvant ADT cohort. To investigate the joint action of the above three hub genes, an immune signature score was constructed. The results showed that immune signature score-based immune subtypes reveal the heterogeneity of the immune microenvironment of PCa and showed significant differences in patient prognosis, tumor immune infiltration, mutation burden, and landscape.

show abstract

“…1c, d). Moreover, few ERG family gene fusions in our cohort were detected, which is consistent with previous studies based on the Chinese population 12,16 .…”

Section: Resultssupporting

confidence: 92%

Immune signature driven by ADT-induced immune microenvironment remodeling in prostate cancer is correlated with recurrence-free survival and immune infiltration

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…The frequency of ERG is significantly higher in Caucasian, when compared to African American or Asian CaP patients 22. These findings provide an impetus to explore genomic driver alteration in ERG negative CaPs 26 and discovery of race/ethnicity associated CaP genomic defects in African Americans 27, 28, 29 and Asian men 23,24.…”

Section: Discussionmentioning

confidence: 83%

“…Lower frequency of ERG among Asian patients has been reported at genomic, gene expression or protein levels 22. These findings have led to new insights into the CaP genomes of ERG negative tumor types of Asian men 23,24. Although the examined CaP specimens in world-wide ERG frequency studies included biopsy or TURP or tissue microarray (TMA) or whole mounted radical prostatectomy specimens and were assayed by either reverse transcription-polymerase chain reaction (RT-PCR), FISH and/or IHC, the overall conclusion is that ERG is most prevalent among CaP patients of Western countries.…”

Section: Introductionmentioning

confidence: 99%

ERG Tumor Type is Less Frequent in High Grade and High Stage Prostate Cancers of Chinese Men

Baohong¹,

Sedarsky²,

Srivastava³

et al. 2019

J. Cancer

View full text Add to dashboard Cite

Background: The incidence of prostatic adenocarcinoma has been rapidly increasing among Chinese men. This alarming trend prompted evaluations of early causal genomic alterations known to drive prostate tumorigenesis. Recurrent activation of the ETS-Related Gene (ERG) by genomic rearrangements is the most recognized early event in prostate cancer. Following the initial detection of ERG rearrangement at gene expression and genomic and levels, development of diagnostic quality antibodies against ERG oncoprotein have streamlined the rapid assessment of ERG frequencies world-wide. Unexpectedly, these studies revealed highest frequencies of ERG among Caucasian descents, lower frequencies among African Americans and even lower prevalence of ERG among Asian men. Objective: To asses in a prospective study ERG frequencies, clinico-pathological and prognostic associations of ERG among prostate cancer patients of the Dalian region of Northeast China, by an established immunohistochemical procedure that have been used in studies world-wide. Methods: Formalin fixed paraffin embedded specimens donated by patients (N=50) diagnosed with prostatic adenocarcinoma who underwent transurethral resection of the prostate (TURP) between 2007 and 2012 were evaluated for ERG by immunohistochemistry. Results: Of the 50 cases, 13/50 (26.0%) tumors were positive for ERG. In all cases, normal prostatic epithelial were ERG negative. ERG was more frequently detected in the lower Gleason score (≤7) and low T-stage. Consistent with reports from Asian countries the results of our study shows lower overall frequencies of ERG positive tumors when compared to reports from Western countries. Conclusion: The intriguing association of even lower ERG frequencies with high Gleason scores and higher T-stages provides impetus for current driver gene discoveries focused on the predominantly ERG negative prostate cancers of Asian men.

show abstract

“…[10] Su et al . [84] , 2018 17 nuclei from 2 primary tumours First report of single nucleus whole-genome sequencing in prostate cancer. Significant spatial heterogeneity within the same gland pave the way for future studies to define the precise molecular mechanisms through which these cancers develop and evolve.…”

Section: Major Significancementioning

confidence: 99%

“…Thus, while prospective validation of these biomarkers is required, it appears highly likely that genomic classifiers will vastly outperform clinical prognostic factors and have the potential to revolutionize treatment stratification for localized prostate cancer. Most prostate cancers are multi-focal [49,77] , and there is substantial genomic heterogeneity associated with separate disease foci [49,77,79,84] , including in genes with established prognostic value (e.g., MYC gain) [49] . Nevertheless, genomic signatures derived from the largest (index) lesion can predict disease aggression with accuracy of at least 85% [10] , far exceeding the performance of established clinical prognostic factors.…”

Section: Clinico-genomics In Localized Prostate Cancermentioning

confidence: 99%

The somatic clinico-genomics of localized, non-indolent prostate cancer

Fraser¹

2018

JTGG

View full text Add to dashboard Cite

Prostate cancer is the second most frequently diagnosed non-skin male malignancy worldwide, with over 1.1 million new diagnoses each year. Population screening based on serum prostate-specific antigen (PSA) has shifted the disease burden toward earlier stage, localized disease. However, clinical outcomes for localized prostate cancer are highly heterogeneous, despite the use of clinical prognostic factors (PSA, Gleason grade, and TNM stage). Recent advances in massively-parallel DNA sequencing and computational biology have permitted detailed genomic analyses of all major human cancer types, including prostate cancer. However, the long natural history of prostate cancer has largely precluded rapid translation of this knowledge into clinical practice. Herein, we provide a "state of the field" overview of prostate cancer genomics, with particular focus on localized, non-indolent disease. We discuss recurrent somatic aberrations, across multiple mutational classes, which characterize this disease state, and suggest strategies through which an improved understanding of these molecular aberrations may be utilized in the curative setting. Finally, we summarize the major outstanding questions in prostate cancer genomics, and discuss hypotheses and potential strategies to begin to address these questions.populations [1] . Localized prostate cancer is triaged into groups that largely define treatment options, risk of disease progression and prostate cancer-specific mortality (PCSM). These risk groups (i.e., low, intermediate, high) are based primarily on three clinical prognostic factors: serum PSA concentration, Gleason/International Society for Urological Pathology grade of the tumour biopsy, and clinical TNM stage [2] . Low risk disease can usually be effectively managed through active surveillance. Intermediate risk prostate cancer is generally treated with curative-intent radical prostatectomy or image-guided radiotherapy (IGRT; externalbeam and/or high dose-rate brachytherapy), while high risk disease is managed with IGRT and (neo)adjuvant androgen-deprivation therapy (ADT) or radical prostatectomy, with or without adjuvant IGRT [3] .Despite these prognostic factors, clinical outcomes are highly heterogeneous across the risk spectrum. For example, 20%-25% of men on active surveillance for low risk prostate cancer will experience clinical or pathological progression, necessitating definitive therapy [4] . Similarly, 10%-15% and 30%-40% of men with intermediate or high-risk prostate cancer, respectively, will experience disease recurrence within 3 years following curative-intent therapy, portending a lethal clinical course [5] . As such, current prognostic factors do not accurately define the risk of disease progression for an individual man with prostate cancer. There is, therefore, an urgent need to define novel prognostic and predictive biomarkers to inform precision medicine protocols for localized prostate cancer. Such biomarkers would allow for more appropriate pre-treatment triage, thus reducing over-treatment ...

show abstract

Spatial Intratumor Genomic Heterogeneity within Localized Prostate Cancer Revealed by Single-nucleus Sequencing

Cited by 42 publications

References 38 publications

Immune signature driven by ADT-induced immune microenvironment remodeling in prostate cancer is correlated with recurrence-free survival and immune infiltration

Immune signature driven by ADT-induced immune microenvironment remodeling in prostate cancer is correlated with recurrence-free survival and immune infiltration

ERG Tumor Type is Less Frequent in High Grade and High Stage Prostate Cancers of Chinese Men

The somatic clinico-genomics of localized, non-indolent prostate cancer

Contact Info

Product

Resources

About