scholarly journals Oncogenic gene fusions in nonneoplastic precursors as evidence that bacterial infection can initiate prostate cancer

2021 ◽  
Vol 118 (32) ◽  
pp. e2018976118
Author(s):  
Eva Shrestha ◽  
Jonathan B. Coulter ◽  
William Guzman ◽  
Busra Ozbek ◽  
Megan M. Hess ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
In Situ Hybridization ◽  
Bacterial Infections ◽  
Precancerous Lesions ◽  
Three Dimensions ◽  
Driver Gene ◽  
Gene Fusions ◽  
Precursor Lesions ◽  
Dna Breaks

Prostate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide, and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers. Infection-driven inflammation is implicated in the formation of ERG+ fusions, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development. We investigated whether bacterial prostatitis is associated with ERG+ precancerous lesions in unique cases with active bacterial infections at the time of radical prostatectomy. We identified a high frequency of ERG+ non–neoplastic-appearing glands in these cases, including ERG+ PIA transitioning to early invasive cancer. These lesions were positive for ERG protein by immunohistochemistry and ERG messenger RNA by in situ hybridization. We additionally verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tricolor fluorescence in situ hybridization. Identification of rearrangement patterns combined with whole-prostate mapping in three dimensions confirmed multiple (up to eight) distinct ERG+ precancerous lesions in infected cases. We further identified the pathogen-derived genotoxin colibactin as a potential source of DNA breaks in clinical cases as well as cultured prostate cells. Overall, we provide evidence that bacterial infections can initiate driver gene alterations in prostate cancer. In addition, our observations indicate that infection-induced ERG+ fusions are an early alteration in the carcinogenic process and that PIA may serve as a direct precursor to prostate cancer.

scholarly journals Oncogenic Gene Fusions in Non-Neoplastic Precursors as Evidence that Bacterial Infection Initiates Prostate Cancer

2020 ◽  
Author(s):  
Eva Shrestha ◽  
Jonathan B. Coulter ◽  
William Guzman ◽  
Busra Ozbek ◽  
Luke Mummert ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bacterial Infections ◽  
Precancerous Lesions ◽  
Driver Gene ◽  
Gene Fusions ◽  
Precursor Lesions ◽  
Dna Breaks ◽  
Prostate Cells ◽  
Prostate Cancers ◽  
Carcinogenic Process

AbstractProstate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers1,2. Infection-driven inflammation is implicated in the formation of ERG+ fusions3, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development. We investigated whether bacterial prostatitis is associated with ERG+ precancerous lesions in unique cases with active bacterial infections at time of radical prostatectomy. We identified a high frequency of ERG+ non-neoplastic-appearing glands in these cases, including ERG+ PIA transitioning to early invasive cancer. We verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tri-color fluorescence in situ hybridization. Identification of rearrangement patterns combined with whole prostate mapping in 3 dimensions confirmed multiple (up to 8) distinct ERG+ precancerous lesions in infected cases. Finally, we identified the pathogen-derived genotoxin colibactin as a potential source of DNA breaks in clinical cases as well as cultured prostate cells. Overall, we provide evidence that bacterial infections initiate driver gene alterations in prostate cancer. Furthermore, infection-induced ERG+ fusions are an early alteration in the carcinogenic process and PIA may serve as a direct precursor to prostate cancer.

scholarly journals Evaluation of Myc Gene Amplification in Prostate Cancer Using a Dual Color Chromogenic in-Situ Hybridization (Dual CISH) Assay

2013 ◽  
Vol 1 (2) ◽  
pp. 81
Author(s):  
Daniel Lerda ◽  
Marta Cabrera ◽  
Jorge Flores ◽  
Luis Gutierrez ◽  
Armando Chierichetti ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
In Situ Hybridization ◽  
Gene Amplification ◽  
Dual Color ◽  
Myc Gene ◽  
Chromogenic In Situ Hybridization

Novel and established EWSR1 gene fusions and associations identified by next-generation sequencing and fluorescence in-situ hybridization

2019 ◽  
Vol 93 ◽  
pp. 65-73 ◽  
Author(s):  
Melissa Krystel-Whittemore ◽  
Martin S. Taylor ◽  
Miguel Rivera ◽  
Jochen K. Lennerz ◽  
Long P. Le ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Next Generation Sequencing ◽  
Fluorescence In Situ Hybridization ◽  
Gene Fusions ◽  
Next Generation ◽  
Ewsr1 Gene ◽  
Generation Sequencing

scholarly journals Antibody-Based Detection of ERG Rearrangements in Prostate Core Biopsies, Including Diagnostically Challenging Cases: ERG Staining in Prostate Core Biopsies

2012 ◽  
Vol 136 (8) ◽  
pp. 935-946 ◽  
Author(s):  
Scott A. Tomlins ◽  
Nallasivam Palanisamy ◽  
Javed Siddiqui ◽  
Arul M. Chinnaiyan ◽  
Lakshmi P. Kunju
Keyword(s):  
Prostate Cancer ◽  
In Situ Hybridization ◽  
Retrospective Cohort ◽  
Intraepithelial Neoplasia ◽  
Prostatic Intraepithelial Neoplasia ◽  
High Grade ◽  
Diagnosis Of Cancer ◽  
Prostate Cancers ◽  
Subsequent Cancer

Context.—Fusions of androgen-regulated genes and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) occur in approximately 50% of prostate cancers, encoding a truncated ERG product. In prostatectomy specimens, ERG rearrangements are greater than 99% specific for prostate cancer or high-grade prostatic intraepithelial neoplasia adjacent to ERG-rearranged prostate cancer by fluorescence in situ hybridization and immunohistochemistry. Objective.—To evaluate ERG staining by immunohistochemistry on needle biopsies, including diagnostically challenging cases. Design.—Biopsies from a retrospective cohort (n  =  111) enriched in cores requiring diagnostic immunohistochemistry and a prospective cohort from all cases during 3 months (n  =  311) were stained with an anti-ERG antibody (clone EPR3864). Results.—Among evaluable cores (n  =  418), ERG staining was confined to cancerous epithelium (71 of 160 cores; 44%), high-grade prostatic intraepithelial neoplasia (12 of 68 cores; 18%), and atypical foci (3 of 28 cores; 11%), with staining in only 2 of 162 cores (1%) diagnosed as benign. The ERG was expressed in about 5 morphologically benign glands across 418 cores and was uniformly expressed by all cancerous glands in 70 of 71 cores (99%). Conclusions.—ERG staining is more prostate cancer–specific than α-methylacyl-coenzyme A racemase, and staining in an atypical focus supports a diagnosis of cancer if high-grade prostatic intraepithelial neoplasia can be excluded. Thus, ERG staining shows utility in diagnostically challenging biopsies and may be useful in molecularly subtyping prostate cancer and in stratifying isolated high-grade prostatic intraepithelial neoplasia by risk of subsequent cancer.

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