Prevalence and Prognostic Significance of PTEN Loss in African-American and European-American Men Undergoing Radical Prostatectomy

Tosoian, Jeffrey J.; Almutairi, Fawaz; Morais, Carlos L.; Glavaris, Stephanie; Hicks, Jessica L.; Sundi, Debasish; Humphreys, Elizabeth B.; Han, Misop; Marzo, Angelo M. De; Ross, Ashley E.; Tomlins, Scott A.; Schaeffer, Edward M.; Trock, Bruce J.; Lotan, Tamara L.

doi:10.1016/j.eururo.2016.07.026

Cited by 71 publications

(83 citation statements)

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“…Previous analyses also suggest that PTEN is less commonly deleted in cohorts of men of African ancestry (2,38). Our data suggest that alteration of the PI3K signaling pathway either through PTEN deletion or PIK3CA mutation is a less common event in AAPC.…”

Section: Resultsmentioning

confidence: 91%

Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations

et al. 2017

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African-American men have the highest incidence and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing (n=102) and targeted validation (n = 90) of localized primary hormone-naïve prostate cancer in African-American men identified several gene mutations not previously observed in this context, including recurrent loss-of-function mutations in ERF, an ETS transcriptional repressor, in 5% of cases. Analysis of existing prostate cancer cohorts revealed ERF deletions in 3% of primary prostate cancers and mutations or deletions in ERF in 3–5% of lethal castration-resistant prostate cancers. Knockdown of ERF confers increased anchorage-independent growth and generates a gene expression signature associated with oncogenic ETS activation and androgen signaling. Together, these results suggest that ERF is a prostate cancer tumor suppressor gene. More generally, our findings support the application of systematic cancer genomic characterization in settings of broader ancestral diversity to enhance discovery and, eventually, therapeutic applications.

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Section: Resultsmentioning

confidence: 91%

Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations

et al. 2017

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“…Most of these cohorts have been previously described, and notably many were created to enrich for adverse oncologic outcomes, so they do not represent an unbiased survey of a radical prostatectomy population. In brief, these consisted of: 1) A cohort of consecutive tumors at radical prostatectomy from 2000–2004, including all tumors with Gleason score >6 (n=462 samples) (31); 2) A cohort of high-grade (Gleason score 9/10) tumors at radical prostatectomy from 1998–2005, designed for comparison to high-grade urothelial carcinomas (n=28) (32); 3) A cohort of all radical prostatectomies from 2004–2014 with primary Gleason pattern 5 and available clinical follow-up (n=71); 4) A cohort of African-American radical prostatectomy samples from 2005–2010, all with Gleason score 4+3=7 and higher (n=84) (31); 5) A cohort of patients who all developed metastatic disease and were treated with abiraterone/enzalutamide after radical prostatectomy at Johns Hopkins from 1995–2011 (n=34); 6) A cohort of patients with ductal adenocarcinoma and/or cribriform Gleason score 8 adenocarcinoma at radical prostatectomy from 1984–2004 (n=46) (33); 7) A case-cohort study of men undergoing radical prostatectomy from 1992–2009 who subsequently developed metastatic disease (n=325) (34); and 8) A cohort of men with biochemical recurrence following radical prostatectomy from 1992–2009 (n=240) (35). 9) Finally, a separate cohort of 43 neuroendocrine prostate carcinomas (NEPC) with confirmed small cell carcinoma histology on TMA was also queried by MSH2 IHC (36).…”

Section: Methodsmentioning

confidence: 99%

MSH2 Loss in Primary Prostate Cancer

Guedes

Antonarakis

Schweizer

et al. 2017

Clinical Cancer Research

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Purpose Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects. Experimental Design 1133 primary prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS). Results Of primary adenocarcinomas and NEPC, 1.2% (14/1176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9–10) had MSH2 loss compared to 0.4% (5/1042) of tumors with any other scores (p<0.05). 5% (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed MSH2 loss-of-function alterations in all (12/12) samples, with bi-allelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in MSH2. Tumors with MSH2 loss had a higher density of infiltrating CD8+ lymphocytes compared to grade-matched controls without MSH2 loss (390 vs. 76 cells/mm2; p=0.008), and CD8+ density was correlated with mutation burden among cases with MSH2 loss (r=0.72, p=0.005). T-cell receptor sequencing on a subset revealed a trend towards higher clonality in cases versus controls. Conclusion Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, where routine screening may be warranted if validated in additional cohorts.

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“…Of the selected articles, the analyzed materials in the studies were: specimens from prostatectomies (10 studies) ( 27 , 28 , 34 , 38 , 46 – 49 , 60 , 64 ), biopsies (6 studies) ( 28 , 29 , 35 , 37 – 39 ), and TUR (3 studies) ( 34 , 38 , 69 ).…”

Section: Resultsmentioning

confidence: 99%

The Role of Immunohistochemical Analysis as a Tool for the Diagnosis, Prognostic Evaluation and Treatment of Prostate Cancer: A Systematic Review of the Literature

et al. 2018

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Background: Prostate cancer (PCa) is a heterogeneous disease that lends itself toward numerous therapeutic options depending on its risk stratification. One of the greatest challenges in PCa urologic practice is to select patients who should be referred for biopsy and, for those patients who are diagnosed with cancer, to differentiate between patients with indolent disease from those with an unfavorable prognosis and, to determine ideal patient management and avoid unnecessary interventions. Accordingly, there is a growing body of literature reporting immunohistochemical studies with the objective of determining a prostate cancer prognosis. Among the most frequent biomarkers studied are Ki-67, p53, PTEN, MYC, and ERG. Based on these findings, we systematically reviewed articles that assessed the role of these main prognostic markers in prostate cancer.Methods: Consistent with PRISMA guidelines, we performed a systematic literature search throughout the Web of Science and PubMed Medline databases. We considered all types of studies evaluating the role of Ki-67, p53, PTEN, MYC, and ERG immunohistochemical analysis in prostate cancer until July 2017.Results: We identified 361 articles, 44 of which were summarized in this review. Diagnostically, no single immunohistochemical marker was able to define a tumor as benign or malignant. Prognostically, Ki-67, p53, and MYC were related to the tumor grade given by Gleason score and to the tumor stage (higher levels related to higher tumor grade). Furthermore, Ki-67 was also related to higher PSA levels, shorter disease-free intervals and shorter tumor-specific survival; the latter was also related to p53. The loss of PTEN protein expression showed a higher association with biochemical recurrence and with a worse prognosis, beyond that predicted by the Gleason score and tumor stage. ERG staining also showed a strong association with biochemical recurrence.Conclusion: There are several studies relating immunohistochemical markers with clinical-laboratorial outcomes in prostate cancer, the most frequent being Ki-67, p53, ERG, PTEN, and MYC. However, none of these markers have been validated by literary consensus to be routinely applied in medical practice.

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Prevalence and Prognostic Significance of PTEN Loss in African-American and European-American Men Undergoing Radical Prostatectomy

Cited by 71 publications

References 10 publications

Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations

Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations

MSH2 Loss in Primary Prostate Cancer

The Role of Immunohistochemical Analysis as a Tool for the Diagnosis, Prognostic Evaluation and Treatment of Prostate Cancer: A Systematic Review of the Literature

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