PTEN Loss as Determined by Clinical-grade Immunohistochemistry Assay Is Associated with Worse Recurrence-free Survival in Prostate Cancer

Lotan, Tamara L.; Wei, Wei; Morais, Carlos L.; Hawley, Sarah T.; Fazli, Ladan; Hurtado-Coll, Antonio; Troyer, Dean A.; McKenney, Jesse K.; Simko, Jeffrey P.; Carroll, Peter R.; Gleave, Martin; Lance, Raymond S.; Lin, Daniel W.; Nelson, Peter S.; Thompson, Ian M.; True, Lawrence D.; Feng, Ziding; Brooks, James D.

doi:10.1016/j.euf.2015.07.005

Cited by 61 publications

(64 citation statements)

References 41 publications

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“…This is notable, given the fact that only a minority of our cases had germline alterations in MSH2 , and suggests that bi-allelic somatic inactivation of MSH2 is frequently an early clonal event when it occurs. This is in stark contrast to other common genomic alterations in primary prostate cancer, such as PTEN deletion or TP53 mutation which are also enriched in metastatic and castration-resistant disease (47, 54, 55) and manifest a much more heterogeneous staining pattern in the primary tumor. Though we did select for cases with more homogeneous alterations in MSH2 by screening for loss using tissue microarray (TMA) punches, PTEN heterogeneity may be easily captured in TMA punches (47, 54), suggesting that this was not likely a major confounder.…”

Section: Discussionmentioning

confidence: 69%

MSH2 Loss in Primary Prostate Cancer

Guedes

Antonarakis

Schweizer

et al. 2017

Clinical Cancer Research

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128

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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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Section: Discussionmentioning

confidence: 69%

MSH2 Loss in Primary Prostate Cancer

Guedes

Antonarakis

Schweizer

et al. 2017

Clinical Cancer Research

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128

146

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“…Findings from multi-institutional integrative clinical sequencing studies reveal that the PTEN gene is frequently lost in advanced PCa (43,44). Moreover, PTEN loss is associated with worse recurrence-free survival after radical prostatectomy (7) and androgen depletion therapy of patients (8). Thus, it can be postulated that PTEN loss in PCa may contribute to IAS.…”

Section: Discussionmentioning

confidence: 99%

“…Aberrant activation of AKT frequently associates with PCa progression, poor prognosis and high risk of recurrence (6). PTEN loss also associates with worse recurrence-free survival in patients treated with radical prostatectomy (7)or ABA (8). These findings imply that PTEN loss may link to IAS.…”

Section: Introductionmentioning

confidence: 99%

PTEN Loss Promotes Intratumoral Androgen Synthesis and Tumor Microenvironment Remodeling via Aberrant Activation of RUNX2 in Castration-Resistant Prostate Cancer

Yang

Bai

et al. 2018

Clinical Cancer Research

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Purpose Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR)reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human PCa cell lines. Pten knockout mice were employed to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo. Results We uncovered that activation of the AKT-RUNX2-OCN-GPRC6A-CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null PCa cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null PCa including CRPC.

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“…PTEN IHC was performed as previously described on the Ventana Discovery Ultra automated staining platform utilizing CC1 antigen retrieval buffer (Roche-Ventana Medical Systems, Tucson, AZ) for 32 minutes at 100°C, followed by incubation with a rabbit anti-human PTEN antibody (Clone D4.3 XP; Cell Signaling, Danvers, MA; 1:75 dilution) at 36°C for 32 minutes, followed by the Optiview HRP multimer secondary detection system [33, 34]. …”

Section: Methodsmentioning

confidence: 99%

“…PTEN immunohistochemistry was blindly scored using a previously genetically validated dichotomous scoring system [33, 34, 36] by two pathologists (LG and TLL). A tissue core was considered to have PTEN protein loss if the intensity of cytoplasmic and nuclear staining was markedly decreased or entirely negative across >10% of tumor cells compared to surrounding benign glands and/or stroma, which provide internal positive controls for PTEN protein expression.…”

Section: Methodsmentioning

confidence: 99%

ERG and PTEN status of isolated high-grade PIN occurring in cystoprostatectomy specimens without invasive prostatic adenocarcinoma

Morais¹,

Guedes²,

Hicks³

et al. 2016

Human Pathology

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High grade prostatic intraepithelial neoplasia (HGPIN) is widely believed to represent a precursor to invasive prostatic adenocarcinoma. However, recent molecular studies have suggested that retrograde spread of invasive adenocarcinoma into pre-existing prostatic ducts can morphologically mimic HGPIN. Thus, previous molecular studies characterizing morphologically-identified HGPIN occurring in radical prostatectomies or needle biopsies with concurrent invasive carcinoma may be partially confounded by intraductal spread of invasive tumor. To assess ERG and PTEN status in HGPIN foci likely to represent true precursor lesions in the prostate, we studied isolated HGPIN occurring without associated invasive adenocarcinoma in cystoprostatectomies performed at Johns Hopkins between 2009 and 2014. Of 344 cystoprostatectomies, 33% (115/344) contained invasive prostatic adenocarcinoma in the partially submitted prostate (10 blocks/case on average) and were excluded from the study. Of the remaining cases without sampled cancer, 32% (73/229) showed 133 separate foci of HGPIN and were immunostained for ERG and PTEN using genetically validated protocols. Of foci of HGPIN with evaluable staining, 7% (8/107) were positive for ERG. PTEN loss was not seen in any HGPIN lesion (0/88). Because these isolated HGPIN foci at cystoprostatectomy are unlikely to represent retrograde spread of invasive tumor, our study suggests that ERG rearrangement, but not PTEN loss, is present in a minority of potential neoplastic precursor lesions in the prostate.

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PTEN Loss as Determined by Clinical-grade Immunohistochemistry Assay Is Associated with Worse Recurrence-free Survival in Prostate Cancer

Cited by 61 publications

References 41 publications

MSH2 Loss in Primary Prostate Cancer

MSH2 Loss in Primary Prostate Cancer

PTEN Loss Promotes Intratumoral Androgen Synthesis and Tumor Microenvironment Remodeling via Aberrant Activation of RUNX2 in Castration-Resistant Prostate Cancer

ERG and PTEN status of isolated high-grade PIN occurring in cystoprostatectomy specimens without invasive prostatic adenocarcinoma

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