A Prospective Investigation of PTEN Loss and ERG Expression in Lethal Prostate Cancer

Ahearn, Thomas U.; Pettersson, Andreas; Ebot, Ericka M.; Gerke, Travis; Graff, Rebecca E.; Morais, Carlos L.; Hicks, Jessica L.; Wilson, Kathryn M.; Rider, Jennifer R.; Sesso, Howard D.; Fiorentino, Michelangelo; Flavin, Richard; Finn, Stephen P.; Giovannucci, Edward; Loda, Massimo; Stampfer, Meir J.; Marzo, Angelo M. De; Mucci, Lorelei A.; Lotan, Tamara L.

doi:10.1093/jnci/djv346

Cited by 164 publications

(204 citation statements)

References 49 publications

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“…When all cases were evaluated on standard histologic slides, MSH2 staining was homogenously lost in all tumor cells sampled in the dominant tumor nodule from each case, suggesting that it was an early and clonal event in the evolution of the tumor. This is in stark contrast to other genomic alterations that we have profiled in situ , such as PTEN deletion (47). …”

Section: Resultscontrasting

confidence: 64%

“…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: 68%

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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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Section: Resultscontrasting

confidence: 64%

Section: Discussionmentioning

confidence: 68%

MSH2 Loss in Primary Prostate Cancer

Guedes

Antonarakis

Schweizer

et al. 2017

Clinical Cancer Research

Self Cite

133

146

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“…When considered in the context of ERG fusion, any PTEN loss was associated with PCSM in fusion negative cases, but PTEN loss in fusion positive cases was not independently predictive of survival. [90] Thus the presence of TMPRSS2:ERG fusion may modify the effects of PTEN loss on the disease biology. In spite of these complexities, the PTEN/TMPRSS:ERG test (Metamark, Cambridge, MA, USA) is a commercially available assay.…”

Section: Currently Available Testsmentioning

confidence: 99%

Tissue-based biomarkers in prostate cancer

Clinton

Bagrodia²,

Lotan³

et al. 2017

Expert Review of Precision Medicine and Drug Development

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Introduction Prostate cancer is a heterogeneous disease. Existing risk stratification tools based on standard clinlicopathologic variables (prostate specific antigen [PSA], Gleason score, and tumor stage) provide a modest degree of predictive ability. Advances in high-throughput sequencing has led to the development of several novel tissue-based biomarkers that can improve prognostication in prostate cancer management. Areas Covered The authors review commercially-available, tissue-based biomarker assays that improve upon existing risk-stratification tools in several areas of prostate cancer management, including the appropriateness of active surveillance and aiding in decision making regarding the use of adjuvant therapy. Additionally, some of the obstacles to the widespread adoption of these biomarkers and discuss several investigational sources of new biomarkers are discussed. Expert Commentary Work is ongoing to answer pertinent clinical questions in prostate cancer management including which patients should undergo biopsy, active surveillance, receive adjuvant therapy, and what systemic therapy is best in the first-line. Incorporation into novel biomarkers may allow for the incorporation of a ‘personalized’ approach to management. Further validation will be required and questions of cost must be considered before wide scale adoption of these biomarkers. Tumor heterogeneity may impose a ceiling on the prognostic ability of biomarkers using currently available techniques.

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“…ETS fusion-positive cancer is associated with disease aggressiveness and poor prognosis (15,41), which may aid in effective clinical choices for re-biopsy (31). For an ETS fusion-negative cancer subtype, PTEN loss may be an independent indicator of poor survival and the increased risk of lethal progression following prostatectomy (42,43). Epigenetic alteration of tumor suppressors, DNA damage repair or other repair genes through hypermethylation is associated with prostate cancer tumorigenesis, and these alterations are frequently identified in solid tumor cells and the bodily fluids of patients (25,44).…”

Section: Genetic Biomarkers For Risk Stratification Of Aggressive Cancermentioning

confidence: 99%

“…Its loss leads to uncontrolled signaling that promotes cancer cell proliferation and growth. Therefore, drugs that inhibit the altered PI3K/Akt/mTOR signaling activity may be used to treat a cancer with PTEN loss or mutation (42,43,61). Cancer cells with defective mutations in DNA repair genes (including BRCA2 and ATM) have increased susceptibility to the impairment of the base excision repair pathway; therefore, patients with this genetic defect may benefit from treatment with platinum agents or PARP inhibitors (61).…”

Section: Therapies Targeting To Tumor Genetic Aberrationsmentioning

confidence: 99%

The context of prostate cancer genomics in personalized medicine

Liu

2017

Oncology Letters

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Abstract. Prostate cancer is one of the most common types of cancer in males. Heterogeneous genomic aberrations may lead to prostate cancer onset, progression and metastasis. This heterogeneity also contributes to the variety in cancer risk and outcomes, different drug responses and progression, observed between individual patients. Classical prognostic factors, including prostate-specific antigen, Gleason Score and clinical tumor staging, are not sufficient to portray the complexity of a clinically relevant cancer diagnosis, risk prognosis, treatment choice and therapy monitoring. There is a requirement for novel genetic biomarkers in order to understand the oncogenic heterogeneity in a patient-personalized clinical setting and to improve the efficacy of risk prognosis and treatment choice. A number of biomarkers and gene panels have been established from patient sample cohort studies. These previous studies have provided distinct information to the investigation of heterogeneous malignancy in prostate cancer, which aids in clinical decision-making. Biomarker-guided therapies may facilitate the effective selection of drugs during early treatment; therefore, are beneficial to the individual patient. A non-invasive approach allows for convenient and repeated sampling to screen for cancer and monitor treatment response without the requirement for invasive tissue biopsies. With the current availability of numerous advanced technologies, reliable detection of the minimal tumor residues present following treatment may become clinical practice and, therefore, inform further in the field of personalized medicine.

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A Prospective Investigation of PTEN Loss and ERG Expression in Lethal Prostate Cancer

Abstract: Background: PTEN is a tumor suppressor frequently deleted in prostate cancer that may be a useful prognostic biomarker. However, the association of PTEN loss with lethal disease has not been tested in a large, predominantly surgically treated cohort.

Cited by 164 publications

References 49 publications

MSH2 Loss in Primary Prostate Cancer

MSH2 Loss in Primary Prostate Cancer

Tissue-based biomarkers in prostate cancer

The context of prostate cancer genomics in personalized medicine

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