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A Ari Hakimi,
Irina Ostrovnaya,
Boris A Reva,
Nikolaus Schultz, Ying-Bei Chen,
Mithat Gonen,
Han Liu,
Shugaku Takeda,
Martin H Voss,
Satish K Tickoo,
Victor E Reuter,
Paul Russo,
Emily H Cheng,
Chris Sander,
Robert J Motzer,
James J-D Hsieh
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ABSTRACT: Purpose To investigate the impact of newly identified chromosome 3p21 epigenetic tumor suppressors PBRM1, SETD2, and BAP1 on cancer specific survival (CSS) of 609 clear cell renal cell carcinoma (ccRCC) patients from two distinct cohorts. Patients and Methods Select sequencing on 3p tumor suppressors of 188 patients who underwent resection of primary ccRCC at the Memorial Sloan-Kettering Cancer Center (MSKCC) was performed to interrogate the genotype-phenotype associations. These findings were compared to analyses of the genomic and clinical dataset from our non-overlapping The Cancer Genome Atlas (TCGA) cohort of 421 primary ccRCC patients. Results 3p21 tumor suppressors are frequently mutated in both the MSKCC (PBRM1, 30.3%; SETD2, 7.4%; BAP1, 6.4%) and the TCGA (PBRM1, 33.5%; SETD2, 11.6%; BAP1, 9.7%) cohorts. BAP1 mutations are associated with worse CSS in both cohorts (MSKCC, p=0.002, HR 7.71 (2.08-28.6); TCGA, p=0.002, HR 2.21 (1.35-3.63)). SETD2 are associated with worse CSS in the TCGA cohort (p=0.036, HR 1.68 (1.04-2.73)). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS. Conclusion The chromosome 3p21 locus harbors three frequently mutated ccRCC tumor suppressor genes. BAP1 and SETD2 mutations (6-12%) are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations (30-34%) do not impact CSS, implicating its principal role in the tumor initiation. Future efforts should focus on therapeutic interventions and further clinical, pathologic and molecular interrogation of this novel class of tumor suppressors.
Clinical Cancer Research 04/2013; · 7.74 Impact Factor
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Wenlei He,
John C Cheville,
Peter M Sadow,
Anuradha Gopalan,
Samson W Fine,
Hikmat A Al-Ahmadie, Ying-Bei Chen,
Esther Oliva,
Paul Russo,
Victor E Reuter,
Satish K Tickoo
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ABSTRACT: The 2004 World Health Organization classification of tumors defines epithelioid angiomyolipoma of kidney as a potentially malignant mesenchymal neoplasm with reported metastasis in approximately one-third of the cases. However, this conclusion was based primarily on individual case reports and small retrospective series. More recently reported larger series have shown varying results. We reviewed 437 consecutive renal angiomyolipomas with primary resection at three tertiary-care institutions with high nephrectomy volumes. Only tumors showing >80% epithelioid histology were included in this study. Tumors resected elsewhere and reviewed in consultation were not included. Twenty of these 437 (4.6%) were classified as epithelioid angiomyolipoma. The female to male ratio was 11:9, mean age 49.7 (range, 30-80) years, and mean tumor size 8.7 (range, 1-25) cm. Microscopic tumor necrosis was present in 10 (50%) tumors and mitotic activity (range, <1-5/10 high power fields) in 8 (40%); atypical mitoses were seen in only 1 (5%) tumor. Pleomorphic ganglion-like or multinucleated giant cells were seen in 18 (90%) tumors. With a mean follow-up of 82.5 (range, 1-356) months, seventeen patients were alive with no-evidence-of-disease at the time of last follow-up; two patients died of unrelated causes with no-evidence-of-disease, and one patient (5%) developed distant metastases. Our data, based on consecutively resected angiomyolipomas with long clinical follow-up, suggests that epithelioid angiomyolipomas constitute a small proportion of all angiomyolipomas, and the rate of aggressive behavior among epithelioid angiomyolipomas, even when showing morphologic features previously reported to portend aggressive clinical behavior, is very low.Modern Pathology advance online publication, 19 April 2013; doi:10.1038/modpathol.2013.72.
Modern Pathology 04/2013; · 4.79 Impact Factor
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Ying-Bei Chen,
Miguel A Aon,
Yi-Te Hsu,
Lucian Soane,
Xinchen Teng,
J Michael McCaffery,
Wen-Chih Cheng,
Bing Qi,
Hongmei Li,
Kambiz N Alavian,
Margaret Dayhoff-Brannigan,
Shifa Zou,
Fernando J Pineda,
Brian O'Rourke,
Young H Ko,
Peter L Pedersen,
Leonard K Kaczmarek,
Elizabeth A Jonas,
J Marie Hardwick
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Ying-Bei Chen,
Miguel A Aon,
Yi-Te Hsu,
Lucian Soane,
Xinchen Teng,
J Michael McCaffery,
Wen-Chih Cheng,
Bing Qi,
Hongmei Li,
Kambiz N Alavian,
Margaret Dayhoff-Brannigan,
Shifa Zou,
Fernando J Pineda,
Brian O'Rourke,
Young H Ko,
Peter L Pedersen,
Leonard K Kaczmarek,
Elizabeth A Jonas,
J Marie Hardwick
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Ying-Bei Chen,
Miguel A Aon,
Yi-Te Hsu,
Lucian Soane,
Xinchen Teng,
J Michael McCaffery,
Wen-Chih Cheng,
Bing Qi,
Hongmei Li,
Kambiz N Alavian,
Margaret Dayhoff-Brannigan,
Shifa Zou,
Fernando J Pineda,
Brian O'Rourke,
Young H Ko,
Peter L Pedersen,
Leonard K Kaczmarek,
Elizabeth A Jonas,
J Marie Hardwick
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Ying-Bei Chen,
Miguel A Aon,
Yi-Te Hsu,
Lucian Soane,
Xinchen Teng,
J Michael McCaffery,
Wen-Chih Cheng,
Bing Qi,
Hongmei Li,
Kambiz N Alavian,
Margaret Dayhoff-Brannigan,
Shifa Zou,
Fernando J Pineda,
Brian O'Rourke,
Young H Ko,
Peter L Pedersen,
Leonard K Kaczmarek,
Elizabeth A Jonas,
J Marie Hardwick
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Ying-Bei Chen,
Miguel A Aon,
Yi-Te Hsu,
Lucian Soane,
Xinchen Teng,
J Michael McCaffery,
Wen-Chih Cheng,
Bing Qi,
Hongmei Li,
Kambiz N Alavian,
Margaret Dayhoff-Brannigan,
Shifa Zou,
Fernando J Pineda,
Brian O'Rourke,
Young H Ko,
Peter L Pedersen,
Leonard K Kaczmarek,
Elizabeth A Jonas,
J Marie Hardwick
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Ying-Bei Chen,
Miguel A Aon,
Yi-Te Hsu,
Lucian Soane,
Xinchen Teng,
J Michael McCaffery,
Wen-Chih Cheng,
Bing Qi,
Hongmei Li,
Kambiz N Alavian,
Margaret Dayhoff-Brannigan,
Shifa Zou,
Fernando J Pineda,
Brian O'Rourke,
Young H Ko,
Peter L Pedersen,
Leonard K Kaczmarek,
Elizabeth A Jonas,
J Marie Hardwick
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A Ari Hakimi, Ying-Bei Chen,
James Wren,
Mithat Gonen,
Omar Abdel-Wahab,
Adriana Heguy,
Han Liu,
Shugaku Takeda,
Satish K Tickoo,
Victor E Reuter,
Martin H Voss,
Robert J Motzer,
Jonathan A Coleman,
Emily H Cheng,
Paul Russo,
James J Hsieh
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ABSTRACT: BACKGROUND: Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent sequencing efforts have identified several novel frequent mutations of histone modifying and chromatin remodeling genes in ccRCC including PBRM1, SETD2, BAP1, and KDM5C. PBRM1, SETD2, and BAP1 are located in close proximity to VHL within a commonly lost (approximately 90%) 3p locus. To date, the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown. OBJECTIVE: To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC. DESIGN, SETTING, AND PARTICIPANTS: Targeted sequencing was performed in 185 ccRCCs and matched normal tissues from a single institution. Pathologic features, baseline patient characteristics, and follow-up data were recorded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The linkage between mutations and clinical and pathologic outcomes was interrogated with the Fisher exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer-specific survival [CSS]). RESULTS AND LIMITATIONS: PBRM1, BAP1, SETD2, and KDM5C are mutated at 29%, 6%, 8%, and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2, or KDM5C (19%) are more likely to present with stage III disease or higher (p=0.01 and p=0.001, respectively). Small tumors (<4cm) with PBRM1 mutations are more likely to exhibit stage III pathologic features (odds ratio: 6.4; p=0.001). BAP1 mutations tend to occur in Fuhrman grade III-IV tumors (p=0.052) and are associated with worse CSS (p=0.01). Clinical outcome data are limited by the number of events. CONCLUSIONS: Most mutations of chromatin modulators discovered in ccRCC are loss of function, associated with advanced stage, grade, and possibly worse CSS. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted.
European urology 09/2012; · 7.67 Impact Factor
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ABSTRACT: Classical apoptotic cell death is now sufficiently well understood to be interrogated with mathematical modeling and manipulated with targeted drugs for clinical benefit. However, a biological black hole has emerged with the realization that apoptosis regulators are functionally multipolar. BCL-2 family proteins appear to have much greater effects on cells than can be explained by their known roles in apoptosis. Although these effects may be observable simply because the cell is not dead, the general assumption is that BCL-2 proteins have undiscovered biochemical activities. Conversely, these as yet uncharacterized day-jobs also may underlie their profound effects on cell survival, challenging current assumptions about classical apoptosis. Even their sub-mitochondrial localizations remain controversial. Here we attempt to integrate seemingly conflicting information with the prospect that BCL-2 proteins themselves may be the critical crosstalk between life and death.
Trends in cell biology 05/2012; 22(6):318-28. · 12.12 Impact Factor
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ABSTRACT: Cystic lesions of the kidney may be accompanied by a range of neoplasms with distinct prognoses and future risks of developing additional tumors. In addition, some renal tumors, with or without accompanying renal cysts, may show a prominent cystic component. In the adult population, neoplasms occurring in a background of renal cystic diseases and cystic renal neoplasms often pose diagnostic challenges because of their many overlapping features.
To review the clinicopathologic characteristics of common entities in the spectrum of neoplastic and potential preneoplastic cystic lesions encountered in adults, with an emphasis on renal cystic diseases associated with tumor development and on renal neoplasms with predominantly cystic morphology.
The relevant English-language literature was reviewed, accompanied by the authors' experience at their practicing institution.
The presence of multiple renal cysts, both acquired and syndromic, can be associated with a variety of renal tumors. The morphology of the cysts and associated tumor types can help predict the genetic or acquired basis of the lesions, and particularly in specimens with no accompanying pertinent clinical history, such potential associations should be suggested in surgical pathology reports.
Archives of pathology & laboratory medicine 04/2012; 136(4):400-9. · 2.58 Impact Factor
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Dimitry Ofengeim, Ying-Bei Chen,
Takahiro Miyawaki,
Hongmei Li,
Silvio Sacchetti,
Richard J Flannery,
Kambiz N Alavian,
Fabrizio Pontarelli,
Brian A Roelofs,
John A Hickman,
J Marie Hardwick,
R Suzanne Zukin,
Elizabeth A Jonas
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ABSTRACT: Transient global ischemia in rats induces delayed death of hippocampal CA1 neurons. Early events include caspase activation, cleavage of anti-death Bcl-2 family proteins and large mitochondrial channel activity. However, whether these events have a causal role in ischemia-induced neuronal death is unclear. We found that the Bcl-2 and Bcl-x(L) inhibitor ABT-737, which enhances death of tumor cells, protected rats against neuronal death in a clinically relevant model of brain ischemia. Bcl-x(L) is prominently expressed in adult neurons and can be cleaved by caspases to generate a pro-death fragment, ΔN-Bcl-x(L). We found that ABT-737 administered before or after ischemia inhibited ΔN-Bcl-x(L)-induced mitochondrial channel activity and neuronal death. To establish a causal role for ΔN-Bcl-x(L), we generated knock-in mice expressing a caspase-resistant form of Bcl-x(L). The knock-in mice exhibited markedly reduced mitochondrial channel activity and reduced vulnerability to ischemia-induced neuronal death. These findings suggest that truncated Bcl-x(L) could be a potentially important therapeutic target in ischemic brain injury.
Nature Neuroscience 02/2012; 15(4):574-80. · 15.53 Impact Factor
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Ying-Bei Chen,
Miguel A Aon,
Yi-Te Hsu,
Lucian Soane,
Xinchen Teng,
J Michael McCaffery,
Wen-Chih Cheng,
Bing Qi,
Hongmei Li,
Kambiz N Alavian,
Margaret Dayhoff-Brannigan,
Shifa Zou,
Fernando J Pineda,
Brian O'Rourke,
Young H Ko,
Peter L Pedersen,
Leonard K Kaczmarek,
Elizabeth A Jonas,
J Marie Hardwick
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ABSTRACT: Mammalian Bcl-x(L) protein localizes to the outer mitochondrial membrane, where it inhibits apoptosis by binding Bax and inhibiting Bax-induced outer membrane permeabilization. Contrary to expectation, we found by electron microscopy and biochemical approaches that endogenous Bcl-x(L) also localized to inner mitochondrial cristae. Two-photon microscopy of cultured neurons revealed large fluctuations in inner mitochondrial membrane potential when Bcl-x(L) was genetically deleted or pharmacologically inhibited, indicating increased total ion flux into and out of mitochondria. Computational, biochemical, and genetic evidence indicated that Bcl-x(L) reduces futile ion flux across the inner mitochondrial membrane to prevent a wasteful drain on cellular resources, thereby preventing an energetic crisis during stress. Given that F(1)F(O)-ATP synthase directly affects mitochondrial membrane potential and having identified the mitochondrial ATP synthase β subunit in a screen for Bcl-x(L)-binding partners, we tested and found that Bcl-x(L) failed to protect β subunit-deficient yeast. Thus, by bolstering mitochondrial energetic capacity, Bcl-x(L) may contribute importantly to cell survival independently of other Bcl-2 family proteins.
The Journal of Cell Biology 10/2011; 195(2):263-76. · 10.26 Impact Factor
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ABSTRACT: Mesonephric remnant hyperplasia is a very rare benign mimicker of prostate adenocarcinoma. As most reported cases are from transurethral resection specimens, the anatomic location and histologic spectrum of this entity have not been fully elucidated. Its immunohistochemical profile using current prostatic diagnostic markers has also not been well studied. In this study, we retrospectively characterized 10 cases of mesonephric remnant hyperplasia involving the prostate and periprostatic tissue, including 8 cases seen in radical prostatectomy specimens, with emphasis on the histopathologic and immunohistochemical features. Patients ranged in age from 48 to 70 years (average, 60 y). Seven of them had concurrent prostatic adenocarcinoma and underwent radical prostatectomy; one patient underwent prostatectomy because of the misdiagnosis of mesonephric remnant hyperplasia on transurethral resection as carcinoma; 2 patients had transurethral resection for urinary obstruction. The distribution of prostatic mesonephric hyperplasia was concentrated in 2 areas: one was in the anterior fibromuscular stroma and adjacent anterolateral periprostatic tissue (n=6 of 8); the other was located toward the base posteriorly and posterolaterally either within or exterior to the prostate and around the seminal vesicle (n=4 of 8). Histologic patterns observed included the following: small-to-medium-sized acini or tubules with a lobular distribution (n=10 of 10); cysts either in clusters or scattered containing secretions (n=8 of 10); small or ill-formed glands with an infiltrative growth (n=7 of 10); glands with papillary infoldings or micropapillary tufts (n=4 of 10); and 2 cases exceptionally displayed nodules of ill-formed small glands intermixed with spindle cells, mimicking sclerosing adenosis or Gleason pattern 5 prostate cancer. Most cases (7 of 10) had florid hyperplasia and harbored 3 or more growth patterns. All cases were negative for prostate-specific antigen. Cytokeratin 34βE12 was diffusely positive in 4 of 9 cases, and showed focal immunoreactivity in the remaining 5 cases. Except for focal positivity seen in 4 of 7 cases, p63 was largely negative. Racemase was focally positive in 4 of 7 cases. Small glands with an infiltrative growth pattern, the most difficult to distinguish from cancer, were negative (n=3 of 6) or only focally positive (n=3 of 6) for 34βE12, negative for p63 (n=6 of 6), and focally positive for racemase (n=4 of 6). All cases examined in the study were diffusely positive for PAX8. In conclusion, mesonephric remnant hyperplasia not only involves the bladder neck and base of the prostate as previously described, but may also present as a florid growth in the anterior fibromuscular stroma from the apex to the base, closely mimicking prostate cancer. Although basal cell marker and racemase expression overlaps with prostate cancer, mesonephric hyperplasia's unique morphology along with distinctive immunohistochemical expression of PAX8 and lack of prostate-specific antigen can help in distinguishing this benign entity from prostatic adenocarcinoma.
The American journal of surgical pathology 07/2011; 35(7):1054-61. · 4.06 Impact Factor
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Christopher G Przybycin,
Angel M Cronin,
Farbod Darvishian,
Anuradha Gopalan,
Hikmat A Al-Ahmadie,
Samson W Fine, Ying-bei Chen,
Melanie Bernstein,
Paul Russo,
Victor E Reuter,
Satish K Tickoo
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ABSTRACT: Despite multiple studies, many clinicopathologic issues about chromophobe renal cell carcinoma (RCC) remain contentious; for example, its biological behavior-whether better or similar to papillary RCC, the incidence of sarcomatoid features, and whether pathologic features such as necrosis, nuclear grade, and tumor stage predict worse outcome. We studied 203 consecutive primary chromophobe RCCs resected at our institution in an attempt to answer these and other questions. The tumors showed significant progressive decrease in size and stage (P=0.047 and 0.001) from 1980 to 2000. Five patients had metastasis at presentation, and further disease-specific events (recurrence/metastasis/death due to disease) occurred in 8 more. Only 4 of 203 tumors had sarcomatoid features. Over median follow-up of 6.1 years (range, 0.1 to 18 y), 5-year and 10-year disease-specific events occurred in 3.7% (95% CI, 1.5%, 7.4%) and 6.4% (95% CI, 2.7%, 12.2%) patients. Outcomes showed significant association with tumor size, small-vessel invasion, sarcomatoid features, and microscopic necrosis (P≤0.05 each). pT stage or nodal metastasis tended to show some association, without reaching statistical significance (P=0.05 and 0.06, respectively). A modified tumor grading scheme, somewhat similar to that proposed recently, mitotic index, cytologic eosinophilia, and architecture, were not significantly associated with outcome. In conclusion, sarcomatoid differentiation is quite uncommon in chromophobe RCC. Tumor size, small-vessel invasion, sarcomatoid differentiation, and microscopic necrosis are the only features that are significantly associated with adverse outcome. On the basis of this long follow-up on a large number of cases, chromophobes seem to have better clinical outcomes than those reported for clear cell and papillary RCCs.
The American journal of surgical pathology 07/2011; 35(7):962-70. · 4.06 Impact Factor
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Hikmat A Al-Ahmadie,
Gopa Iyer,
Manickam Janakiraman,
Oscar Lin,
Adriana Heguy,
Satish K Tickoo,
Samson W Fine,
Anuradha Gopalan, Ying-bei Chen,
Arjun Balar,
Jamie Riches,
Bernard Bochner,
Guido Dalbagni,
Dean F Bajorin,
Victor E Reuter,
Matthew I Milowsky,
David B Solit
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ABSTRACT: FGFR3 mutations are common in low-grade urothelial carcinoma and represent a potential therapeutic target in this disease. Their incidence and functional role in high-grade urothelial carcinoma (HGUC), which displays an increased propensity for recurrence and muscularis propria invasion, is less well defined. We developed a mass spectrometry-based genotyping assay to define the incidence of FGFR3 mutations in a large clinically annotated set of urothelial carcinomas. FGFR3 mutations were found in 17% of HGUC versus 84% of low-grade lesions. Retrospective pathological review of the class of FGFR3 mutant HGUC revealed unique histological features, characterized by a bulky, exophytic component with branching papillary architecture as well as irregular nuclei with a koilocytoid appearance. The predictive value of this histological appearance was confirmed using a prospective set of 49 additional HGUCs. Prospective histological review was able to correctly predict for the presence of an FGFR3 mutation in 13/24 HGUC specimens that exhibited the distinct morphology (54%). All 25 specimens lacking the defined histological features were FGFR3 wild-type for a negative predictive value of 100%. Macrodissection of individual tumours confirmed the presence of the FGFR3 mutant allele in non-invasive and invasive, low and high-grade regions of individual tumours and in the lymph node metastases of patients whose tumours possessed the characteristic morphological signature, suggesting that FGFR3 mutations are not restricted to the more clinically indolent regions of HGUCs. These data suggest that histological screening of HGUCs followed by confirmatory genotyping can be used to enrich for the population of HGUCs most likely to harbour activating mutations in the FGFR-3 receptor tyrosine kinase. Histological review could thus aid in the development of targeted inhibitors of FGFR-3 by facilitating the identification of the subset of patients most likely to harbour activating mutations in the FGFR3 gene.
The Journal of Pathology 06/2011; 224(2):270-9. · 6.32 Impact Factor
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ABSTRACT: Primary carcinoid tumors of the urinary bladder are exceedingly rare. Although they have been considered to be potentially malignant neuroendocrine neoplasms, some previously reported cases were associated with a carcinoma component that might have altered the outcome. Only 8 histologically well-documented cases of pure carcinoid tumors of the bladder and 1 of the prostatic urethra have been reported in the literature. In this study, we describe 6 additional primary pure carcinoid tumors arising in the bladder (5 cases) or prostatic urethra (1 case). Patients (4 male, 2 female) ranged in age from 45 to 60 years (average, 55 y) and presented with hematuria (n = 5 of 6), obstruction (n = 1 of 6), or for concurrent genitourinary disease (n = 1 of 6). All 6 cases shared gross and microscopic findings. Cystoscopic examination showed small, smooth surfaced, or polypoid nodules. The 5 cases in the bladder were all located within or near the trigone and bladder neck region. Microscopically, these 6 tumors were subepithelial and confined within the lamina propria, associated with adjacent cystitis cystica et glandularis. The tumors were composed of uniform, cuboidal, or columnar cells with finely stippled chromatin and inconspicuous nucleoli in a prominent pseudoglandular pattern composed of acinar and cribriform structures. The cells had moderate-to-abundant cytoplasm and basally located Paneth cell-like eosinophilic granules. Although occasional atypical cells with prominent nucleoli could be seen, mitotic activity was absent or rare and cases lacked necrosis. Neuroendocrine differentiation was confirmed by immunohistochemistry in all 6 cases. All tumors were completely excised by biopsies. There was no evidence of disease recurrence or progression in all 6 patients, including 3 patients who had clinical follow-up for >4 years. Primary pure carcinoid tumors of the urinary bladder (and prostatic urethra) have distinct pathologic characteristics, with their prominent pseudoglandular features leading to difficulty in diagnosis. They are likely to have a very favorable clinical outcome, and should be distinguished from mixed carcinoid tumors or urothelial carcinomas with neuroendocrine differentiation that show focal carcinoid-like histologic features.
The American journal of surgical pathology 03/2011; 35(3):442-6. · 4.06 Impact Factor
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David S Rickman, Ying-Bei Chen,
Samprit Banerjee,
Yihang Pan,
Jindan Yu,
Terry Vuong,
Sven Perner,
Christopher J Lafargue,
Kirsten D Mertz,
Sunita R Setlur,
Kanishka Sircar,
Arul M Chinnaiyan,
Tarek A Bismar,
Mark A Rubin,
Francesca Demichelis
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ABSTRACT: To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC), we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3) emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP)-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq) revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC) and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.
Neoplasia (New York, N.Y.) 12/2010; 12(12):1031-40. · 5.48 Impact Factor
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ABSTRACT: Limited data exist on radical prostatectomy findings performed for cancer on repeat biopsy following an initial atypical biopsy (atypical glands suspicious but not diagnostic for carcinoma).
We compared 169 such men to 15,810 without an initial diagnosis of atypical glands suspicious for carcinoma who underwent radical prostatectomy from 1993 to 2008.
Median time between atypical biopsy and repeat biopsy showing cancer was 6.1 months (range 0.7 to 94.8). An initial diagnosis of atypical glands suspicious but not diagnostic for carcinoma correlated significantly with nonpalpable disease, biopsy Gleason score 6 and lower tumor volume on needle cores. Compared to radical prostatectomy without prior atypical findings, radical prostatectomy cases with an initial atypical biopsy had a significantly lower Gleason score (p <0.0001) and pathological stage (p = 0.001), with 126 (74.5%) Gleason score 6 and 140 (83.0%) organ confined. Only 2 (1.2%) cases showed seminal vesicle involvement and none had lymph node metastases. In addition to known preoperative parameters (clinical stage and biopsy Gleason score), the presence of initial atypical biopsy was an independent predictor of organ confined disease at radical prostatectomy. However, when tumor volume on needle biopsy was included in the multivariate analysis a diagnosis of atypical glands suspicious but not diagnostic for carcinoma lost its independent predictive value.
Prostate cancer diagnosed on needle biopsy following a diagnosis of atypical glands suspicious but not diagnostic of carcinoma demonstrates a significantly lower tumor grade and pathological stage at radical prostatectomy than cancer without such a diagnosis. Correlating with lower tumor volume on biopsy, the presence of initial atypical biopsy predicts organ confined disease at radical prostatectomy. However, a few cases with high Gleason score and advanced pathological stage in this group emphasize the importance of re-biopsy within 3 to 6 months following such a diagnosis.
The Journal of urology 11/2010; 184(5):1953-7. · 4.02 Impact Factor
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Luciana Schultz,
Roula Albadine,
Jessica Hicks,
Sana Jadallah,
Angelo M DeMarzo, Ying-Bei Chen,
Matthew E Nielsen,
Matthew E Neilsen,
Mark L Gonzalgo,
David Sidransky,
Mark Schoenberg,
George J Netto
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ABSTRACT: Bladder urothelial carcinoma has high rates of mortality and morbidity. Identifying novel molecular prognostic factors and targets of therapy is crucial. Mammalian target of rapamycin (mTOR) pathway plays a pivotal role in establishing cell shape, migration, and proliferation.
Tissue microarrays were constructed from 132 cystectomies (1994-2002). Immunohistochemistry was performed for Pten, c-myc, p27, phosphorylated (phos)Akt, phosS6, and 4E-BP1. Markers were evaluated for pattern, percentage, and intensity of staining.
Mean length of follow-up was 62.6 months (range, 1-182 months). Disease progression, overall survival (OS), and disease-specific survival (DSS) rates were 42%, 60%, and 68%, respectively. Pten showed loss of expression in 35% of bladder urothelial carcinoma. All markers showed lower expression in invasive bladder urothelial carcinoma compared with benign urothelium with the exception of 4E-BP1. Pten, p27, phosAkt, phosS6, and 4E-BP1 expression correlated with pathologic stage (pathological stage; P<.03). Pten, 4E-BP1, and phosAkt expression correlated with divergent aggressive histology and invasion. phosS6 expression inversely predicted OS (P=.01), DSS (P=.001), and progression (P=.05). c-myc expression inversely predicted progression (P=.01). In a multivariate analysis model that included TNM stage grouping, divergent aggressive histology, concomitant carcinoma in situ, phosS6, and c-myc expression, phosS6 was an independent predictor of DSS (P=.03; hazard ratio [HR], -0.19), whereas c-myc was an independent predictor of progression (P=.02; HR, -0.38). In a second model substituting organ-confined disease and lymph node status for TNM stage grouping, phosS6 and c-myc remained independent predictors of DSS (P=.03; HR, -0.21) and progression (P=.03; HR, -0.34), respectively.
We found an overall down-regulation of mTOR pathway in bladder urothelial carcinoma. phosS6 independently predicted DSS, and c-myc independently predicted progression.
Cancer 10/2010; 116(23):5517-26. · 4.77 Impact Factor
