Publications by authors named "Xuhong Cao"

109 Publications

Assessment of Clinical Benefit of Integrative Genomic Profiling in Advanced Solid Tumors.

JAMA Oncol 2021 Feb 25. Epub 2021 Feb 25.

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor.

Importance: Use of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain.

Objective: To determine which patients derived the greatest degree of clinical benefit from NGS profiling.

Design, Setting, And Participants: Patients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020.

Main Outcomes And Measures: Patients' subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer.

Results: During the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses.

Conclusions And Relevance: The high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.
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http://dx.doi.org/10.1001/jamaoncol.2020.7987DOI Listing
February 2021

Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination.

Nat Med 2021 01 4;27(1):152-164. Epub 2021 Jan 4.

Department of Surgery, University of Michigan, Ann Arbor, MI, USA.

Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8 T cells from systemic circulation. Within the liver, activated antigen-specific FasCD8 T cells undergo apoptosis following their interaction with FasLCD11bF4/80 monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8 T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.
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http://dx.doi.org/10.1038/s41591-020-1131-xDOI Listing
January 2021

Targeting transcriptional regulation of SARS-CoV-2 entry factors and .

Proc Natl Acad Sci U S A 2020 Dec 11. Epub 2020 Dec 11.

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109;

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, employs two key host proteins to gain entry and replicate within cells, angiotensin-converting enzyme 2 (ACE2) and the cell surface transmembrane protease serine 2 (TMPRSS2). was first characterized as an androgen-regulated gene in the prostate. Supporting a role for sex hormones, males relative to females are disproportionately affected by COVID-19 in terms of mortality and morbidity. Several studies, including one employing a large epidemiological cohort, suggested that blocking androgen signaling is protective against COVID-19. Here, we demonstrate that androgens regulate the expression of , , and androgen receptor (AR) in subsets of lung epithelial cells. AR levels are markedly elevated in males relative to females greater than 70 y of age. In males greater than 70 y old, smoking was associated with elevated levels of AR and ACE2 in lung epithelial cells. Transcriptional repression of the AR enhanceosome with AR or bromodomain and extraterminal domain (BET) antagonists inhibited SARS-CoV-2 infection in vitro. Taken together, these studies support further investigation of transcriptional inhibition of critical host factors in the treatment or prevention of COVID-19.
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http://dx.doi.org/10.1073/pnas.2021450118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817128PMC
December 2020

Screening and mechanistic study of key sites of the hemagglutinin-neuraminidase protein related to the virulence of Newcastle disease virus.

Poult Sci 2020 Jul 4;99(7):3374-3384. Epub 2020 May 4.

College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi Province, China. Electronic address:

Newcastle disease is a kind of avian infectious disease caused by Newcastle disease virus (NDV). The virulence of NDV is dependent mainly on the fusion (F) protein and hemagglutinin-neuraminidase (HN) protein. The genomes of 2 viruses, NDV-Blackbird and NDV-Dove, are 99.9% similar, while NDV-Blackbird is a velogenic virus, and NDV-Dove is a lentogenic virus. Further analysis revealed that the F proteins of the 2 strains were identical, and only 5 amino acid sites on the HN proteins were inconsistent. Five different HN mutant plasmids were constructed and analyzed in this study. The results showed that the mutation F110L caused a significant increase in fusion-promotion activity caused by an increase in neuraminidase activity. Because of the increase in receptor-binding activity caused by G116R, there was a significant increase in fusion-promotion activity. The mutation G54S resulted in a slight decrease in the fusion-promotion activity caused by a slight decrease in receptor-binding activity. The slight increase in the fusion-promotion activity caused by A469V was associated with a significant increase in neuraminidase activity. Therefore, the amino acids L110 and R116 played a key role in determining the virulence difference between NDV-Blackbird and NDV-Dove, which could lay a foundation for illuminating the virulence differences of NDV strains, as well as the development of attenuated vaccines.
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http://dx.doi.org/10.1016/j.psj.2020.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597932PMC
July 2020

An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development.

Nat Commun 2020 06 4;11(1):2817. Epub 2020 Jun 4.

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.

Both KRAS and EGFR are essential mediators of pancreatic cancer development and interact with Argonaute 2 (AGO2) to perturb its function. Here, in a mouse model of mutant KRAS-driven pancreatic cancer, loss of AGO2 allows precursor lesion (PanIN) formation yet prevents progression to pancreatic ductal adenocarcinoma (PDAC). Precursor lesions with AGO2 ablation undergo oncogene-induced senescence with altered microRNA expression and EGFR/RAS signaling, bypassed by loss of p53. In mouse and human pancreatic tissues, PDAC progression is associated with increased plasma membrane localization of RAS/AGO2. Furthermore, phosphorylation of AGO2 disrupts both the wild-type and oncogenic KRAS-AGO2 interaction, albeit under different conditions. ARS-1620 (G12C-specific inhibitor) disrupts the KRAS-AGO2 interaction, suggesting that the interaction is targetable. Altogether, our study supports a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an AGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical for PDAC progression.
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http://dx.doi.org/10.1038/s41467-020-16309-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272436PMC
June 2020

Next-generation RNA Sequencing-based Biomarker Characterization of Chromophobe Renal Cell Carcinoma and Related Oncocytic Neoplasms.

Eur Urol 2020 07 13;78(1):63-74. Epub 2020 Apr 13.

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, Ann Arbor, MI, USA; Rogel Cancer Center, Michigan Medicine, Ann Arbor, MI, USA. Electronic address:

Background: Renal cell carcinomas (RCCs) are a heterogeneous group of neoplasms. Recent sequencing studies revealed various molecular features associated with histologic RCC subtypes, including chromophobe renal cell carcinoma (ChRCC).

Objective: To characterize the gene expression and biomarker signatures associated with ChRCC.

Design, Setting, And Participants: We performed integrative analysis on RNA sequencing data available from 1049 RCC specimens from The Cancer Genome Atlas and in-house studies. Our workflow identified genes relatively enriched in ChRCC, including Forkhead box I1 (FOXI1), Rh family C glycoprotein (RHCG), and LINC01187. We assessed the expression pattern of FOXI1 and RHCG protein by immunohistochemistry (IHC) and LINC01187 mRNA by RNA in situ hybridization (RNA-ISH) in whole tissue sections representing a cohort of 197 RCC cases, including both primary and metastatic tumors.

Outcome Measurements And Statistical Analysis: The FOXI1 and RHCG IHC staining, as well as the LINC01187 RNA-ISH staining, was evaluated in each case for intensity, pattern, and localization of expression.

Results And Limitations: All primary and metastatic classic ChRCCs demonstrated homogeneous positive labeling for FOXI1, RHCG proteins, and LINC01187 transcript. Unclassified RCC with oncocytic features, oncocytoma, and hybrid oncocytic tumor, as well as all but two cases of eosinophilic ChRCC also stained positive. Importantly, metastatic and primary RCC of all other subtypes did not demonstrate any unequivocal staining for FOXI1, RHCG, or LINC01187. In normal kidney, FOXI1, RHCG, and LINC01187 were detected in the distal nephron segment, specifically in intercalated cells. Two cases of eosinophilic ChRCC with focal expression of FOXI1 and LINC01187, and Golgi-like RHCG staining were found to contain MTOR gene mutations upon DNA sequencing.

Conclusions: We demonstrate a pipeline for the identification and validation of RCC subtype-specific biomarkers that can aid in the confirmation of cell of origin and may facilitate accurate classification and diagnosis of renal tumors.

Patient Summary: FOXI1, RHCG, and LINC01187 are lineage-specific signature genes for chromophobe renal cell carcinoma.
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http://dx.doi.org/10.1016/j.eururo.2020.03.003DOI Listing
July 2020

Androgen receptor degraders overcome common resistance mechanisms developed during prostate cancer treatment.

Neoplasia 2020 02 10;22(2):111-119. Epub 2020 Jan 10.

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address:

Androgen receptor (AR) antagonists, such as enzalutamide, have had a major impact on the treatment of metastatic castration-resistant prostate cancer (CRPC). However, even with the advent of AR antagonist therapies, patients continue to develop resistance, and new strategies to combat continued AR signalling are needed. Here, we develop AR degraders using PROteolysis TArgeting Chimeric (PROTAC) technology in order to determine whether depletion of AR protein can overcome mechanisms of resistance commonly associated with current AR-targeting therapies. ARD-61 is the most potent of the AR degraders and effectively induces on-target AR degradation with a mechanism consistent with the PROTAC design. Compared to clinically-approved AR antagonists, administration of ARD-61 in vitro and in vivo results in more potent anti-proliferative, pro-apoptotic effects and attenuation of downstream AR target gene expression in prostate cancer cells. Importantly, we demonstrate that ARD-61 functions in enzalutamide-resistant model systems, characterized by diverse proposed mechanisms of resistance that include AR amplification/overexpression, AR mutation, and expression of AR splice variants, such as AR-V7. While AR degraders are unable to bind and degrade AR-V7, they continue to inhibit tumor cell growth in models overexpressing AR-V7. To further explore this, we developed several isogenic prostate cell line models in which AR-V7 is highly expressed, which also failed to influence the cell inhibitory effects of AR degraders, suggesting that AR-V7 is not a functional resistance mechanism for AR antagonism. These data provide compelling evidence that full-length AR remains a prominent oncogenic driver of prostate cancers which have developed resistance to AR antagonists and highlight the clinical potential of AR degraders for treatment of CRPC.
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http://dx.doi.org/10.1016/j.neo.2019.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957805PMC
February 2020

Plasmacytoid urothelial carcinoma: a rapid autopsy case report with unique clinicopathologic and genomic profile.

Diagn Pathol 2019 Oct 21;14(1):113. Epub 2019 Oct 21.

Department of Pathology, University of Michigan Medical School, 2800 Plymouth Rd, Building 35, Ann Arbor, MI, 48109, USA.

Background: Rapid ("warm") autopsies of patients with advanced metastatic cancer provide important insight into the natural history, pathobiology and histomorphology of disease in treatment-resistant tumors. Plasmacytoid urothelial carcinoma (PUC) is a rare variant of urothelial carcinoma characterized by neoplastic cells morphologically resembling plasma cells. PUC is typically aggressive, high-stage at presentation, and associated with poor outcomes. Recurrence is common in PUC, with the majority of recurrences occurring in the peritoneum.

Case Presentation: Here, we report rapid autopsy findings from a patient with recurrent PUC. The patient had persistent pain after cystoprostatectomy, although initial post-operative imaging showed no evidence of disease. Imaging obtained shortly before his death showed only subtle growth along vascular tissue planes; however, extensive disease was seen on autopsy. Plasmacytoid tumor cells formed sheets involving many serosal surfaces. Molecular interrogation confirmed a mutation in CDH1 exon 12 leading to early truncation of the CDH1 protein in the tumor cells.

Conclusions: The sheet-like growth pattern of PUC makes early phases of disease spread much more difficult to capture on cross-sectional imaging. Alternative forms of surveillance may be required for detection of recurrent PUC, and providers may need to treat based on symptoms and clinical suspicion.
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http://dx.doi.org/10.1186/s13000-019-0896-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802321PMC
October 2019

Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer.

Nature 2019 07 26;571(7765):413-418. Epub 2019 Jun 26.

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.

Abtract: Forkhead box A1 (FOXA1) is a pioneer transcription factor that is essential for the normal development of several endoderm-derived organs, including the prostate gland. FOXA1 is frequently mutated in hormone-receptor-driven prostate, breast, bladder and salivary-gland tumours. However, it is unclear how FOXA1 alterations affect the development of cancer, and FOXA1 has previously been ascribed both tumour-suppressive and oncogenic roles. Here we assemble an aggregate cohort of 1,546 prostate cancers and show that FOXA1 alterations fall into three structural classes that diverge in clinical incidence and genetic co-alteration profiles, with a collective prevalence of 35%. Class-1 activating mutations originate in early prostate cancer without alterations in ETS or SPOP, selectively recur within the wing-2 region of the DNA-binding forkhead domain, enable enhanced chromatin mobility and binding frequency, and strongly transactivate a luminal androgen-receptor program of prostate oncogenesis. By contrast, class-2 activating mutations are acquired in metastatic prostate cancers, truncate the C-terminal domain of FOXA1, enable dominant chromatin binding by increasing DNA affinity and-through TLE3 inactivation-promote metastasis driven by the WNT pathway. Finally, class-3 genomic rearrangements are enriched in metastatic prostate cancers, consist of duplications and translocations within the FOXA1 locus, and structurally reposition a conserved regulatory element-herein denoted FOXA1 mastermind (FOXMIND)-to drive overexpression of FOXA1 or other oncogenes. Our study reaffirms the central role of FOXA1 in mediating oncogenesis driven by the androgen receptor, and provides mechanistic insights into how the classes of FOXA1 alteration promote the initiation and/or metastatic progression of prostate cancer. These results have direct implications for understanding the pathobiology of other hormone-receptor-driven cancers and rationalize the co-targeting of FOXA1 activity in therapeutic strategies.
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http://dx.doi.org/10.1038/s41586-019-1347-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661908PMC
July 2019

Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer.

Clin Cancer Res 2019 07 27;25(13):4038-4048. Epub 2019 Mar 27.

Michigan Center for Translational Pathology, University of Michigan.

Purpose: The bromodomain and extraterminal (BET)-containing proteins (BRD2/3/4) are essential epigenetic coregulators for prostate cancer growth. BRD inhibitors have shown promise for treatment of metastatic castration-resistant prostate cancer (mCRPC), and have been shown to function even in the context of resistance to next-generation AR-targeted therapies such as enzalutamide and abiraterone. Their clinical translation, however, has been limited by off-target effects, toxicity, and rapid resistance.

Experimental Design: We have developed a series of molecules that target BET bromodomain proteins through their proteasomal degradation, improving efficacy and specificity of standard inhibitors. We tested their efficacy by utilizing prostate cancer cell lines and patient-derived xenografts, as well as several techniques including RNA-sequencing, mass spectroscopic proteomics, and lipidomics.

Results: BET degraders function and to suppress prostate cancer growth. These drugs preferentially affect AR-positive prostate cancer cells (22Rv1, LNCaP, VCaP) over AR-negative cells (PC3 and DU145), and proteomic and genomic mechanistic studies confirm disruption of oncogenic AR and MYC signaling at lower concentrations than BET inhibitors. We also identified increases in polyunsaturated fatty acids (PUFA) and thioredoxin-interacting protein (TXNIP) as potential pharmacodynamics biomarkers for targeting BET proteins.

Conclusions: Compounds inducing the pharmacologic degradation of BET proteins effectively target the major oncogenic drivers of prostate cancer, and ultimately present a potential advance in the treatment of mCRPC. In particular, our compound dBET-3, is most suited for further clinical development.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606381PMC
July 2019

Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma.

Neoplasia 2019 03 21;21(3):322-330. Epub 2019 Feb 21.

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Studies on the efficacy of small molecule inhibitors in Merkel cell carcinoma (MCC) have been limited and largely inconclusive. In this study, we investigated the therapeutic potential of a potent BET degrader, BETd-246, in the treatment of MCC. We found that MCC cell lines were significantly more sensitive to BETd-246 than to BET inhibitor treatment. Therapeutic targeting of BET proteins resulted in a loss of "MCC signature" genes but not MYC expression as previously described irrespective of Merkel cell polyomavirus (MCPyV) status. In MCPyV+ MCC cells, BETd-246 alone suppressed downstream targets in the MCPyV-LT Ag axis. We also found enrichment of HOX and cell cycle genes in MCPyV- MCC cell lines that were intrinsically resistant to BETd-246. Our findings uncover a requirement for BET proteins in maintaining MCC lineage identity and point to the potential utility of BET degraders for treating MCC.
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http://dx.doi.org/10.1016/j.neo.2019.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384317PMC
March 2019

The Landscape of Circular RNA in Cancer.

Cell 2019 02;176(4):869-881.e13

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

Circular RNAs (circRNAs) are an intriguing class of RNA due to their covalently closed structure, high stability, and implicated roles in gene regulation. Here, we used an exome capture RNA sequencing protocol to detect and characterize circRNAs across >2,000 cancer samples. When compared against Ribo-Zero and RNase R, capture sequencing significantly enhanced the enrichment of circRNAs and preserved accurate circular-to-linear ratios. Using capture sequencing, we built the most comprehensive catalog of circRNA species to date: MiOncoCirc, the first database to be composed primarily of circRNAs directly detected in tumor tissues. Using MiOncoCirc, we identified candidate circRNAs to serve as biomarkers for prostate cancer and were able to detect circRNAs in urine. We further detected a novel class of circular transcripts, termed read-through circRNAs, that involved exons originating from different genes. MiOncoCirc will serve as a valuable resource for the development of circRNAs as diagnostic or therapeutic targets across cancer types.
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http://dx.doi.org/10.1016/j.cell.2018.12.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601354PMC
February 2019

Metastatic castration resistant prostate cancer with squamous cell, small cell, and sarcomatoid elements-a clinicopathologic and genomic sequencing-based discussion.

Med Oncol 2019 Feb 2;36(3):27. Epub 2019 Feb 2.

Department of Pathology, University of Michigan Medical School, 2800 Plymouth Road, Building 35, Ann Arbor, MI, USA.

Histologic variants are uncommon but well reported amongst cases of prostatic adenocarcinoma, including those in the setting of hormonal and/or chemoradiation therapy and castration resistance. However, the spectrum of morphologic phenotypes and molecular alterations present in such histologic variants are still incompletely understood. Herein, we describe a case of metastatic prostatic adenocarcinoma with hormonal and chemoradiation therapy-associated differentiation, displaying a combination of squamous cell, small cell, and sarcomatoid elements. The morphologic, immunohistochemical, and molecular observations are discussed with attention given to the gene alterations present, including in TP53, NF1, AR, PTEN, and RB1. Finally, we will compare our findings with those observed in uncommonly reported similar cases so as to detail the molecular underpinnings of such processes which may carry therapeutic implications.
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http://dx.doi.org/10.1007/s12032-019-1250-8DOI Listing
February 2019

Association of ERG/PTEN status with biochemical recurrence after radical prostatectomy for clinically localized prostate cancer.

Med Oncol 2018 Oct 5;35(12):152. Epub 2018 Oct 5.

Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA.

We have previously demonstrated a significant correlative relationship between PTEN deletion and ERG rearrangement, both in the development of clinically localized prostate cancers and metastases. Herein, we evaluate the cooperative role of ERG and PTEN in oncological outcomes after radical prostatectomy for clinically localized prostate cancer. We evaluated ERG and PTEN status using three previously described cohorts. The first cohort included 235 clinically localized prostate cancer cases represented on tissue microarrays (TMA), evaluated using previously validated FISH assays for ERG and PTEN. The second cohort included 167 cases of clinically localized prostate cancer on TMAs evaluated for PTEN by FISH, and for PTEN and ERG by dual IHC. The third cohort comprised 59 clinically localized prostate cancer cases assessed by array comparative genomic hybridization (aCGH). Kaplan-Meir plots and long rank tests were used to assess the association of ERG and PTEN status with biochemical recurrence after radical prostatectomy for clinically localized prostate cancer. Of the 317 cases eligible for analyses with evaluable ERG and PTEN status, 88 (27.8%) patients developed biochemical recurrence over a median follow-up of 5.7 years. Overall, 45% (142/317) of cases demonstrated ERG rearrangement and 20% (62/317) of cases demonstrated PTEN loss. Hemizygous and homozygous deletion of PTEN was seen in 10% (18/175) and 3% (5/175) of ERG-negative cases, respectively. In contrast, hemizygous and homozygous deletion of PTEN was seen in 11% (15/142) and 17% (24/123) of ERG-positive cases, respectively. PTEN loss (heterozygous or homozygous) was significantly associated with shorter time to biochemical recurrence compared to no PTEN loss (p < 0.001). However, ERG rearrangement versus no rearrangement was not associated with time to PSA recurrence (p = 0.15). Patients who exhibited ERG rearrangement and loss of PTEN had no significant difference in time to recurrence compared to patients with wild-type ERG and loss of PTEN (p = 0.30). Our findings confirm a mutual cooperative role of ERG and PTEN in the pathogenesis of prostate cancer, particularly for homozygous PTEN deletion. ERG did not stratify outcome either alone or in combination with PTEN in this cohort.
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http://dx.doi.org/10.1007/s12032-018-1212-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601345PMC
October 2018

VSTM2A Overexpression Is a Sensitive and Specific Biomarker for Mucinous Tubular and Spindle Cell Carcinoma (MTSCC) of the Kidney.

Am J Surg Pathol 2018 12;42(12):1571-1584

Michigan Center for Translational Pathology.

Our recent study revealed recurrent chromosomal losses and somatic mutations of genes in the Hippo pathway in mucinous tubular and spindle cell carcinoma (MTSCC). Here, we performed an integrative analysis of 907 renal cell carcinoma (RCC) samples (combined from The Cancer Genome Atlas and in-house studies) and the Knepper data set of microdissected rat nephrons. We identified VSTM2A and IRX5 as novel cancer-specific and lineage-specific biomarkers in MTSCC. We then assessed their expression by RNA in situ hybridization (ISH) in 113 tumors, including 33 MTSCC, 40 type 1 papillary RCC, 8 type 2 papillary RCC, 2 unclassified RCC, 15 clear cell RCC, and 15 chromophobe RCC. Sensitivity and specificity were calculated as the area under the receiver operating characteristics curve (AUC). All MTSCC tumors demonstrated moderate to high expression of VSTM2A (mean ISH score=255). VSTM2A gene expression assessed by RNA sequencing strongly correlated with VSTM2A ISH score (r(2)=0.81, P=0.00016). The majority of non-MTSCC tumors demonstrated negative or low expression of VSTM2A. IRX5, nominated as a lineage-specific biomarker, showed moderate to high expression in MTSCC tumors (mean ISH score=140). IRX5 gene expression assessed by RNA sequencing strongly correlated with IRX5 ISH score (r(2)=0.69, P=0.00291). VSTM2A (AUC: 99.2%) demonstrated better diagnostic efficacy than IRX5 (AUC: 87.5%), and may thus serve as a potential diagnostic marker to distinguish tumors with overlapping histology. Furthermore, our results suggest MTSCC displays an overlapping phenotypic expression pattern with the loop of Henle region of normal nephrons.
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http://dx.doi.org/10.1097/PAS.0000000000001150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903805PMC
December 2018

MiPanda: A Resource for Analyzing and Visualizing Next-Generation Sequencing Transcriptomics Data.

Neoplasia 2018 11 27;20(11):1144-1149. Epub 2018 Sep 27.

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

The Michigan Portal for the Analysis of NGS data portal (http://mipanda.org) is an open-access online resource that provides the scientific community with access to the results of a large-scale computational analysis of thousands of high-throughput RNA sequencing (RNA-seq) samples. The portal provides access to gene expression profiles, enabling users to interrogate expression of genes across myriad normal and cancer tissues and cell lines. From these data, tissue- and cancer-specific expression patterns can be identified. Gene-gene coexpression profiles can also be interrogated. The current portal contains data for over 20,000 RNA-seq samples and will be continually updated.
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http://dx.doi.org/10.1016/j.neo.2018.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171536PMC
November 2018

Epigenetic Reprogramming with Antisense Oligonucleotides Enhances the Effectiveness of Androgen Receptor Inhibition in Castration-Resistant Prostate Cancer.

Cancer Res 2018 10 22;78(20):5731-5740. Epub 2018 Aug 22.

Michigan Center for Translational Pathology, Ann Arbor, Michigan.

Advanced prostate cancer initially responds to androgen deprivation therapy (ADT), but the disease inevitably recurs as castration-resistant prostate cancer (CRPC). Although CRPC initially responds to abiraterone and enzalutamide, the disease invariably becomes nonresponsive to these agents. Novel approaches are required to circumvent resistance pathways and to extend survival, but the mechanisms underlying resistance remain poorly defined. Our group previously showed the histone lysine--methyltransferase EZH2 to be overexpressed in prostate cancer and quantitatively associated with progression and poor prognosis. In this study, we screened a library of epigenetic inhibitors for their ability to render CRPC cells sensitive to enzalutamide and found that EZH2 inhibitors specifically potentiated enzalutamide-mediated inhibition of proliferation. Moreover, we identified antisense oligonucleotides (ASO) as a novel drug strategy to ablate EZH2 and androgen receptor (AR) expression, which may have advantageous properties in certain settings. RNA-seq, chromatin immunoprecipitation sequencing, and assay for transposase-accessible chromatin using sequencing demonstrated that EZH2 inhibition altered the AR cistrome to significantly upregulate AR signaling, suggesting an enhanced dependence of CRPC cells on this pathway following inhibition of EZH2. Combination treatment with ASO targeting EZH2 and AR transcripts inhibited prostate cancer cell growth and better than single agents. In sum, this study identifies EZH2 as a critical epigenetic regulator of ADT resistance and defines ASO-based cotargeting of EZH2 and AR as a promising strategy for the treatment of CRPC. Simultaneous targeting of lysine methyltransferase EZH2 and the AR with ASO proves a novel and effective therapeutic strategy in patients with CRPC. .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191320PMC
October 2018

Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency.

Eur J Hum Genet 2018 11 5;26(11):1582-1587. Epub 2018 Jul 5.

Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Medical genomics research performed in diverse population facilitates a better understanding of the genetic basis of developmental disorders, with regional implications for community genetics. Autosomal recessive mitochondrial complex I deficiency (MCID) accounts for a constellation of clinical features, including encephalopathies, myopathies, and Leigh Syndrome. Using whole-exome sequencing, we identified biallelic missense variants in NDUFV1 that encodes the 51-kD subunit of complex I (NADH dehydrogenase) NDUFV1. Mapping the variants on published crystal structures of mitochondrial complex I demonstrate that the novel c.1118T > C (p.(Phe373Ser)) variant is predicted to diminish the affinity of the active pocket of NDUFV1 for FMN that correlates to an early onset of debilitating MCID symptoms. The c.1156C > T (p.(Arg386Cys)) variant is predicted to alter electron shuttling required for energy production and correlate to a disease onset in childhood. NDUFV1 c.1156C > T (p.(Arg386Cys)) represents a founder variant in South Asian populations that have value in prioritizing this variant in a population-specific manner for genetic diagnostic evaluation. In conclusion, our results demonstrate the advantage of analyzing population-specific sequences to understand the disease pathophysiology and prevalence of inherited risk variants in the underrepresented populations.
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http://dx.doi.org/10.1038/s41431-018-0209-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189076PMC
November 2018

Somatic Bi-allelic Loss of TSC Genes in Eosinophilic Solid and Cystic Renal Cell Carcinoma.

Eur Urol 2018 10 23;74(4):483-486. Epub 2018 Jun 23.

Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, Ann Arbor, MI, USA. Electronic address:

Renal cell carcinomas (RCC) with overlapping histomorphologic features poses diagnostic challenges. This is exemplified in RCCs with eosinophilic cytoplasm that include eosinophilic solid and cystic RCC (ESC RCC), RCCs in germline aberrations of tuberous sclerosis complex (TSC) genes mutated (TSC RCC) individuals, and other RCC subtypes. We used next-generation sequencing (NGS) technology to molecularly profile seven ESC RCC tumors. Mutational and copy number analysis of NGS data revealed mutually exclusively somatic bi-allelic loss of TSC1 or TSC2 genes-both negative regulators of the mammalian target of rapamycin (mTOR) pathway in 85% (6/7) of evaluated cases. Thus, lack of germline TSC aberration in matched non-neoplastic renal parenchyma distinguishes ESC RCC from TSC RCC. Immunohistochemistry data shows mTOR pathway activation in all tumors, thus supporting a pathognomonic role for TSC aberrations in ESC RCC. Our study clarifies the molecular identity of ESC RCC, provides basis for the revision of current RCC classification, and may guide future therapeutic strategies.

Patient Summary: Molecular characterization of eosinophilic solid and cystic renal cell carcinomas (ESC RCC) revealed recurrent and mutually exclusive somatic homozygous loss of tuberous sclerosis complex family genes. This observation provides greater insight into the unique biology of this novel type of tumor and potentially expands the therapeutic options for ESC RCC patients.
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http://dx.doi.org/10.1016/j.eururo.2018.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390848PMC
October 2018

Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer.

Cell 2018 06;173(7):1770-1782.e14

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

Using integrative genomic analysis of 360 metastatic castration-resistant prostate cancer (mCRPC) samples, we identified a novel subtype of prostate cancer typified by biallelic loss of CDK12 that is mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations. CDK12 loss is enriched in mCRPC relative to clinically localized disease and characterized by focal tandem duplications (FTDs) that lead to increased gene fusions and marked differential gene expression. FTDs associated with CDK12 loss result in highly recurrent gains at loci of genes involved in the cell cycle and DNA replication. CDK12 mutant cases are baseline diploid and do not exhibit DNA mutational signatures linked to defects in homologous recombination. CDK12 mutant cases are associated with elevated neoantigen burden ensuing from fusion-induced chimeric open reading frames and increased tumor T cell infiltration/clonal expansion. CDK12 inactivation thereby defines a distinct class of mCRPC that may benefit from immune checkpoint immunotherapy.
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http://dx.doi.org/10.1016/j.cell.2018.04.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084431PMC
June 2018

Clinical validation of the Tempus xO assay.

Oncotarget 2018 May 25;9(40):25826-25832. Epub 2018 May 25.

Tempus Labs, Inc., Chicago, Illinois 60654, USA.

We have developed a clinically validated NGS assay that includes tumor, germline and RNA sequencing. We apply this assay to clinical specimens and cell lines, and we demonstrate a clinical sensitivity of 98.4% and positive predictive value of 100% for the clinically actionable variants measured by the assay. We also demonstrate highly accurate copy number measurements and gene rearrangement identification.
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http://dx.doi.org/10.18632/oncotarget.25381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995233PMC
May 2018

Multi-focal sequencing of a diffuse intrinsic pontine glioma establishes PTEN loss as an early event.

NPJ Precis Oncol 2017 14;1(1):32. Epub 2017 Sep 14.

Department of Pediatrics, Division of Pediatric Hematology/Oncology, Michigan Medicine, Ann Arbor, MI 48109 USA.

Improved molecular understanding is needed for rational treatment of diffuse intrinsic pontine gliomas (DIPG). Here, using multi-focal paired tumor and germline exome DNA and RNA sequencing, we uncovered phosphatase and tensin homolog () loss as a clonal mutation in the case of a 6-year-old boy with a diffuse intrinsic pontine glioma, and incorporated copy number alteration analyses to provide a more detailed understanding of clonal evolution in diffuse intrinsic pontine gliomas. As well, using the PedcBioPortal, we found alterations in in 16 of 326 (4.9%) cases of pediatric high-grade glioma (3 of 154 (1.9%) brainstem) for which full sequencing data was available. Our data strengthens the association with loss in diffuse intrinsic pontine gliomas and provides further argument for the inclusion of in future targeted sequencing panels for pediatric diffuse intrinsic pontine gliomas and for the development and optimization of mTOR/PI3K inhibitors with optimal central nervous system penetration.
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http://dx.doi.org/10.1038/s41698-017-0033-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871904PMC
September 2017

Analysis of the androgen receptor-regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression.

Nat Genet 2018 06 28;50(6):814-824. Epub 2018 May 28.

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.

The androgen receptor (AR) plays a critical role in the development of the normal prostate as well as prostate cancer. Using an integrative transcriptomic analysis of prostate cancer cell lines and tissues, we identified ARLNC1 (AR-regulated long noncoding RNA 1) as an important long noncoding RNA that is strongly associated with AR signaling in prostate cancer progression. Not only was ARLNC1 induced by the AR protein, but ARLNC1 stabilized the AR transcript via RNA-RNA interaction. ARLNC1 knockdown suppressed AR expression, global AR signaling and prostate cancer growth in vitro and in vivo. Taken together, these data support a role for ARLNC1 in maintaining a positive feedback loop that potentiates AR signaling during prostate cancer progression and identify ARLNC1 as a novel therapeutic target.
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http://dx.doi.org/10.1038/s41588-018-0120-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980762PMC
June 2018

Clinically Integrated Sequencing Alters Therapy in Children and Young Adults With High-Risk Glial Brain Tumors.

JCO Precis Oncol 2018 4;2. Epub 2018 May 4.

University of Michigan School of Medicine, Ann Arbor, MI.

Purpose: Brain tumors have become the leading cause of cancer-related mortality in young patients. Novel effective therapies on the basis of the unique biology of each tumor are urgently needed. The goal of this study was to evaluate the feasibility, utility, and clinical impact of integrative clinical sequencing and genetic counseling in children and young adults with high-risk brain tumors.

Patients And Methods: Fifty-two children and young adults with brain tumors designated by the treating neuro-oncologist to be high risk (> 25% chance for treatment failure; mean age, 10.2 years; range, 0 to 39 years) were enrolled in a prospective, observational, consecutive case series, in which participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed in a multi-institutional brain tumor precision medicine teleconference.

Results: Sequencing revealed a potentially actionable germline or tumor alteration in 25 (63%) of 40 tumors with adequate tissue, of which 21 (53%) resulted in an impact on treatment or change of diagnosis. Platelet-derived growth factor receptor or fibroblast growth factor receptor pathway alterations were seen in nine of 20 (45%) glial tumors. Eight (20%) sequenced tumors harbored an oncogenic fusion isolated on RNA sequencing. Seventeen of 20 patients (85%) with glial tumors were found to have a potentially actionable result, which resulted in change of therapy in 14 (70%) patients. Patients with recurrent brain tumors receiving targeted therapy had a median progression-free survival (from time on therapy) of 4 months.

Conclusion: Selection of personalized agents for children and young adults with highrisk brain tumors on the basis of integrative clinical sequencing is feasible and resulted in a change in therapy in more than two thirds of children and young adults with high-risk glial tumors.
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http://dx.doi.org/10.1200/po.17.00133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434092PMC
May 2018

Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012.

J Clin Oncol 2018 04 20;36(10):991-999. Epub 2017 Dec 20.

Maha Hussain, Robert H. Lurie Comprehensive Cancer Center, Northwestern University; Walter M. Stadler, University of Chicago, Chicago; Daniel H. Shevrin, NorthShore University Health System, Evanston, IL; Maha Hussain, Stephanie Daignault-Newton, Lakshmi P. Kunju, Javed Siddiqui, Yi-Mi Wu, Dan Robinson, Robert J. Lonigro, Xuhong Cao, Scott A. Tomlins, Rohit Mehra, David C. Smith, Megan V. Caram, and Arul M. Chinnaiyan, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; Przemyslaw W. Twardowski, City of Hope Cancer Center, Duarte; Felix Y. Feng, University of California San Francisco, San Francisco, CA; Costantine Albany, Simon Cancer Center, Indiana University, Indianapolis, IN; Mark N. Stein, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ; Kathleen A. Cooney, University of Utah, Salt Lake City, UT; Bruce Montgomery, University of Washington, Seattle, WA; Emmanuel S. Antonarakis, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; Paul G. Corn, University of Texas MD Anderson Cancer Center, Houston, TX; Young E. Whang, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; and Karen E. Knudsen, Thomas Jefferson University, Philadelphia, PA.

Purpose To determine whether cotargeting poly (ADP-ribose) polymerase-1 plus androgen receptor is superior to androgen receptor inhibition in metastatic castration-resistant prostate cancer (mCRPC) and whether ETS fusions predict response. Patients and Methods Patients underwent metastatic site biopsy and were stratified by ETS status and randomly assigned to abiraterone plus prednisone without (arm A) or with veliparib (arm B). Primary objectives were: confirmed prostate-specific antigen (PSA) response rate (RR) and whether ETS fusions predicted response. Secondary objectives were: safety, measurable disease RR (mRR), progression-free survival (PFS), and molecular biomarker analysis. A total of 148 patients were randomly assigned to detect a 20% PSA RR improvement. Results A total of 148 patients with mCRPC were randomly assigned: arm A, n = 72; arm B, n = 76. There were no differences in PSA RR (63.9% v 72.4%; P = .27), mRR (45.0% v 52.2%; P = .51), or median PFS (10.1 v 11 months; P = .99). ETS fusions did not predict response. Exploratory analysis of tumor sequencing (80 patients) revealed: 41 patients (51%) were ETS positive, 20 (25%) had DNA-damage repair defect (DRD), 41 (51%) had AR amplification or copy gain, 34 (43%) had PTEN mutation, 33 (41%) had TP53 mutation, 39 (49%) had PIK3CA pathway activation, and 12 (15%) had WNT pathway alteration. Patients with DRD had significantly higher PSA RR (90% v 56.7%; P = .007) and mRR (87.5% v 38.6%; P = .001), PSA decline ≥ 90% (75% v 25%; P = .001), and longer median PFS (14.5 v 8.1 months; P = .025) versus those with wild-type tumors. Median PFS was longer in patients with normal PTEN (13.5 v 6.7 months; P = .02), TP53 (13.5 v 7.7 months; P = .01), and PIK3CA (13.8 v 8.3 months; P = .03) versus those with mutation or activation. In multivariable analysis adjusting for clinical covariates, DRD association with PFS remained significant. Conclusion Veliparib and ETS status did not affect response. Exploratory analysis identified a novel DRD association with mCRPC outcomes.
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http://dx.doi.org/10.1200/JCO.2017.75.7310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075827PMC
April 2018

Oncogenic Role of THOR, a Conserved Cancer/Testis Long Non-coding RNA.

Cell 2017 Dec;171(7):1559-1572.e20

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Large-scale transcriptome sequencing efforts have vastly expanded the catalog of long non-coding RNAs (lncRNAs) with varying evolutionary conservation, lineage expression, and cancer specificity. Here, we functionally characterize a novel ultraconserved lncRNA, THOR (ENSG00000226856), which exhibits expression exclusively in testis and a broad range of human cancers. THOR knockdown and overexpression in multiple cell lines and animal models alters cell or tumor growth supporting an oncogenic role. We discovered a conserved interaction of THOR with IGF2BP1 and show that THOR contributes to the mRNA stabilization activities of IGF2BP1. Notably, transgenic THOR knockout produced fertilization defects in zebrafish and also conferred a resistance to melanoma onset. Likewise, ectopic expression of human THOR in zebrafish accelerated the onset of melanoma. THOR represents a novel class of functionally important cancer/testis lncRNAs whose structure and function have undergone positive evolutionary selection.
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http://dx.doi.org/10.1016/j.cell.2017.11.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734106PMC
December 2017

Targeting the MYCN-PARP-DNA Damage Response Pathway in Neuroendocrine Prostate Cancer.

Clin Cancer Res 2018 02 14;24(3):696-707. Epub 2017 Nov 14.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

We investigated MYCN-regulated molecular pathways in castration-resistant prostate cancer (CRPC) classified by morphologic criteria as adenocarcinoma or neuroendocrine to extend the molecular phenotype, establish driver pathways, and identify novel approaches to combination therapy for neuroendocrine prostate cancer (NEPC). Using comparative bioinformatics analyses of CRPC-Adeno and CRPC-Neuro RNA sequence data from public data sets and a panel of 28 PDX models, we identified a MYCN-PARP-DNA damage response (DDR) pathway that is enriched in CRPC with neuroendocrine differentiation (NED) and CRPC-Neuro. ChIP-PCR assay revealed that N-MYC transcriptionally activates PARP1, PARP2, BRCA1, RMI2, and TOPBP1 through binding to the promoters of these genes. MYCN or PARP1 gene knockdown significantly reduced the expression of MYCN-PARP-DDR pathway genes and NED markers, and inhibition with MYCNsi and/or PARPsi, BRCA1si, or RMI2si significantly suppressed malignant activities, including cell viability, colony formation, and cell migration, in C4-2b4 and NCI-H660 cells. Targeting this pathway with AURKA inhibitor PHA739358 and PARP inhibitor olaparib generated therapeutic effects similar to those of gene knockdown and significantly suppressed tumor growth in both C4-2b4 and MDACC PDX144-13C subcutaneous models Our results identify a novel MYCN-PARP-DDR pathway that is driven by N-MYC in a subset of CRPC-Adeno and in NEPC. Targeting this pathway using and CRPC-Adeno and CRPC-Neuro models demonstrated a novel therapeutic strategy for NEPC. Further investigation of N-MYC-regulated DDR gene targets and the biological and clinical significance of MYCN-PARP-DDR signaling will more fully elucidate the importance of the MYCN-PARP-DDR signaling pathway in the development and maintenance of NEPC. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823274PMC
February 2018

The utility of SDHB and FH immunohistochemistry in patients evaluated for hereditary paraganglioma-pheochromocytoma syndromes.

Hum Pathol 2018 01 24;71:47-54. Epub 2017 Oct 24.

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; Comprehensive Cancer Center, Michigan Medicine, Ann Arbor, MI; Michigan Center for Translational Pathology, Ann Arbor, MI 48109. Electronic address:

A significant portion of paragangliomas (PGL) and pheochromocytomas (PCC) occur in patients with hereditary PGL/PCC syndromes, including those with germline mutations in succinate dehydrogenase (SDHx) subunit genes. Recently, germline fumarate hydratase (FH) mutations have been identified in a subset of PGL/PCC, and patients with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) may have an increased risk of developing PGL/PCC. SDHB immunohistochemistry (IHC) has previously been shown to be useful for identifying SDHx-deficient PGL/PCC, however, FH IHC has never been explored in these tumors. Thus, we characterized SDHB and FH IHC in a large cohort of PGL/PCC patients (n = 41) at our institution who were evaluated for hereditary PGL/PCC syndromes. Overall, there was strong, positive correlation between germline SDHx subunit gene mutation status and SDHB IHC status (r = 0.77; P < .0001), with high corresponding sensitivity, specificity, positive predictive value, and negative predictive value (95.0%, 81.8%, 82.6%, and 94.7%, respectively). Although SDHB loss by IHC was highly correlated with germline SDHx gene mutations, its utility in this population was dependent on clinicopathologic context: while all head and neck PGL patients with SDHB-deficient tumors had germline SDHx gene mutations, only a small subset (25.0%) of PCC patients with SDHB-deficient tumors harbored a germline SDHx gene mutation. Finally, although our cohort contained only one HLRCC patient, their tumor was FH-deficient by IHC, and all other PGL/PCC showed retained FH IHC. Thus, in the appropriate clinical setting, SDHB and FH IHC may be useful for identifying PGL/PCC patients for Medical Genetics evaluation.
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http://dx.doi.org/10.1016/j.humpath.2017.10.013DOI Listing
January 2018

Blood-brain barrier-adapted precision medicine therapy for pediatric brain tumors.

Transl Res 2017 10 10;188:27.e1-27.e14. Epub 2017 Aug 10.

University of Michigan Medical School, Ann Arbor, Mich. Electronic address:

Targeted chemotherapeutics provide a promising new treatment option in neuro-oncology. The ability of these compounds to penetrate the blood-brain barrier is crucial for their successful incorporation into patient care. "CNS Targeted Agent Prediction" (CNS-TAP) is a multi-institutional and multidisciplinary translational program established at the University of Michigan for evaluating the central nervous system (CNS) activity of targeted therapies in neuro-oncology. In this report, we present the methodology of CNS-TAP in a series of pediatric and adolescent patients with high-risk brain tumors, for which molecular profiling (academic and commercial) was sought and targeted agents were incorporated. Four of five of the patients had potential clinical benefit (partial response or stable disease greater than 6 months on therapy). We further describe the specific drug properties of each agent chosen and discuss characteristics relevant in their evaluation for therapeutic suitability. Finally, we summarize both tumor and drug characteristics that impact the ability to successfully incorporate targeted therapies into CNS malignancy management.
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http://dx.doi.org/10.1016/j.trsl.2017.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584679PMC
October 2017

Detection of 6 TFEB-amplified renal cell carcinomas and 25 renal cell carcinomas with MITF translocations: systematic morphologic analysis of 85 cases evaluated by clinical TFE3 and TFEB FISH assays.

Mod Pathol 2018 01 25;31(1):179-197. Epub 2017 Aug 25.

Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA.

Renal cell carcinomas with MITF aberrations demonstrate a wide morphologic spectrum, highlighting the need to consider these entities within the differential diagnosis of renal tumors encountered in clinical practice. Herein, we describe our experience with application of clinical fluorescence in situ hybridization (FISH) assays for detection of TFE3 and TFEB gene aberrations from 85 consecutive renal cell carcinoma cases submitted to our genitourinary FISH service. Results from 170 FISH assays performed on these tumors were correlated with available clinicopathologic findings. Ninety-eight percent of renal tumors submitted for FISH evaluation were from adult patients. Thirty-one (37%) tumors were confirmed to demonstrate MITF aberrations (21 TFE3 translocation, 4 TFEB translocation, and 6 TFEB amplification cases). Overall, renal cell carcinomas with MITF aberrations demonstrated morphologic features overlapping with clear cell, papillary, or clear cell papillary renal cell carcinomas. Renal cell carcinomas with MITF aberrations were significantly more likely to demonstrate dual (eosinophilic and clear) cytoplasmic tones (P=0.030), biphasic TFEB translocation renal cell carcinoma-like morphology (P=0.002), psammomatous calcifications (P=0.002), and nuclear pseudoinclusions (P=0.001) than renal cell carcinomas without MITF aberrations. Notably, 7/9 (78%) renal cell carcinomas exhibiting subnuclear clearing and linear nuclear array (6 of which showed high World Health Organization/International Society of Urological Pathology nucleolar grade) demonstrated TFE3 translocation, an association that was statistically significant when compared with renal cell carcinomas without MITF aberrations (P=0.009). In this cohort comprising consecutive cases, TFEB-amplified renal cell carcinomas were more commonly identified than renal cell carcinomas with TFEB translocations, and four (67%) of these previously unreported TFEB-amplified renal cell carcinomas demonstrated oncocytic and papillary features with a high World Health Organization/International Society of Urological Pathology nucleolar grade. In summary, TFE3 and TFEB FISH evaluation aids in identification and accurate classification of renal cell carcinomas with MITF aberrations, including TFEB-amplified renal cell carcinoma, which may demonstrate aggressive behavior.
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http://dx.doi.org/10.1038/modpathol.2017.99DOI Listing
January 2018