Publications by authors named "Bogdan Czerniak"

132 Publications

Prognostic markers in pT3 bladder cancer: A study from the international bladder cancer tissue microarray project.

Urol Oncol 2021 Feb 6. Epub 2021 Feb 6.

Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: We evaluated the prognostic value of 10 putative tumor markers by immunohistochemistry in a large multi-institutional cohort of patients with locally advanced urothelial cancer of the bladder (UCB) with the aim to validate their clinical value and to harmonize protocols for their evaluation.

Materials And Methods: Primary tumor specimens from 576 patients with pathologic (p)T3 UCB were collected from 24 institutions in North America and Europe. Three replicate 0.6-mm core diameter samples were collected for the construction of a tissue microarray (TMA). Immunohistochemistry (IHC) for 10 previously described tumor markers was performed and scored at 3 laboratories independently according to a standardized protocol. Associations between marker positivity and freedom from recurrence (FFR) or overall survival (OS) were analyzed separately for each individual laboratory using Cox regression analysis.

Results: The overall agreement of the IHC scoring among laboratories was poor. Correlation among the 3 laboratories varied across the 10 markers. There was generally a lack of association between the individual markers and FFR or OS. The number of altered cell cycle regulators (p53, Rb, and p21) was associated with increased risk of cancer recurrence (P < 0.032). There was no clear pattern in the relationship between the percentage of markers altered in an 8-marker panel and FFR or OS.

Conclusions: This large international TMA of locally advanced (pT3) UCB suggests that altered expression of p53, Rb, and p21 is associated with worse outcome. However this study also highlights limitations in the reproducibility of IHC even in the most expert hands.
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http://dx.doi.org/10.1016/j.urolonc.2021.01.021DOI Listing
February 2021

Total Tibial Allograft Reconstruction for Adamantinoma: A Case Report With 2-Year Follow-up.

JBJS Case Connect 2020 12 21;10(4):e20.00046. Epub 2020 Dec 21.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

Case: A 47-year-old woman with adamantinoma of the entire left tibia and distal fibula underwent resection and reconstruction using a total tibia allograft-prosthetic composite with rotating hinged knee replacement and ankle fusion. She is ambulating without tumor recurrence with 2-year follow-up.

Conclusion: This case report offers a unique reconstruction option for extensive tibia bone primary malignancy. To our knowledge, this is the longest survival for total tibia allograft prosthetic composite reconstruction.
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http://dx.doi.org/10.2106/JBJS.CC.20.00046DOI Listing
December 2020

Inhibition of the CCL2 receptor, CCR2, enhances tumor response to immune checkpoint therapy.

Commun Biol 2020 Nov 27;3(1):720. Epub 2020 Nov 27.

Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.

Immunotherapies targeting the PD-1/PD-L1 axis are now a mainstay in the clinical management of multiple cancer types, however, many tumors still fail to respond. CCL2 is highly expressed in various cancer types and has been shown to be associated with poor prognosis. Inhibition or blockade of the CCL2/CCR2 signaling axis has thus been an area of interest for cancer therapy. Here we show across multiple murine tumor and metastasis models that CCR2 antagonism in combination with anti-PD-1 therapy leads to sensitization and enhanced tumor response over anti-PD-1 monotherapy. We show that enhanced treatment response correlates with enhanced CD8 T cell recruitment and activation and a concomitant decrease in CD4 regulatory T cell. These results provide strong preclinical rationale for further clinical exploration of combining CCR2 antagonism with PD-1/PD-L1-directed immunotherapies across multiple tumor types especially given the availability of small molecule CCR2 inhibitors and antibodies.
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http://dx.doi.org/10.1038/s42003-020-01441-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699641PMC
November 2020

Secondary tumors of the bladder: A survival outcome study.

Ann Diagn Pathol 2020 Oct 14;48:151593. Epub 2020 Aug 14.

University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

The urinary bladder may be involved by a variety of secondary tumors that originate from other organs. Bladder secondary tumors are rare and may be mistaken as bladder primary tumors because of their overlapping morphologic features. To avoid the diagnostic pitfalls, we analyzed the clinicopathologic features of bladder secondary tumors in a large cohort of patients. Our patient cohort consisted of 45 females and 38 males with a mean age of 58.7 ± 15.4 years (range 10-87 years). The tumors involved the bladder via direct extension from adjacent organs (n = 42) and distant metastasis (n = 41). In females, the majority of secondary tumors originated from the gynecologic tract (n = 25), and other common origins included the colon/rectum (n = 5) and breast (n = 4). In males, the most common origin was the prostate (n = 18), followed by the colon/rectum (n = 4) and kidney (n = 3). 75.9% of the secondary tumors were adenocarcinoma (n = 63), and other common tumor types included sarcoma (n = 6), squamous cell carcinoma (n = 5), melanoma (n = 4), and neuroendocrine carcinoma (n = 3). 67.5% of patients (n = 56) died of the disease with a median overall survival of 23 months from the time of secondary involvement of the bladder. Patients with secondary tumors via direct extension had a median survival time of 20 months, which was not significantly different from that for patients with secondary involvement via distant metastasis (24 months) (p = 0.83). Median survival in cases with prostate primary was 20 months as compared to 23 months for all other tumor types (p = 0.68). The majority of secondary tumors are composed of adenocarcinoma, which highlights the importance of differentiating primary from secondary involvement in bladder adenocarcinoma. Regardless of the origin, bladder secondary tumors are associated with a poor prognosis.
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http://dx.doi.org/10.1016/j.anndiagpath.2020.151593DOI Listing
October 2020

Assessment of Luminal and Basal Phenotypes in Bladder Cancer.

Sci Rep 2020 06 16;10(1):9743. Epub 2020 Jun 16.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Genomic profiling studies have demonstrated that bladder cancer can be divided into two molecular subtypes referred to as luminal and basal with distinct clinical behaviors and sensitivities to frontline chemotherapy. We analyzed the mRNA expressions of signature luminal and basal genes in bladder cancer tumor samples from publicly available and MD Anderson Cancer Center cohorts. We developed a quantitative classifier referred to as basal to luminal transition (BLT) score which identified the molecular subtypes of bladder cancer with 80-94% sensitivity and 83-93% specificity. In order to facilitate molecular subtyping of bladder cancer in primary care centers, we analyzed the protein expressions of signature luminal (GATA3) and basal (KRT5/6) markers by immunohistochemistry, which identified molecular subtypes in over 80% of the cases. In conclusion, we provide a tool for assessment of molecular subtypes of bladder cancer in routine clinical practice.
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http://dx.doi.org/10.1038/s41598-020-66747-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298008PMC
June 2020

Urothelial-to-Neural Plasticity Drives Progression to Small Cell Bladder Cancer.

iScience 2020 Jun 27;23(6):101201. Epub 2020 May 27.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

We report a comprehensive molecular analysis of 34 cases of small cell carcinoma (SCC) and 84 cases of conventional urothelial carcinoma (UC), with The Cancer Genome Atlas cohort of 408 conventional UC bladder cancers used as the reference. SCCs showed mutational landscapes characterized by nearly uniform inactivation of TP53 and were dominated by Sanger mutation signature 3 associated with loss of BRCA1/2 function. SCCs were characterized by downregulation of luminal and basal markers and were referred to as double-negative. Transcriptome analyses indicated that SCCs displayed lineage plasticity driven by a urothelial-to-neural phenotypic switch with a dysregulated epithelial-to-mesenchymal transition network. SCCs were depleted of immune cells, and expressed high levels of the immune checkpoint receptor, adenosine receptor A2A (ADORA2A), which is a potent inhibitor of immune infiltration. Our observations have important implications for the prognostication and development of more effective therapies for this lethal bladder cancer variant.
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http://dx.doi.org/10.1016/j.isci.2020.101201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286965PMC
June 2020

Bladder Cancer Involving Smooth Muscle of Indeterminate Type or Muscularis Mucosae in Transurethral Biopsy Specimens.

Am J Clin Pathol 2020 07;154(2):208-214

Departments of Pathology, The University of Texas MD Anderson Cancer Center, Houston.

Objectives: Bladder cancers invading the muscularis mucosae (MM) are treated differently from those invading the muscularis propria (MP). However, it may be difficult to determine the type of smooth muscle in transurethral resection (TUR) or biopsy specimens. We aimed to investigate the clinicopathologic features of bladder cancers involving smooth muscle of indeterminate type (SMIT) in TUR specimens in comparison with those invading the MM.

Methods: We identified 103 patients with bladder cancer involving SMIT (n = 27) or the MM (n = 76) in TUR specimens. All patients underwent subsequent restaging TUR or cystectomy.

Results: Bladder cancer with SMIT invasion showed a significantly higher rate of MP invasion in the subsequent specimens than those invading the MM (52% vs 29%). Lack of MP in the TUR specimens had a significantly higher risk of MP invasion in the subsequent specimens than those with the MP (61% vs 40%). The overall survival time for patients with SMIT invasion was significantly shorter than those with MM invasion.

Conclusions: Bladder cancers with SMIT invasion in TUR specimens show more frequent cancer upstaging in the subsequent specimens and a poorer clinical outcome than those invading the MM, which highlights the importance of a cancer restaging procedure for these patients.
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http://dx.doi.org/10.1093/ajcp/aqaa030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768762PMC
July 2020

TCF21 Promotes Luminal-Like Differentiation and Suppresses Metastasis in Bladder Cancer.

Mol Cancer Res 2020 06 2;18(6):811-821. Epub 2020 Mar 2.

Department of Urology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Little is known regarding the subclone evolution process in advanced bladder cancer, particularly with respect to the genomic alterations that lead to the development of metastatic lesions. In this project, we identify gene expression signatures associated with metastatic bladder cancer through mRNA expression profiling of RNA isolated from 33 primary bladder cancer and corresponding lymph node (LN) metastasis samples. Gene expression profiling (GEP) was performed on RNA isolated using the Illumina DASL platform. We identified the developmental transcription factor TCF21 as being significantly higher in primary bladder cancer compared with LN metastasis samples. To elucidate its function in bladder cancer, loss- and gain-of-function experiments were conducted in bladder cancer cell lines with high and low expression of TCF21, respectively. We also performed GEP in bladder cancer cell lines following TCF21 overexpression. We identified 2,390 genes differentially expressed in primary bladder cancer and corresponding LN metastasis pairs at an FDR cutoff of 0.1 and a fold change of 1. Among those significantly altered, expression of TCF21 was higher in the primary tumor compared with LN metastasis. We validated this finding with qPCR and IHC on patient samples. Moreover, TCF21 expression was higher in luminal cell lines and knockdown of TCF21 increased invasion, tumor cell dissemination, and metastasis. In contrast, overexpression of TCF21 in highly metastatic basal bladder cancer cell lines decreased their invasive and metastatic potential. IMPLICATIONS: TCF21 is differentially overexpressed in primary bladder cancer compared with matched LN metastasis, with and studies demonstrating a metastasis suppressor function of this transcription factor.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0766DOI Listing
June 2020

Cardiac paragangliomas: A case series with clinicopathologic features and succinate dehydrogenase B immunostaining.

Ann Diagn Pathol 2020 Apr 5;45:151477. Epub 2020 Feb 5.

Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Weill Medical College of Cornell University, New York, NY 10065, USA. Electronic address:

Cardiac paragangliomas (PGs) are very rare tumors that comprise less than 1% of all cardiac tumors. PGs can occur sporadically, but inherited syndromes may also play a role in the development of PGs. Approximately one-third of PGs are associated with mutations in the succinate dehydrogenase (SDH) complex, specifically SDHB, as part of syndrome-associated PGs or sporadic PGs. SDH mutations have been assessed by SDHB immunohistochemistry, as negative staining indicates a high likelihood of mutation in PGs in other sites, but not in cardiac PGs. This study aims to evaluate the clinical and pathologic characteristic of cardiac PG cases and assess the expression of SDHB by immunohistochemistry. A retrospective chart analysis of 10 patients with cardiac PG was performed to assess the patient age, sex, size, site of the tumor, and clinical symptoms. Histologically the tumors showed the classic pattern of nested tumor cells surrounded by sustentacular cells. Immunohistochemistry for SDHB was performed in five cases. One case showed a complete absence of SDHB immunohistochemical staining and the others showed staining ranging from a weak-to-strong granular cytoplasmic staining pattern. We conclude that SDHB immunostaining is cost-effective in identifying cases with SDH mutation. It is recommended to assess SDH mutation in patients with cardiac PG to predict the aggressive behavior that has been reported by previous studies from PGs of other sites.
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http://dx.doi.org/10.1016/j.anndiagpath.2020.151477DOI Listing
April 2020

Time-to-progression after front-line fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy for chronic lymphocytic leukaemia: a retrospective, multicohort study.

Lancet Oncol 2019 11 30;20(11):1576-1586. Epub 2019 Sep 30.

Department of Pathology, The Ohio State University, Columbus, OH, USA. Electronic address:

Background: Fludarabine, cyclophosphamide, and rituximab (FCR) has become a gold-standard chemoimmunotherapy regimen for patients with chronic lymphocytic leukaemia. However, the question remains of how to treat treatment-naive patients with IGHV-unmutated chronic lymphocytic leukaemia. We therefore aimed to develop and validate a gene expression signature to identify which of these patients are likely to achieve durable remissions with FCR chemoimmunotherapy.

Methods: We did a retrospective cohort study in two cohorts of treatment-naive patients (aged ≥18 years) with chronic lymphocytic leukaemia. The discovery and training cohort consisted of peripheral blood samples collected from patients treated at the University of Texas MD Anderson Cancer Center (Houston, TX, USA), who fulfilled the diagnostic criteria of the International Workshop on Chronic Lymphocytic Leukemia, had received at least three cycles of FCR chemoimmunotherapy, and had been treated between Oct 10, 2000, and Oct 26, 2006 (ie, the MDACC cohort). We did transcriptional profiling on samples obtained from the MDACC cohort to identify genes associated with time to progression. We did univariate Cox proportional hazards analyses and used significant genes to cluster IGHV-unmutated samples into two groups (intermediate prognosis and unfavourable prognosis). After using cross-validation to assess robustness, we applied the Lasso method to standardise the gene expression values to find a minimum gene signature. We validated this signature in an external cohort of treatment-naive patients with IGHV-unmutated chronic lymphocytic leukaemia enrolled on the CLL8 trial of the German Chronic Lymphocytic Leukaemia Study Group who were treated between July 21, 2003, and April 4, 2006 (ie, the CLL8 cohort).

Findings: The MDACC cohort consisted of 101 patients and the CLL8 cohort consisted of 109 patients. Using the MDACC cohort, we identified and developed a 17-gene expression signature that distinguished IGHV-unmutated patients who were likely to achieve a long-term remission following front-line FCR chemoimmunotherapy from those who might benefit from alternative front-line regimens (hazard ratio 3·83, 95% CI 1·94-7·59; p<0·0001). We validated this gene signature in the CLL8 cohort; patients with an unfavourable prognosis versus those with an intermediate prognosis had a cause-specific hazard ratio of 1·90 (95% CI 1·18-3·06; p=0·008). Median time to progression was 39 months (IQR 22-69) for those with an unfavourable prognosis compared with 59 months (28-84) for those with an intermediate prognosis.

Interpretation: We have developed a robust, reproducible 17-gene signature that identifies a subset of treatment-naive patients with IGHV-unmutated chronic lymphocytic leukaemia who might substantially benefit from treatment with FCR chemoimmunotherapy. We recommend testing the value of this gene signature in a prospective study that compares FCR treatment with newer alternative therapies as part of a randomised clinical trial.

Funding: Chronic Lymphocytic Leukaemia Global Research Foundation and the National Institutes of Health/National Cancer Institute.
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http://dx.doi.org/10.1016/S1470-2045(19)30503-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147008PMC
November 2019

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer.

Cell Rep 2019 05;27(6):1781-1793.e4

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.
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http://dx.doi.org/10.1016/j.celrep.2019.04.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546434PMC
May 2019

Whole-Organ Genomic Characterization of Mucosal Field Effects Initiating Bladder Carcinogenesis.

Cell Rep 2019 02;26(8):2241-2256.e4

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

We used whole-organ mapping to study the locoregional molecular changes in a human bladder containing multifocal cancer. Widespread DNA methylation changes were identified in the entire mucosa, representing the initial field effect. The field effect was associated with subclonal low-allele frequency mutations and a small number of DNA copy alterations. A founder mutation in the RNA splicing gene, ACIN1, was identified in normal mucosa and expanded clonally with an additional 21 mutations in progression to carcinoma. The patterns of mutations and copy number changes in carcinoma in situ and foci of carcinoma were almost identical, confirming their clonal origins. The pathways affected by the DNA copy alterations and mutations, including the Kras pathway, were preceded by the field changes in DNA methylation, suggesting that they reinforced mechanisms that had already been initiated by methylation. The results demonstrate that DNA methylation can serve as the initiator of bladder carcinogenesis.
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http://dx.doi.org/10.1016/j.celrep.2019.01.095DOI Listing
February 2019

Outcomes of nonmetastatic micropapillary variant upper tract urothelial carcinoma.

Urol Oncol 2019 06 16;37(6):354.e19-354.e26. Epub 2019 Feb 16.

Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Purpose: Micropapillary variant upper tract urothelial cancer (MP-UTUC) is a rare malignancy with little known regarding its clinical course and/or optimal treatment. In this case series, we describe patient characteristics, surgical treatment, oncologic outcomes, and response to perioperative chemotherapy.

Materials And Methods: We conducted a review to identify patients with MP-UTUC treated at our center between January 1994 and October 2017. Clinicopathologic data was obtained. Descriptive statistics, Kaplan-Meier analysis, Cox proportional hazards, and nearest neighbor matching were used to examine the cohort.

Results: Eighteen, (4.3%) of 416 patients were found to have MP-UTUC at our institution over a 23-year period. The majority of patients had ≥pT3 disease at the time of extirpative surgery (13/18, 72%) and one was identified as MP-UTUC prior to surgery. Seven patients received neoadjuvant chemotherapy and six patients received adjuvant chemotherapy. Median overall, cancer specific, and recurrence free survival were 3.29, 3.29, and 1.69 years, respectively for MP-UTUC. There was no survival difference between conventional UTUC and MP-UTUC when matched for age, stage, grade, lymphovascular invasion, and margins (HR 1.18, P = 0.567). No MP-UTUC patients receiving neoadjuvant and adjuvant chemotherapy had apparent pathologic down staging, and of those receiving adjuvant chemotherapy two-thirds died of disease within 2 years.

Conclusions: MP-UTUC is a rare, and in most cases aggressive malignancy that commonly presents as locally advanced disease. In this case series, MP-UTUC does not appear to respond to perioperative chemotherapy as neoadjuvant and adjuvant chemotherapy did not result in apparent pathologic down staging and the majority of those receiving adjuvant chemotherapy died from MP-UTUC.
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http://dx.doi.org/10.1016/j.urolonc.2019.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511295PMC
June 2019

Bladder Cancer in the Genomic Era.

Arch Pathol Lab Med 2019 06 23;143(6):695-704. Epub 2019 Jan 23.

From the Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston.

Context.—: Bladder cancer is a heterogeneous disease that exhibits a wide spectrum of clinical and pathologic features. The classification of bladder cancer has been traditionally based on morphologic assessment with the aid of immunohistochemistry. However, recent genomic studies have revealed that distinct alterations of DNA and RNA in bladder cancer may underlie its diverse clinicopathologic features, leading to a novel molecular classification of this common human cancer.

Objective.—: To update recent developments in genomic characterization of bladder cancer, which may shed insights on the molecular mechanisms underlying the origin of bladder cancer, dual-track oncogenic pathways, intrinsic molecular subtyping, and development of histologic variants.

Data Sources.—: Peer-reviewed literature retrieved from PubMed search and authors' own research.

Conclusions.—: Bladder cancer is likely to arise from different uroprogenitor cells through papillary/luminal and nonpapillary/basal tracks. The intrinsic molecular subtypes of bladder cancer referred to as and exhibit distinct expression signatures, clinicopathologic features, and sensitivities to standard chemotherapy. Genomic characterization of bladder cancer provides new insights to understanding the biological nature of this complex disease, which may lead to more effective treatment.
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http://dx.doi.org/10.5858/arpa.2018-0329-RADOI Listing
June 2019

Urine cell-based DNA methylation classifier for monitoring bladder cancer.

Clin Epigenetics 2018 30;10:71. Epub 2018 May 30.

2Laboratory and Department of Urology, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain.

Background: Current standard methods used to detect and monitor bladder cancer (BC) are invasive or have low sensitivity. This study aimed to develop a urine methylation biomarker classifier for BC monitoring and validate this classifier in patients in follow-up for bladder cancer (PFBC).

Methods: Voided urine samples ( = 725) from BC patients, controls, and PFBC were prospectively collected in four centers. Finally, 626 urine samples were available for analysis. DNA was extracted from the urinary cells and bisulfite modificated, and methylation status was analyzed using pyrosequencing. Cytology was available from a subset of patients ( = 399). In the discovery phase, seven selected genes from the literature (, , , , , , and ) were studied in 111 BC and 57 control samples. This training set was used to develop a gene classifier by logistic regression and was validated in 458 PFBC samples (173 with recurrence).

Results: A three-gene methylation classifier containing , , and was developed in the training set (AUC 0.874). The classifier achieved an AUC of 0.741 in the validation series. Cytology results were available for 308 samples from the validation set. Cytology achieved AUC 0.696 whereas the classifier in this subset of patients reached an AUC 0.768. Combining the methylation classifier with cytology results achieved an AUC 0.86 in the validation set, with a sensitivity of 96%, a specificity of 40%, and a positive and negative predictive value of 56 and 92%, respectively.

Conclusions: The combination of the three-gene methylation classifier and cytology results has high sensitivity and high negative predictive value in a real clinical scenario (PFBC). The proposed classifier is a useful test for predicting BC recurrence and decrease the number of cystoscopies in the follow-up of BC patients. If only patients with a positive combined classifier result would be cystoscopied, 36% of all cystoscopies can be prevented.
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http://dx.doi.org/10.1186/s13148-018-0496-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975622PMC
May 2019

Small cell carcinoma of the urinary bladder: a clinicopathological and immunohistochemical analysis of 81 cases.

Hum Pathol 2018 09 12;79:57-65. Epub 2018 May 12.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. Electronic address:

Small cell carcinoma (SmCC) of the bladder is a rare disease. We retrospectively studied a large series of bladder SmCC from a single institution. The patients included 69 men and 12 women with a mean age of 68 years. Most bladder SmCCs were presented at advanced stage, with tumors invading the muscularis propria and beyond (n = 77). SmCC was pure in 27 cases and mixed with other histologic types in 54 cases, including urothelial carcinoma (UC) (n = 32), UC in situ (n = 26), glandular (n = 14), micropapillary (n = 4), sarcomatoid (n = 4), squamous (n = 3), and plasmacytoid (n = 1) features. Most SmCCs expressed neuroendocrine markers synaptophysin (41/56), chromogranin (26/55), and CD56 (39/41); however, they did not express UC luminal markers CK20 (0/17), GATA3 (1/30), and uroplakin II (1/22). Some SmCCs showed focal expression of CK5/6 (9/25), a marker for the basal molecular subtype. Furthermore, expression of the retinoblastoma 1 (RB1) gene protein was lost in most of the bladder SmCCs (2/23). The patients' survival was significantly associated with cancer stage but did not show a significant difference between mixed and pure SmCCs. Compared with conventional UC at similar stages, SmCC had a worse prognosis only when patients developed metastatic diseases. In conclusion, bladder SmCC is an aggressive disease that is frequently present at an advanced stage. A fraction of SmCCs show a basal molecular subtype, which may underlie its good response to chemotherapy. Inactivation of the RB1 gene may be implicated in the oncogenesis of bladder SmCC.
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http://dx.doi.org/10.1016/j.humpath.2018.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133751PMC
September 2018

Detection of Bladder Cancer in Urine Sediments by a Novel Multicolor Fluorescence In Situ Hybridization (Quartet) Test.

Eur Urol Focus 2019 07 7;5(4):664-675. Epub 2018 Feb 7.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Background: Bladder cancer is among the common human malignancies that show a heavy mutational load and copy number variations of numerous chromosomes, which makes them a target for diagnostic explorations.

Objective: We aimed to design a multicolor fluorescence in situ hybridization (FISH) test referred to as the quartet test for the detection of bladder cancer in urine.

Design, Setting, And Participants: We performed genome-wide copy number variation analysis on cohorts from the University of Texas MD Anderson Cancer Center (n=40) and The Cancer Genome Atlas (n=129), and identified the most frequently amplified chromosomal regions. These data were used to select four of the amplified regions to design a multicolor FISH test, referred to as the quartet test. Assay validation was performed on urine samples from 98 patients with bladder cancer: 56 with low-grade papillary, 42 with high-grade invasive disease, and 48 benign controls.

Intervention: The quartet test can be used in clinical practice for noninvasive detection of bladder cancer.

Outcome Measurements And Statistical Analysis: We initially analyzed samples using a fraction of abnormal cell scores and then by the quantitative score, which included not only the proportion of cells with abnormal copy numbers, but also the proportion of cells with numbers of altered copies and degree of amplification. We used receiver operator characteristic (ROC) curves to identify cutoff values for the scores at which performances of sensitivity and specificity were maximized.

Results And Limitations: The copy number status assessed by probes detected in voided urine reflected the amplification status of the primary tumor. An ROC curve summarizing the proportion of assayed cells with any abnormal copy numbers gave specificity of 93.8% and sensitivity of 78.6% using the proportion of cells with abnormal copy numbers. The quantitative score giving extra weight to cells with multiple simultaneous amplifications provided 95.8% specificity and 76.8% sensitivity. Both percentage of abnormal cells and quantitative scores were highly effective for assessing the grade of the tumor. The full spectrum of potential clinical applications was not explored in the current study, and further validation studies are needed.

Conclusions: The quartet test shows promising specificity and sensitivity results, but it requires validation on a larger multi-institutional cohort of samples.

Patient Summary: The quartet test can be used for noninvasive detection of bladder cancer in voided urine. It can also be used to assess the grade of the tumor and tumor recurrence as well as post-treatment effects.
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http://dx.doi.org/10.1016/j.euf.2018.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081265PMC
July 2019

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer.

Cell 2017 Oct 5;171(3):540-556.e25. Epub 2017 Oct 5.

Scott Department of Urology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.
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http://dx.doi.org/10.1016/j.cell.2017.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687509PMC
October 2017

Carcinoma of the urethra.

Hum Pathol 2018 02 18;72:35-44. Epub 2017 Aug 18.

Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States. Electronic address:

Primary carcinomas of the urethra are rare and poorly understood lesions; hence, their clinical and pathologic spectrum is not completely defined. We analyzed a series of 130 primary urethral tumors and classified 106 of them as primary urethral carcinomas. The age at diagnosis of patients with primary urethral carcinomas ranged from 42 to 97 years (mean, 69.4 years; median, 70 years). There were 73 male and 33 female patients with a ratio of 2.2:1. In male patients, the tumors most frequently developed in the bulbous-membranous segment of the urethra. In female patients, the entire length of the urethra was typically involved. Microscopically, they were poorly differentiated carcinomas with hybrid squamous and urothelial features and developed from precursor intraepithelial conditions such as dysplasia and carcinoma in situ, which were frequently present in the adjacent urethral mucosa. High-risk human papilloma virus infection could be documented in 31.6% of these tumors. Follow-up information was available for 95 patients. Twenty-three patients died of the disease with a mean and median survival of 39 and 21 months, respectively. Urethral carcinomas are aggressive tumors with a high propensity for regional and distant metastases with mean and median survival of 39 and 21 months, respectively. Our observations have important implications for the management of patients with primary carcinoma of the urethra by defining them as a unique entity linked to human papilloma virus infection.
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http://dx.doi.org/10.1016/j.humpath.2017.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975388PMC
February 2018

High-grade neuroendocrine carcinoma of the urachus-report of 3 cases.

Hum Pathol 2017 09 18;67:126-133. Epub 2017 Aug 18.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

Most urachal malignancies are composed of pure adenocarcinoma with mucin production. Urachal neuroendocrine carcinoma (NEC) is extremely rare, with only a few cases reported in the literature. Here we report 3 cases of urachal NEC, the largest series of this rare disease from a single institution. The patients were young, with a mean age of 27 years (range, 23-34). The urachal tumors showed 2 distinct components: high-grade NEC and enteric-type adenocarcinoma. The urachal NECs were composed of small cell carcinoma (n=2) or large cell NEC (n=1). The subsequent resection specimens showed that all the tumors were at advanced Sheldon stages. All 3 patients developed metastases, which were composed of NEC exclusively. Two patients died from disease in 10 and 31 months, respectively, and the third patient was alive with widespread metastases at 21 months. Our findings suggest that urachal NEC is an aggressive variant with an overwhelming growth advantage over conventional adenocarcinoma. The presence of high-grade NEC in the urachus is associated with poor prognosis.
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http://dx.doi.org/10.1016/j.humpath.2017.08.003DOI Listing
September 2017

Impact of High-risk Features and Effect of Neoadjuvant Chemotherapy in Urothelial Cancer Patients with Invasion into the Lamina Propria on Transurethral Resection in the Absence of Deep Muscle Invasion.

Eur Urol Focus 2017 12 13;3(6):577-583. Epub 2017 Jul 13.

Departments of Urology at the University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Electronic address:

Background: High-risk non-muscle-invasive bladder cancer (NMIBC) that invades into the lamina propria is frequently understaged and is associated with a risk of lymph node metastasis and death.

Objective: To identify high-risk features (HRFs) for NMIBC that may identify patients with poorer prognosis who may benefit from neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC).

Design, Setting, And Participants: We performed a single-center retrospective review of patients who underwent RC for NMIBC with invasion into the lamina propria between 1995 and 2013. HRFs included hydronephrosis, abnormal examination under anesthesia, lymphovascular invasion, or variant histology.

Outcome Measurements And Statistical Analysis: Pathology at RC, and overall (OS) and disease-specific (DSS) survival were evaluated and analyzed by Fisher's exact test, Student t test, Cox proportional hazards regression analysis, and the Kaplan-Meier method.

Results And Limitations: We identified 336 patients with a median follow-up of 130 mo. Of these, 159 (47%) had no HRF, 140 (41.5%) had one HRF, and 37 (11%) had ≥2 HRFs. At RC, patients with ≥2 HRFs had a significantly higher rate of pathologic T stage upstaging and lymph node metastasis (p<0.05). Median OS was 139 mo for those with no HRF, 127 mo for those with one HRF, and 56 mo for those with ≥2 HRF (p=0.0057). HRFs are also associated with a decreased DSS (p=0.0009). Patients with ≥2 HRFs (11/37) who received NAC showed improved OS (21% vs 55% 5-yr OS, p=0.0353) and trended toward an improvement in DSS (25% vs 56% 5-yr OS, p=0.0716) compared with RC alone.

Conclusions: The presence of ≥2 HRFs in NMIBC invading the lamina propria is associated with worse pathology at RC and a significant decrease in OS and DSS. NAC appears to provide benefit for these patients. Limitations include retrospective design and limited sample size.

Patient Summary: The presence of high-risk features in urothelial cancer with invasion into the lamina propria has a worse prognosis that may be mitigated by neoadjuvant chemotherapy.
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http://dx.doi.org/10.1016/j.euf.2017.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767145PMC
December 2017

Sarcomatoid Renal Cell Carcinoma Has a Distinct Molecular Pathogenesis, Driver Mutation Profile, and Transcriptional Landscape.

Clin Cancer Res 2017 Nov 14;23(21):6686-6696. Epub 2017 Jul 14.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Sarcomatoid renal cell carcinoma (SRCC) ranks among the most aggressive clinicopathologic phenotypes of RCC. However, the paucity of high-quality, genome-wide molecular examinations of SRCC has hindered our understanding of this entity. We interrogated the mutational, copy number, and transcriptional characteristics of SRCC and compared these data with those of nonsarcomatoid RCC (RCC). We evaluated whole-exome sequencing, single-nucleotide polymorphism, and RNA sequencing data from patients with SRCC ( = 65) and RCC ( = 598) across different parent RCC subtypes, including clear-cell RCC, papillary RCC, and chromophobe RCC subtypes. SRCC was molecularly discrete from RCC and clustered according to its parent RCC subtype, though with upregulation of TGFβ signaling across all subtypes. The epithelioid (E-) and spindled (S-) histologic components of SRCC did not show differences in mutational load among cancer-related genes despite a higher mutational burden in S-. Notably, sarcomatoid clear-cell RCC (SccRCC) showed significantly fewer deletions at 3p21-25, a lower rate of two-hit loss for and , and more mutations in , , and compared with ccRCC. A two-hit loss involving predicted for ccRCC and a better prognosis, whereas mutations in , , or predicted for SccRCC and worse prognosis. SRCC segregates by parent subtype, and SccRCC has a fundamentally different early molecular pathogenesis, usually lacking the classic 3p21-25 deletion and showing distinctive mutational and transcriptional profiles. These features prompt a more precise molecular classification of RCC, with diagnostic, prognostic, and therapeutic implications. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683086PMC
November 2017

Comprehensive Genomic Characterization of Upper Tract Urothelial Carcinoma.

Eur Urol 2017 10 7;72(4):641-649. Epub 2017 Jun 7.

Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Background: Upper urinary tract urothelial cancer (UTUC) may have unique etiologic and genomic factors compared to bladder cancer.

Objective: To characterize the genomic landscape of UTUC and provide insights into its biology using comprehensive integrated genomic analyses.

Design, Setting, And Participants: We collected 31 untreated snap-frozen UTUC samples from two institutions and carried out whole-exome sequencing (WES) of DNA, RNA sequencing (RNAseq), and protein analysis.

Outcome Measurements And Statistical Analysis: Adjusting for batch effects, consensus mutation calls from independent pipelines identified DNA mutations, gene expression clusters using unsupervised consensus hierarchical clustering (UCHC), and protein expression levels that were correlated with relevant clinical variables, The Cancer Genome Atlas, and other published data.

Results And Limitations: WES identified mutations in FGFR3 (74.1%; 92% low-grade, 60% high-grade), KMT2D (44.4%), PIK3CA (25.9%), and TP53 (22.2%). APOBEC and CpG were the most common mutational signatures. UCHC of RNAseq data segregated samples into four molecular subtypes with the following characteristics. Cluster 1: no PIK3CA mutations, nonsmokers, high-grade
Conclusions: Mutations in UTUC occur at differing frequencies from bladder cancer, with four unique molecular and clinical subtypes. A novel SH3KBP1 fusion regulates RTK signaling. Further studies are needed to validate the described subtypes, explore their responses to therapy, and better define the novel fusion mutation.

Patient Summary: We conducted a comprehensive study of the genetics of upper urinary tract urothelial cancer by evaluating DNA, RNA and protein expression in 31 tumors. We identified four molecular subtypes with distinct behaviors. Future studies will determine if these subtypes appear to have different responses to treatments.
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http://dx.doi.org/10.1016/j.eururo.2017.05.048DOI Listing
October 2017

Primary Ewing Sarcoma / Primitive Neuroectodermal Tumor of the Kidney: A Clinicopathologic Study of 23 Cases.

Pathol Oncol Res 2018 Jan 20;24(1):153-159. Epub 2017 Apr 20.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Primary Ewing sarcoma / primitive neuroectodermal tumor (ES) of the kidney is a rare neoplasm with limited clinicopathologic data. We report 23 such cases with no history of ES elsewhere in the body. The patients included 13 male and 10 female, aged 8-70 years (mean, 31 years). The average tumor size was 11.7 cm (range, 5-20 cm). Microscopic analysis showed predominantly lobular growth (n = 14), with focal papillary (n = 3), alveolar (n = 1), and hemangiopericytoma-like (n = 1) patterns. Several tumors (n = 11) exhibited robust mitotic activity (>10 mitoses/10 high-power fields). Necrosis (n = 13) and lymphovascular invasion (n = 14) were common. Homer Wright rosettes (n = 6) and perivascular pseudorosettes (n = 1) were also identified. The tumors invaded the renal sinus or perinephric fat (n = 11), renal vein (n = 13), and adrenal gland (n = 2). Molecular and fluorescence in situ hybridization analysis showed rearrangement of EWSR1 gene (10/10), associated with EWSR1-FLI1 gene fusion (7/10). All patients with follow-up information (n = 18) had metastasis, commonly in the lungs (n = 12) and bone (n = 6). Twelve patients died of disease in a mean of 21 months; 6 patients were alive at a mean of 49 months after diagnosis. Primary kidney ES usually present at an advanced stage with extrarenal spread and metastasis. Although renal ES share histologic, immunohistochemical, and molecular features with their bone and soft tissue counterparts, they appear to be more aggressive tumors with poorer clinical outcome.
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http://dx.doi.org/10.1007/s12253-017-0228-0DOI Listing
January 2018

Plasmacytoid Urothelial Carcinoma of the Urinary Bladder: A Clinicopathologic and Immunohistochemical Analysis of 49 Cases.

Am J Clin Pathol 2017 May;147(5):500-506

Departments of Pathology.

Objectives: Plasmacytoid urothelial carcinoma (PUC) of the bladder is a rare histologic variant. We retrospectively analyzed a large series of bladder PUC from a single institution.

Methods: The patients consisted of 44 men and five women with a mean age of 62 years (range, 45-86 years).

Results: PUC was pure in 23 cases and mixed with other histologic types in 26 cases. All PUCs diffusely invaded the bladder wall. Most PUCs lacked immunoreactivity for the retinoblastoma (RB) gene protein (12/32) and E-cadherin (8/30). Of the 44 patients with follow-up information, 25 died of PUC at a mean of 23 months, whereas 19 patients were alive at a mean of 22 months.

Conclusions: Our findings support that bladder PUC is a highly aggressive disease. The lack of E-cadherin expression in PUCs may underlie the distinct discohesive histologic appearance, and abnormal function of the RB gene may be implicated in the development of PUC.
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http://dx.doi.org/10.1093/ajcp/aqx029DOI Listing
May 2017

Aurora Kinase A is a Biomarker for Bladder Cancer Detection and Contributes to its Aggressive Behavior.

Sci Rep 2017 01 19;7:40714. Epub 2017 Jan 19.

Department Pathology, The University of Texas at MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA.

The effects of AURKA overexpression associated with poor clinical outcomes have been attributed to increased cell cycle progression and the development of genomic instability with aneuploidy. We used RNA interference to examine the effects of AURKA overexpression in human bladder cancer cells. Knockdown had minimal effects on cell proliferation but blocked tumor cell invasion. Whole genome mRNA expression profiling identified nicotinamide N-methyltransferase (NNMT) as a downstream target that was repressed by AURKA. Chromatin immunoprecipitation and NNMT promoter luciferase assays revealed that AURKA's effects on NNMT were caused by PAX3-mediated transcriptional repression and overexpression of NNMT blocked tumor cell invasion in vitro. Overexpression of AURKA and activation of its downstream pathway was enriched in the basal subtype in primary human tumors and was associated with poor clinical outcomes. We also show that the FISH test for the AURKA gene copy number in urine yielded a specificity of 79.7% (95% confidence interval [CI] = 74.2% to 84.1%), and a sensitivity of 79.6% (95% CI = 74.2% to 84.1%) with an AUC of 0.901 (95% CI = 0.872 to 0.928; P < 0.001). These results implicate AURKA as an effective biomarker for bladder cancer detection as well as therapeutic target especially for its basal type.
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http://dx.doi.org/10.1038/srep40714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244380PMC
January 2017

Functional CAR models for large spatially correlated functional datasets.

J Am Stat Assoc 2016 18;111(514):772-786. Epub 2016 Aug 18.

The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.

We develop a functional conditional autoregressive (CAR) model for spatially correlated data for which functions are collected on areal units of a lattice. Our model performs functional response regression while accounting for spatial correlations with potentially nonseparable and nonstationary covariance structure, in both the space and functional domains. We show theoretically that our construction leads to a CAR model at each functional location, with spatial covariance parameters varying and borrowing strength across the functional domain. Using basis transformation strategies, the nonseparable spatial-functional model is computationally scalable to enormous functional datasets, generalizable to different basis functions, and can be used on functions defined on higher dimensional domains such as images. Through simulation studies, we demonstrate that accounting for the spatial correlation in our modeling leads to improved functional regression performance. Applied to a high-throughput spatially correlated copy number dataset, the model identifies genetic markers not identified by comparable methods that ignore spatial correlations.
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http://dx.doi.org/10.1080/01621459.2015.1042581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5176110PMC
August 2016

Specific micro-RNA expression patterns distinguish the basal and luminal subtypes of muscle-invasive bladder cancer.

Oncotarget 2016 Dec;7(49):80164-80174

Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

The roles of non-coding RNAs in controlling clinical and biological heterogeneity in bladder cancer remain unclear. We used TCGA's published dataset (n = 405 tumors) as a discovery cohort and created a new validation cohort to define the miRNA expression patterns in the basal and luminal molecular subtypes of muscle-invasive bladder cancer (MIBC). We identified 63 miRNAs by PAM, which optimally identified basal and luminal tumors. The targets of the top luminal miRNAs were activators of EMT (ZEB1, ZEB2) and basal subtype transcription (IL-6, EGFR, STAT3), whereas the targets of the top basal miRNAs were involved in adipogenesis pathways and luminal breast cancer (ERBB2, ERBB3). We also identified a 15-miRNA signature that identified stromally infiltrated basal and luminal MIBCs corresponding to the "cluster IV/immune undifferentiated/claudin-low" and "cluster II/luminal immune" subtypes identified previously, which likely contain samples with higher infiltration rates. Using the 63-miRNA signature, we accurately assigned MIBCs to the basal and luminal subtypes and confirmed that patients with basal tumors had shorter overall survival. The results strongly suggest that miRNAs contribute to the control of the gene expression patterns observed in basal and luminal MIBCs and that they can be used as biomarkers and candidate therapeutic targets.
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http://dx.doi.org/10.18632/oncotarget.13284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348311PMC
December 2016