Publications by authors named "Vinay Varadan"

42 Publications

Untangling a complex web: Computational analyses of tumor molecular profiles to decode driver mechanisms.

J Genet Genomics 2020 10 28;47(10):595-609. Epub 2020 Nov 28.

Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address:

Genome-scale studies focusing on molecular profiling of cancers across tissue types have revealed a plethora of aberrations across the genomic, transcriptomic, and epigenomic scales. The significant molecular heterogeneity across individual tumors even within the same tissue context complicates decoding the key etiologic mechanisms of this disease. Furthermore, it is increasingly likely that biologic mechanisms underlying the pathobiology of cancer involve multiple molecular entities interacting across functional scales. This has motivated the development of computational approaches that integrate molecular measurements with prior biological knowledge in increasingly intricate ways to enable the discovery of driver genomic aberrations across cancers. Here, we review diverse methodological approaches that have powered significant advances in our understanding of the genomic underpinnings of cancer at the cohort and at the individual tumor scales. We outline the key advances and challenges in the computational discovery of cancer mechanisms while motivating the development of systems biology approaches to comprehensively decode the biologic drivers of this complex disease.
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http://dx.doi.org/10.1016/j.jgg.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902422PMC
October 2020

Sexually dimorphic radiogenomic models identify distinct imaging and biological pathways that are prognostic of overall survival in glioblastoma.

Neuro Oncol 2021 02;23(2):251-263

Case Western Reserve University, Cleveland, Ohio, USA.

Background: Recent epidemiological studies have suggested that sexual dimorphism influences treatment response and prognostic outcome in glioblastoma (GBM). To this end, we sought to (i) identify distinct sex-specific radiomic phenotypes-from tumor subcompartments (peritumoral edema, enhancing tumor, and necrotic core) using pretreatment MRI scans-that are prognostic of overall survival (OS) in GBMs, and (ii) investigate radiogenomic associations of the MRI-based phenotypes with corresponding transcriptomic data, to identify the signaling pathways that drive sex-specific tumor biology and treatment response in GBM.

Methods: In a retrospective setting, 313 GBM patients (male = 196, female = 117) were curated from multiple institutions for radiomic analysis, where 130 were used for training and independently validated on a cohort of 183 patients. For the radiogenomic analysis, 147 GBM patients (male = 94, female = 53) were used, with 125 patients in training and 22 cases for independent validation.

Results: Cox regression models of radiomic features from gadolinium T1-weighted MRI allowed for developing more precise prognostic models, when trained separately on male and female cohorts. Our radiogenomic analysis revealed higher expression of Laws energy features that capture spots and ripple-like patterns (representative of increased heterogeneity) from the enhancing tumor region, as well as aggressive biological processes of cell adhesion and angiogenesis to be more enriched in the "high-risk" group of poor OS in the male population. In contrast, higher expressions of Laws energy features (which detect levels and edges) from the necrotic core with significant involvement of immune related signaling pathways was observed in the "low-risk" group of the female population.

Conclusions: Sexually dimorphic radiogenomic models could help risk-stratify GBM patients for personalized treatment decisions.
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http://dx.doi.org/10.1093/neuonc/noaa231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906064PMC
February 2021

Understanding breast cancer disparities-a multi-scale challenge.

Ann Transl Med 2020 Jul;8(14):906

Department of Pharmacology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Despite convergence of overall breast cancer incidence rates between European American (EA) and African American (AA) women, disparities in mortality persist. The factors contributing to differences in mortality rates across population groups remain controversial and range from population genetics to sociodemographic influences. This review explores the complex multi-factorial nature of tumor-intrinsic and -extrinsic factors that impact the biology and clinical outcomes of breast cancer patients. In addition to summarizing the current state of breast cancer disparities research, we also motivate the development of integrative multi-scale approaches involving interdisciplinary teams to tackle this complex clinical challenge.
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http://dx.doi.org/10.21037/atm.2020.04.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396752PMC
July 2020

The transcriptional repressor BCL11A promotes breast cancer metastasis.

J Biol Chem 2020 08 23;295(33):11707-11719. Epub 2020 Jun 23.

Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA

The phenotypes of each breast cancer subtype are defined by their transcriptomes. However, the transcription factors that regulate differential patterns of gene expression that contribute to specific disease outcomes are not well understood. Here, using gene silencing and overexpression approaches, RNA-Seq, and splicing analysis, we report that the transcription factor B-cell leukemia/lymphoma 11A (BCL11A) is highly expressed in triple-negative breast cancer (TNBC) and drives metastatic disease. Moreover, BCL11A promotes cancer cell invasion by suppressing the expression of muscleblind-like splicing regulator 1 (), a splicing regulator that suppresses metastasis. This ultimately increases the levels of an alternatively spliced isoform of integrin-α6 (), which is associated with worse patient outcomes. These results suggest that BCL11A sustains TNBC cell invasion and metastatic growth by repressing MBNL1-directed splicing of Our findings also indicate that BCL11A lies at the interface of transcription and splicing and promotes aggressive TNBC phenotypes.
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http://dx.doi.org/10.1074/jbc.RA120.014018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450125PMC
August 2020

Novel insights into breast cancer copy number genetic heterogeneity revealed by single-cell genome sequencing.

Elife 2020 05 13;9. Epub 2020 May 13.

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.

Copy number alterations (CNAs) play an important role in molding the genomes of breast cancers and have been shown to be clinically useful for prognostic and therapeutic purposes. However, our knowledge of intra-tumoral genetic heterogeneity of this important class of somatic alterations is limited. Here, using single-cell sequencing, we comprehensively map out the facets of copy number alteration heterogeneity in a cohort of breast cancer tumors. Ou/var/www/html/elife/12-05-2020/backup/r analyses reveal: genetic heterogeneity of non-tumor cells (i.e. stroma) within the tumor mass; the extent to which copy number heterogeneity impacts breast cancer genomes and the importance of both the genomic location and dosage of sub-clonal events; the pervasive nature of genetic heterogeneity of chromosomal amplifications; and the association of copy number heterogeneity with clinical and biological parameters such as polyploidy and estrogen receptor negative status. Our data highlight the power of single-cell genomics in dissecting, in its many forms, intra-tumoral genetic heterogeneity of CNAs, the magnitude with which CNA heterogeneity affects the genomes of breast cancers, and the potential importance of CNA heterogeneity in phenomena such as therapeutic resistance and disease relapse.
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http://dx.doi.org/10.7554/eLife.51480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220379PMC
May 2020

Radiogenomic-Based Survival Risk Stratification of Tumor Habitat on Gd-T1w MRI Is Associated with Biological Processes in Glioblastoma.

Clin Cancer Res 2020 04 20;26(8):1866-1876. Epub 2020 Feb 20.

Case Western Reserve University, Cleveland, Ohio.

Purpose: To (i) create a survival risk score using radiomic features from the tumor habitat on routine MRI to predict progression-free survival (PFS) in glioblastoma and (ii) obtain a biological basis for these prognostic radiomic features, by studying their radiogenomic associations with molecular signaling pathways.

Experimental Design: Two hundred three patients with pretreatment Gd-T1w, T2w, T2w-FLAIR MRI were obtained from 3 cohorts: The Cancer Imaging Archive (TCIA; = 130), Ivy GAP ( = 32), and Cleveland Clinic ( = 41). Gene-expression profiles of corresponding patients were obtained for TCIA cohort. For every study, following expert segmentation of tumor subcompartments (necrotic core, enhancing tumor, peritumoral edema), 936 3D radiomic features were extracted from each subcompartment across all MRI protocols. Using Cox regression model, radiomic risk score (RRS) was developed for every protocol to predict PFS on the training cohort ( = 130) and evaluated on the holdout cohort ( = 73). Further, Gene Ontology and single-sample gene set enrichment analysis were used to identify specific molecular signaling pathway networks associated with RRS features.

Results: Twenty-five radiomic features from the tumor habitat yielded the RRS. A combination of RRS with clinical (age and gender) and molecular features (MGMT and IDH status) resulted in a concordance index of 0.81 ( < 0.0001) on training and 0.84 ( = 0.03) on the test set. Radiogenomic analysis revealed associations of RRS features with signaling pathways for cell differentiation, cell adhesion, and angiogenesis, which contribute to chemoresistance in GBM.

Conclusions: Our findings suggest that prognostic radiomic features from routine Gd-T1w MRI may also be significantly associated with key biological processes that affect response to chemotherapy in GBM.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165059PMC
April 2020

LIN9 and NEK2 Are Core Regulators of Mitotic Fidelity That Can Be Therapeutically Targeted to Overcome Taxane Resistance.

Cancer Res 2020 04 13;80(8):1693-1706. Epub 2020 Feb 13.

Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio.

A significant therapeutic challenge for patients with cancer is resistance to chemotherapies such as taxanes. Overexpression of LIN9, a transcriptional regulator of cell-cycle progression, occurs in 65% of patients with triple-negative breast cancer (TNBC), a disease commonly treated with these drugs. Here, we report that LIN9 is further elevated with acquisition of taxane resistance. Inhibiting LIN9 genetically or by suppressing its expression with a global BET inhibitor restored taxane sensitivity by inducing mitotic progression errors and apoptosis. While sustained LIN9 is necessary to maintain taxane resistance, there are no inhibitors that directly repress its function. Hence, we sought to discover a druggable downstream transcriptional target of LIN9. Using a computational approach, we identified NIMA-related kinase 2 (NEK2), a regulator of centrosome separation that is also elevated in taxane-resistant cells. High expression of was predictive of low survival rates in patients who had residual disease following treatment with taxanes plus an anthracycline, suggesting a role for this kinase in modulating taxane sensitivity. Like LIN9, genetic or pharmacologic blockade of NEK2 activity in the presence of paclitaxel synergistically induced mitotic abnormalities in nearly 100% of cells and completely restored sensitivity to paclitaxel, . In addition, suppressing NEK2 activity with two distinct small molecules potentiated taxane response in multiple models of TNBC, including a patient-derived xenograft, without inducing toxicity. These data demonstrate that the LIN9/NEK2 pathway is a therapeutically targetable mediator of taxane resistance that can be leveraged to improve response to this core chemotherapy. SIGNIFICANCE: Resistance to chemotherapy is a major hurdle for treating patients with cancer. Combining NEK2 inhibitors with taxanes may be a viable approach for improving patient outcomes by enhancing mitotic defects induced by taxanes alone.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165041PMC
April 2020

Reduction of Global H3K27me Enhances HER2/ErbB2 Targeted Therapy.

Cell Rep 2019 10;29(2):249-257.e8

Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada. Electronic address:

Monoclonal antibodies (mAbs) targeting the oncogenic receptor tyrosine kinase ERBB2/HER2, such as Trastuzumab, are the standard of care therapy for breast cancers driven by ERBB2 overexpression and activation. However, a substantial proportion of patients exhibit de novo resistance. Here, by comparing matched Trastuzumab-naive and post-treatment patient samples from a neoadjuvant trial, we link resistance with elevation of H3K27me, a repressive histone modification catalyzed by polycomb repressor complex 2 (PRC2). In ErbB2+ breast cancer models, PRC2 silences endogenous retroviruses (ERVs) to suppress anti-tumor type-I interferon (IFN) responses. In patients, elevated H3K27me in tumor cells following Trastuzumab treatment correlates with suppression of interferon-driven viral defense gene expression signatures and poor response. Using an immunocompetent model, we provide evidence that EZH2 inhibitors promote interferon-driven immune responses that enhance the efficacy of anti-ErbB2 mAbs, suggesting the potential clinical benefit of epigenomic reprogramming by H3K27me depletion in Trastuzumab-resistant disease.
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http://dx.doi.org/10.1016/j.celrep.2019.08.105DOI Listing
October 2019

An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis.

Nat Commun 2019 07 1;10(1):2901. Epub 2019 Jul 1.

Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC, H3A 1A3, Canada.

Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer. Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress, permitting sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumourigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.
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http://dx.doi.org/10.1038/s41467-019-10681-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603039PMC
July 2019

Association of Peritumoral Radiomics With Tumor Biology and Pathologic Response to Preoperative Targeted Therapy for HER2 (ERBB2)-Positive Breast Cancer.

JAMA Netw Open 2019 04 5;2(4):e192561. Epub 2019 Apr 5.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio.

Importance: There has been significant recent interest in understanding the utility of quantitative imaging to delineate breast cancer intrinsic biological factors and therapeutic response. No clinically accepted biomarkers are as yet available for estimation of response to human epidermal growth factor receptor 2 (currently known as ERBB2, but referred to as HER2 in this study)-targeted therapy in breast cancer.

Objective: To determine whether imaging signatures on clinical breast magnetic resonance imaging (MRI) could noninvasively characterize HER2-positive tumor biological factors and estimate response to HER2-targeted neoadjuvant therapy.

Design, Setting, And Participants: In a retrospective diagnostic study encompassing 209 patients with breast cancer, textural imaging features extracted within the tumor and annular peritumoral tissue regions on MRI were examined as a means to identify increasingly granular breast cancer subgroups relevant to therapeutic approach and response. First, among a cohort of 117 patients who received an MRI prior to neoadjuvant chemotherapy (NAC) at a single institution from April 27, 2012, through September 4, 2015, imaging features that distinguished HER2+ tumors from other receptor subtypes were identified. Next, among a cohort of 42 patients with HER2+ breast cancers with available MRI and RNaseq data accumulated from a multicenter, preoperative clinical trial (BrUOG 211B), a signature of the response-associated HER2-enriched (HER2-E) molecular subtype within HER2+ tumors (n = 42) was identified. The association of this signature with pathologic complete response was explored in 2 patient cohorts from different institutions, where all patients received HER2-targeted NAC (n = 28, n = 50). Finally, the association between significant peritumoral features and lymphocyte distribution was explored in patients within the BrUOG 211B trial who had corresponding biopsy hematoxylin-eosin-stained slide images. Data analysis was conducted from January 15, 2017, to February 14, 2019.

Main Outcomes And Measures: Evaluation of imaging signatures by the area under the receiver operating characteristic curve (AUC) in identifying HER2+ molecular subtypes and distinguishing pathologic complete response (ypT0/is) to NAC with HER2-targeting.

Results: In the 209 patients included (mean [SD] age, 51.1 [11.7] years), features from the peritumoral regions better discriminated HER2-E tumors (maximum AUC, 0.85; 95% CI, 0.79-0.90; 9-12 mm from the tumor) compared with intratumoral features (AUC, 0.76; 95% CI, 0.69-0.84). A classifier combining peritumoral and intratumoral features identified the HER2-E subtype (AUC, 0.89; 95% CI, 0.84-0.93) and was significantly associated with response to HER2-targeted therapy in both validation cohorts (AUC, 0.80; 95% CI, 0.61-0.98 and AUC, 0.69; 95% CI, 0.53-0.84). Features from the 0- to 3-mm peritumoral region were significantly associated with the density of tumor-infiltrating lymphocytes (R2 = 0.57; 95% CI, 0.39-0.75; P = .002).

Conclusions And Relevance: A combination of peritumoral and intratumoral characteristics appears to identify intrinsic molecular subtypes of HER2+ breast cancers from imaging, offering insights into immune response within the peritumoral environment and suggesting potential benefit for treatment guidance.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.2561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481453PMC
April 2019

Systems Biology Analyses Show Hyperactivation of Transforming Growth Factor-β and JNK Signaling Pathways in Esophageal Cancer.

Gastroenterology 2019 05 12;156(6):1761-1774. Epub 2019 Feb 12.

Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio. Electronic address:

Background & Aims: Esophageal adenocarcinoma (EAC) is resistant to standard chemoradiation treatments, and few targeted therapies are available. We used large-scale tissue profiling and pharmacogenetic analyses to identify deregulated signaling pathways in EAC tissues that might be targeted to slow tumor growth or progression.

Methods: We collected 397 biopsy specimens from patients with EAC and nonmalignant Barrett's esophagus (BE), with or without dysplasia. We performed RNA-sequencing analyses and used systems biology approaches to identify pathways that are differentially activated in EAC vs nonmalignant dysplastic tissues; pathway activities were confirmed with immunohistochemistry and quantitative real-time polymerase chain reaction analyses of signaling components in patient tissue samples. Human EAC (FLO-1 and EsoAd1), dysplastic BE (CP-B, CP-C, CP-D), and nondysplastic BE (CP-A) cells were incubated with pharmacologic inhibitors or transfected with small interfering RNAs. We measured effects on proliferation, colony formation, migration, and/or growth of xenograft tumors in nude mice.

Results: Comparisons of EAC vs nondysplastic BE tissues showed hyperactivation of transforming growth factor-β (TGFB) and/or Jun N-terminal kinase (JNK) signaling pathways in more than 80% of EAC samples. Immunohistochemical analyses showed increased nuclear localization of phosphorylated JUN and SMAD proteins in EAC tumor tissues compared with nonmalignant tissues. Genes regulated by the TGFB and JNK pathway were overexpressed specifically in EAC and dysplastic BE. Pharmacologic inhibition or knockdown of TGFB or JNK signaling components in EAC cells (FLO-1 or EsoAd1) significantly reduced cell proliferation, colony formation, cell migration, and/or growth of xenograft tumors in mice in a SMAD4-independent manner. Inhibition of the TGFB pathway in BE cell lines reduced the proliferation of dysplastic, but not nondysplastic, cells.

Conclusions: In a transcriptome analysis of EAC and nondysplastic BE tissues, we found the TGFB and JNK signaling pathways to be hyperactivated in EACs and the genes regulated by these pathways to be overexpressed in EAC and dysplastic BE. Inhibiting these pathways in EAC cells reduces their proliferation, migration, and formation of xenograft tumors. Strategies to block the TGFB and JNK signaling pathways might be developed for treatment of EAC.
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http://dx.doi.org/10.1053/j.gastro.2019.01.263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701681PMC
May 2019

The DNMT1-associated lincRNA DACOR1 reprograms genome-wide DNA methylation in colon cancer.

Clin Epigenetics 2018 10 22;10(1):127. Epub 2018 Oct 22.

Department of Genetics and Genome Sciences, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.

Background: DNA methylation is a key epigenetic mark in mammalian organisms that plays key roles in chromatin organization and gene expression. Although DNA methylation in gene promoters is generally associated with gene repression, recent studies demonstrate that DNA methylation in gene bodies and intergenic regions of the genome may result in distinct modes of gene regulation. Furthermore, the molecular mechanisms underlying the establishment and maintenance of DNA methylation in human health and disease remain to be fully elucidated. We recently demonstrated that a subset of long non-coding RNAs (lncRNAs) associates with the major DNA methyltransferase DNMT1 in human colon cancer cells, and the dysregulation of such lncRNAs contribute to aberrant DNA methylation patterns.

Results: In the current study, we assessed the impact of a key DNMT1-associated lncRNA, DACOR1, on genome-wide DNA methylation using reduced representation bisulfite sequencing (RRBS). Our findings demonstrated that induction of DACOR1 in colon cancer cells restores DNA methylation at thousands of CpG sites throughout the genome including promoters, gene bodies, and intergenic regions. Importantly, these sites overlap with regions of the genome that become hypomethylated in colon tumors. Furthermore, induction of DACOR1 results in repression of FOS and JUN and, consequently, reduced AP-1 transcription factor activity.

Conclusion: Collectively, our results demonstrate a key role of lncRNAs in regulating DNA methylation in human cells, and the dysregulation of such lncRNAs could emerge as a key mechanism by which DNA methylation patterns become altered in human tumors.
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http://dx.doi.org/10.1186/s13148-018-0555-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196572PMC
October 2018

Clinicopathological, immunohistochemical and molecular correlation of neural crest transcription factor SOX10 expression in triple-negative breast carcinoma.

Hum Pathol 2018 10 9;80:163-169. Epub 2018 Jun 9.

Department of Pathology, University Hospitals Cleveland Medical Center, 44106 Cleveland, OH.

The transcription factor SOX10 mediates the differentiation of neural crest-derived cells, and SOX10 by immunohistochemistry (IHC) is used primarily for the diagnosis of melanoma. SOX10 expression has been previously documented in benign breast myoepithelial cells. However there is limited literature on its expression in triple-negative breast carcinoma (TNBC). The aim was to study the clinical, pathologic and molecular profiles of SOX10+ tumors in TNBC. Tissue microarrays of TNBC were evaluated for SOX10 expression in 48 cases. SOX10 expression was correlated with clinical and pathologic features such as age, grade, and stage. Gene expression was analyzed on RNA extracted from formalin-fixed paraffin-embedded (FFPE) specimens with Affymetrix 2.0 HTA. Co-expression of SOX10 with androgen receptor (AR), WT1, gross cystic disease fluid protein-15 (GCDFP-15), mammaglobin, epidermal growth factor receptor (EGFR), CK5/6 and GATA transcription factor 3 (GATA3) were also assessed. The mean age was 59.38 (range, 28-90 years). Overall, 37.5% cases (18/48) were SOX10+. There was no association between SOX10 expression and age, grade or stage of patients; 6 of 10 (60%) cases of basal-like 1 (BL1), and 5 of 8 cases of unstable (UNS) molecular subtype were SOX10+. One of 5 basal-like-2 (BL2), 1 of 6 immunomodulatory (IM), 1 of 4 mesenchymal (M), 1 of 5 luminal androgen receptor (LAR) and 2 of 8 mesenchymal stem cell (MSL) showed lower frequencies of SOX10 expression. There was negative correlation between SOX10 and AR+ subtypes (P < .002). SOX10 was positively correlated with WT1 (P = .05). SOX10 did not show significant correlation with mammaglobin, GCDFP15, EGFR, CK5/6 and GATA3. SOX10 expression in the basal-like and unstable molecular subtypes supports the concept that these neoplasms show myoepithelial differentiation.
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http://dx.doi.org/10.1016/j.humpath.2018.06.007DOI Listing
October 2018

Radiogenomic analysis of hypoxia pathway is predictive of overall survival in Glioblastoma.

Sci Rep 2018 01 8;8(1). Epub 2018 Jan 8.

Case Western Reserve University, Department of Biomedical Engineering, Cleveland, 44106, USA.

Hypoxia, a characteristic trait of Glioblastoma (GBM), is known to cause resistance to chemo-radiation treatment and is linked with poor survival. There is hence an urgent need to non-invasively characterize tumor hypoxia to improve GBM management. We hypothesized that (a) radiomic texture descriptors can capture tumor heterogeneity manifested as a result of molecular variations in tumor hypoxia, on routine treatment naïve MRI, and (b) these imaging based texture surrogate markers of hypoxia can discriminate GBM patients as short-term (STS), mid-term (MTS), and long-term survivors (LTS). 115 studies (33 STS, 41 MTS, 41 LTS) with gadolinium-enhanced T1-weighted MRI (Gd-T1w) and T2-weighted (T2w) and FLAIR MRI protocols and the corresponding RNA sequences were obtained. After expert segmentation of necrotic, enhancing, and edematous/nonenhancing tumor regions for every study, 30 radiomic texture descriptors were extracted from every region across every MRI protocol. Using the expression profile of 21 hypoxia-associated genes, a hypoxia enrichment score (HES) was obtained for the training cohort of 85 cases. Mutual information score was used to identify a subset of radiomic features that were most informative of HES within 3-fold cross-validation to categorize studies as STS, MTS, and LTS. When validated on an additional cohort of 30 studies (11 STS, 9 MTS, 10 LTS), our results revealed that the most discriminative features of HES were also able to distinguish STS from LTS (p = 0.003).
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http://dx.doi.org/10.1038/s41598-017-18310-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758516PMC
January 2018

Interferon-beta represses cancer stem cell properties in triple-negative breast cancer.

Proc Natl Acad Sci U S A 2017 12 11;114(52):13792-13797. Epub 2017 Dec 11.

Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106;

Triple-negative breast cancer (TNBC), the deadliest form of this disease, lacks a targeted therapy. TNBC tumors that fail to respond to chemotherapy are characterized by a repressed IFN/signal transducer and activator of transcription (IFN/STAT) gene signature and are often enriched for cancer stem cells (CSCs). We have found that human mammary epithelial cells that undergo an epithelial-to-mesenchymal transition (EMT) following transformation acquire CSC properties. These mesenchymal/CSCs have a significantly repressed IFN/STAT gene expression signature and an enhanced ability to migrate and form tumor spheres. Treatment with IFN-beta (IFN-β) led to a less aggressive epithelial/non-CSC-like state, with repressed expression of mesenchymal proteins (VIMENTIN, SLUG), reduced migration and tumor sphere formation, and reexpression of CD24 (a surface marker for non-CSCs), concomitant with an epithelium-like morphology. The CSC-like properties were correlated with high levels of unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), which was previously linked to resistance to DNA damage. Inhibiting the expression of IRF9 (the DNA-binding component of U-ISGF3) reduced the migration of mesenchymal/CSCs. Here we report a positive translational role for IFN-β, as gene expression profiling of patient-derived TNBC tumors demonstrates that an IFN-β metagene signature correlates with improved patient survival, an immune response linked with tumor-infiltrating lymphocytes (TILs), and a repressed CSC metagene signature. Taken together, our findings indicate that repressed IFN signaling in TNBCs with CSC-like properties is due to high levels of U-ISGF3 and that treatment with IFN-β reduces CSC properties, suggesting a therapeutic strategy to treat drug-resistant, highly aggressive TNBC tumors.
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http://dx.doi.org/10.1073/pnas.1713728114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748193PMC
December 2017

Mitotic Vulnerability in Triple-Negative Breast Cancer Associated with LIN9 Is Targetable with BET Inhibitors.

Cancer Res 2017 10 14;77(19):5395-5408. Epub 2017 Aug 14.

Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio.

Triple-negative breast cancers (TNBC) are highly aggressive, lack FDA-approved targeted therapies, and frequently recur, making the discovery of novel therapeutic targets for this disease imperative. Our previous analysis of the molecular mechanisms of action of bromodomain and extraterminal protein inhibitors (BETi) in TNBC revealed these drugs cause multinucleation, indicating BET proteins are essential for efficient mitosis and cytokinesis. Here, using live cell imaging, we show that BET inhibition prolonged mitotic progression and induced mitotic cell death, both of which are indicative of mitotic catastrophe. Mechanistically, the mitosis regulator was a direct target of BET proteins that mediated the effects of BET proteins on mitosis in TNBC. Although BETi have been proposed to function by dismantling super-enhancers (SE), the gene lacks an SE but was amplified or overexpressed in the majority of TNBCs. In addition, its mRNA expression predicted poor outcome across breast cancer subtypes. Together, these results provide a mechanism for cancer selectivity of BETi that extends beyond modulation of SE-associated genes and suggest that cancers dependent upon LIN9 overexpression may be particularly vulnerable to BETi. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626629PMC
October 2017

Erratum to: Global DNA methylation patterns in Barrett's esophagus, dysplastic Barrett's, and esophageal adenocarcinoma are associated with BMI, gender, and tobacco use.

Clin Epigenetics 2017;9:23. Epub 2017 Mar 1.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA.

[This corrects the article DOI: 10.1186/s13148-016-0273-7.].
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http://dx.doi.org/10.1186/s13148-017-0324-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333432PMC
March 2017

Global DNA methylation patterns in Barrett's esophagus, dysplastic Barrett's, and esophageal adenocarcinoma are associated with BMI, gender, and tobacco use.

Clin Epigenetics 2016 27;8:111. Epub 2016 Oct 27.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA ; Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195 USA.

Background: The risk of developing Barrett's esophagus (BE) and/or esophageal adenocarcinoma (EAC) is associated with specific demographic and behavioral factors, including gender, obesity/elevated body mass index (BMI), and tobacco use. Alterations in DNA methylation, an epigenetic modification that can affect gene expression and that can be influenced by environmental factors, is frequently present in both BE and EAC and is believed to play a role in the formation of BE and its progression to EAC. It is currently unknown whether obesity or tobacco smoking influences the risk of developing BE/EAC via the induction of alterations in DNA methylation. To investigate this possibility, we assessed the genome-wide methylation status of 81 esophageal tissues, including BE, dysplastic BE, and EAC epithelia using HumanMethylation450 BeadChips (Illumina).

Results: We found numerous differentially methylated loci in the esophagus tissues when comparing males to females, obese to lean individuals, and smokers to nonsmokers. Differences in DNA methylation between these groups were seen in a variety of functional genomic regions and both within and outside of CpG islands. Several cancer-related pathways were found to have differentially methylated genes between these comparison groups.

Conclusions: Our findings suggest obesity and tobacco smoking may influence DNA methylation in the esophagus and raise the possibility that these risk factors affect the development of BE, dysplastic BE, and EAC through influencing the epigenetic status of specific loci that have a biologically plausible role in cancer formation.
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http://dx.doi.org/10.1186/s13148-016-0273-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082363PMC
April 2017

RNA Sequencing Identifies Transcriptionally Viable Gene Fusions in Esophageal Adenocarcinomas.

Cancer Res 2016 10 8;76(19):5628-5633. Epub 2016 Aug 8.

Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.

Esophageal adenocarcinoma is a deadly cancer with increasing incidence in the United States, but mechanisms underlying pathogenesis are still mostly elusive. In addressing this question, we assessed gene fusion landscapes by comprehensive RNA sequencing (RNAseq) of 55 pretreatment esophageal adenocarcinoma and 49 nonmalignant biopsy tissues from patients undergoing endoscopy for Barrett's esophagus. In this cohort, we identified 21 novel candidate esophageal adenocarcinoma-associated fusions occurring in 3.33% to 11.67% of esophageal adenocarcinomas. Two candidate fusions were selected for validation by PCR and Sanger sequencing in an independent set of pretreatment esophageal adenocarcinoma (N = 115) and nonmalignant (N = 183) biopsy tissues. In particular, we observed RPS6KB1-VMP1 gene fusion as a recurrent event occurring in approximately 10% of esophageal adenocarcinoma cases. Notably, esophageal adenocarcinoma cases harboring RPS6KB1-VMP1 fusions exhibited significantly poorer overall survival as compared with fusion-negative cases. Mechanistic investigations established that the RPS6KB1-VMP1 transcript coded for a fusion protein, which significantly enhanced the growth rate of nondysplastic Barrett's esophagus cells. Compared with the wild-type VMP1 protein, which mediates normal cellular autophagy, RPS6KB1-VMP1 fusion exhibited aberrant subcellular localization and was relatively ineffective in triggering autophagy. Overall, our findings identified RPS6KB1-VMP1 as a genetic fusion that promotes esophageal adenocarcinoma by modulating autophagy-related processes, offering new insights into the molecular pathogenesis of esophageal adenocarcinomas. Cancer Res; 76(19); 5628-33. ©2016 AACR.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5050127PMC
http://dx.doi.org/10.1158/0008-5472.CAN-16-0979DOI Listing
October 2016

Network-Based Enriched Gene Subnetwork Identification: A Game-Theoretic Approach.

Biomed Eng Comput Biol 2016 5;7(Suppl 2):1-14. Epub 2016 Apr 5.

Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.

Identifying subsets of genes that jointly mediate cancer etiology, progression, or therapy response remains a challenging problem due to the complexity and heterogeneity in cancer biology, a problem further exacerbated by the relatively small number of cancer samples profiled as compared with the sheer number of potential molecular factors involved. Pure data-driven methods that merely rely on multiomics data have been successful in discovering potentially functional genes but suffer from high false-positive rates and tend to report subsets of genes whose biological interrelationships are unclear. Recently, integrative data-driven models have been developed to integrate multiomics data with signaling pathway networks in order to identify pathways associated with clinical or biological phenotypes. However, these approaches suffer from an important drawback of being restricted to previously discovered pathway structures and miss novel genomic interactions as well as potential crosstalk among the pathways. In this article, we propose a novel coalition-based game-theoretic approach to overcome the challenge of identifying biologically relevant gene subnetworks associated with disease phenotypes. The algorithm starts from a set of seed genes and traverses a protein-protein interaction network to identify modulated subnetworks. The optimal set of modulated subnetworks is identified using Shapley value that accounts for both individual and collective utility of the subnetwork of genes. The algorithm is applied to two illustrative applications, including the identification of subnetworks associated with (i) disease progression risk in response to platinum-based therapy in ovarian cancer and (ii) immune infiltration in triple-negative breast cancer. The results demonstrate an improved predictive power of the proposed method when compared with state-of-the-art feature selection methods, with the added advantage of identifying novel potentially functional gene subnetworks that may provide insights into the mechanisms underlying cancer progression.
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http://dx.doi.org/10.4137/BECB.S38244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822726PMC
April 2016

Biochemical and functional characterization of glycosylation-associated mutational landscapes in colon cancer.

Sci Rep 2016 Mar 23;6:23642. Epub 2016 Mar 23.

Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland OH 44106, U.S.A.

The molecular basis of aberrant protein glycosylation, a pathological alteration widespread in colorectal cancers (CRC), and the mechanisms by which it contributes to tumor progression remain largely unknown. We performed targeted re-sequencing of 430 glycosylation-associated genes in a series of patient-derived CRC cell lines (N = 31) and matched primary tumor tissues, identifying 12 new significantly mutated glycosylation-associated genes in colon cancer. In particular, we observed an enrichment of mutations in genes (B3GNT2, B4GALT2, ST6GALNAC2) involved in the biosynthesis of N- and Cores 1-3 O-linked glycans in the colon, accounting for ~16% of the CRCs tested. Analysis of independent large-scale tumor tissue datasets confirmed recurrent mutations within these genes in colon and other gastrointestinal cancers. Systematic biochemical and phenotypic characterization of the candidate wild-type and mutant glycosyltransferases demonstrated these mutations as either markedly altering protein localization, post-translational modification, encoded enzymatic activities and/or the migratory potential of colon carcinoma cells. These findings suggest that functionally deleterious mutations in glycosyltransferase genes in part underlie aberrant glycosylation, and contribute to the pathogenesis of molecular subsets of colon and other gastrointestinal malignancies.
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http://dx.doi.org/10.1038/srep23642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804330PMC
March 2016

Biomarkers for Predicting Response to Anti-HER2 Agents.

Adv Exp Med Biol 2016 ;882:155-67

Seidman Cancer Center, Cleveland, OH, USA.

The HER2 receptor is amplified or overexpressed in approximately 20% of all breast cancers, but despite significant efforts of the clinical research community and a growing number of anti-HER2 agents, a significant number of patients with HER2-positive breast cancer either progress or suffer disease relapse within 5-10 years. The development of robust biomarkers that predict response to anti-HER2 agents is therefore an important clinical need to prevent overtreatment and to enable earlier assignment of patients to more optimal therapies. Here we review some of the recent advances in the field by focusing on pathways mediating resistance to anti-HER2 therapies, and the role of the immune system and cancer stem cells in therapy response. We also review preoperative treatment strategies and research paradigms that show promise in identifying novel biomarkers of response while also enabling the delineation of the mechanisms underlying clinical benefit from anti-HER2 therapies.
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http://dx.doi.org/10.1007/978-3-319-22909-6_6DOI Listing
August 2016

Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors.

Cancer Cell 2016 Mar;29(3):255-269

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

Using transgenic mouse models, cell line-based functional studies, and clinical specimens, we show that cyclin D1/CDK4 mediate resistance to targeted therapy for HER2-positive breast cancer. This is overcome using CDK4/6 inhibitors. Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC1 activity. This relieves feedback inhibition of upstream EGFR family kinases, resensitizing tumors to EGFR/HER2 blockade. Consequently, dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of TSC2 phosphorylation and hence mTORC1/S6K/S6RP activity. The suppression of both Rb and S6RP enhances G1 arrest and a phenotype resembling cellular senescence. In vivo, CDK4/6 inhibitors sensitize patient-derived xenograft tumors to HER2-targeted therapies and delay tumor recurrence in a transgenic model of HER2-positive breast cancer.
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http://dx.doi.org/10.1016/j.ccell.2016.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794996PMC
March 2016

Immune Signatures Following Single Dose Trastuzumab Predict Pathologic Response to PreoperativeTrastuzumab and Chemotherapy in HER2-Positive Early Breast Cancer.

Clin Cancer Res 2016 07 3;22(13):3249-59. Epub 2016 Feb 3.

Case Western Reserve University School of Medicine, Cleveland, Ohio.

Purpose: Recent data suggest that intrinsic subtype and immune cell infiltration may predict response to trastuzumab-based therapy. We studied the interaction between these factors, changes in immune signatures following brief exposure to trastuzumab, and achievement of pathologic complete response (pCR) to subsequent preoperative trastuzumab and chemotherapy in HER2-positive breast cancer.

Experimental Design: In patients enrolled on two multicenter trials (03-311 and 211B), tumor core biopsies were obtained at baseline and after brief exposure to single-agent trastuzumab or nab-paclitaxel. Gene expression profiles were assessed to assign PAM50 subtypes, measure immune cell activation, and were correlated with response.

Results: The pCR rate was significantly higher in HER2-enriched tumors in the Discovery, 03-311 (36%, P = 0.043) dataset, as compared with other subtypes, which validated in 211B (50%, P = 0.048). Significant increases in a signature of immune cell admixture (Immune Index) were observed only following brief exposure to trastuzumab in HER2-enriched tumors (Discovery/03-311, P = 0.05; Validation/211B, P = 0.02). Increased Immune Index was predictive of response after brief exposure (03-311, P = 0.03; 211B, P = 0.04), but not at baseline, in addition to increased expression of a CD4(+) follicular helper T-cell signature (03-311, P = 0.05; 211B, P = 0.04). Brief exposure to trastuzumab significantly increased gene expression of the T-cell marker PD-1 in HER2-enriched tumors (Discovery/03-311, P = 0.045) and PD-1 positivity by IHC (Validation/211B, P = 0.035).

Conclusions: Correlations between pCR rates, increases in Immune Index and markers of T-cell activity following brief exposure to trastuzumab in HER2-enriched tumors provide novel insights into the interaction between tumor biology, antitumor immunity, and response to treatment, and suggest potential clinically useful biomarkers in HER2(+) breast cancers. Clin Cancer Res; 22(13); 3249-59. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439498PMC
July 2016

Non-linear Bayesian framework to determine the transcriptional effects of cancer-associated genomic aberrations.

Annu Int Conf IEEE Eng Med Biol Soc 2015 ;2015:6514-8

While the tumorigenic effects of specific recurrent mutations in known cancer driver-genes is well-characterized, not much is known about the functional relevance of the vast majority of recurrent mutations observed across cancers. Prior studies have attempted to identify functional genomic aberrations by integrating multi-omics measurements in cancer samples with community-curated biological pathway networks. However, the majority of these approaches overlook the following biological considerations: i) signaling pathway networks are highly tissue-specific and their regulatory interactions differ across tissue types; ii) regulatory factors exhibit heterogeneous influence on downstream gene transcription; iii) epigenetic and genomic alterations exhibit nonlinear impact on gene transcription. In order to accommodate these biological effects, we propose a hybrid Bayesian method to learn tissue-specific pairwise influence models amongst genes and to predict a gene's expression level as a nonlinear-function of its epigenetic and regulatory influences. We employ a novel tree-based depth-penalization mechanism in order to capture the higher regulatory impact of closer neighbors in the regulatory network. Using a breast cancer multi-omics dataset (N=1190), we show that our proposed method has superior prediction power over optimization-based regression models, with the additional advantage of revealing gene deregulations potentially driven by somatic mutations.
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http://dx.doi.org/10.1109/EMBC.2015.7319885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341149PMC
September 2016

Identifying gene subnetworks associated with clinical outcome in ovarian cancer using Network Based Coalition Game.

Annu Int Conf IEEE Eng Med Biol Soc 2015 ;2015:6509-13

The problem of identifying interacting genes that jointly are associated with a phenotype is considered. When the number of features are extremely large compared to the number of samples, there may be several subsets of features that provide acceptable levels of predictability. This is particularly true in cancer genomics, where we are interested in finding functionally related gene sets likely to jointly drive cancer phenotypes. In this paper, a novel game theoretic solution is proposed by modeling genes as players of a Coalition Game. This method discovers and develops informative gene subnetworks by integrating gene expression profiling of cancer tissues with protein-protein interaction (PPI) networks. These subnetworks are gradually developed by selective addition of candidate genes that present maximal Shapely values in coalition with subnetworks of genes. We applied the proposed algorithm to an ovarian cancer dataset (N = 201), in order to identify optimal subnetworks that can predict cancer progression risk in response to platinum-based therapy. We show improved predictive power of the proposed method when compared to state-of-the-art feature selection methods, with the added advantage of identifying potentially functional gene subnetworks that may provide insights into the mechanisms underlying cancer progression.
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http://dx.doi.org/10.1109/EMBC.2015.7319884DOI Listing
September 2016

Brief-exposure to preoperative bevacizumab reveals a TGF-β signature predictive of response in HER2-negative breast cancers.

Int J Cancer 2016 Feb 31;138(3):747-57. Epub 2015 Aug 31.

Seidman Cancer Center, University Hospitals, Cleveland, OH.

To best define biomarkers of response, and to shed insight on mechanism of action of certain clinically important agents for early breast cancer, we used a brief-exposure paradigm in the preoperative setting to study transcriptional changes in patient tumors that occur with one dose of therapy prior to combination chemotherapy. Tumor biopsies from breast cancer patients enrolled in two preoperative clinical trials were obtained at baseline and after one dose of bevacizumab (HER2-negative), trastuzumab (HER2-positive) or nab-paclitaxel, followed by treatment with combination chemo-biologic therapy. RNA-Sequencing based PAM50 subtyping at baseline of 46 HER2-negative patients revealed a strong association between the basal-like subtype and pathologic complete response (pCR) to chemotherapy plus bevacizumab (p ≤ 0.0027), but did not provide sufficient specificity to predict response. However, a single dose of bevacizumab resulted in down-regulation of a well-characterized TGF-β activity signature in every single breast tumor that achieved pCR (p ≤ 0.004). The TGF-β signature was confirmed to be a tumor-specific read-out of the canonical TGF-β pathway using pSMAD2 (p ≤ 0.04), with predictive power unique to brief-exposure to bevacizumab (p ≤ 0.016), but not trastuzumab or nab-paclitaxel. Down-regulation of TGF-β activity was associated with reduction in tumor hypoxia by transcription and protein levels, suggesting therapy-induced disruption of an autocrine-loop between tumor stroma and malignant cells. Modulation of the TGF-β pathway upon brief-exposure to bevacizumab may provide an early functional readout of pCR to preoperative anti-angiogenic therapy in HER2-negative breast cancer, thus providing additional avenues for exploration in both preclinical and clinical settings with these agents.
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http://dx.doi.org/10.1002/ijc.29808DOI Listing
February 2016

ENVE: a novel computational framework characterizes copy-number mutational landscapes in colorectal cancers from African American patients.

Genome Med 2015 20;7:69. Epub 2015 Jul 20.

Division of General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, OH 44106 USA ; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106 USA ; Department of Medicine, Case Western Reserve University, Cleveland, OH 44106 USA ; Case Western Reserve University, 2103 Cornell Road, Wolstein Research Building, Cleveland, OH 44106 USA.

Reliable detection of somatic copy-number alterations (sCNAs) in tumors using whole-exome sequencing (WES) remains challenging owing to technical (inherent noise) and sample-associated variability in WES data. We present a novel computational framework, ENVE, which models inherent noise in any WES dataset, enabling robust detection of sCNAs across WES platforms. ENVE achieved high concordance with orthogonal sCNA assessments across two colorectal cancer (CRC) WES datasets, and consistently outperformed a best-in-class algorithm, Control-FREEC. We subsequently used ENVE to characterize global sCNA landscapes in African American CRCs, identifying genomic aberrations potentially associated with CRC pathogenesis in this population. ENVE is downloadable at https://github.com/ENVE-Tools/ENVE.
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http://dx.doi.org/10.1186/s13073-015-0192-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534088PMC
May 2016

Reply to Ashktorab et al.: Mutational landscape of colon cancers in African Americans.

Proc Natl Acad Sci U S A 2015 Jun 4;112(22):E2853. Epub 2015 May 4.

Case Comprehensive Cancer Center, and Department of Medicine, Case Medical Center, Case Western Reserve University, Cleveland, OH 44106; Department of Pathology.

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http://dx.doi.org/10.1073/pnas.1505059112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460466PMC
June 2015

Novel recurrently mutated genes in African American colon cancers.

Proc Natl Acad Sci U S A 2015 Jan 12;112(4):1149-54. Epub 2015 Jan 12.

Case Comprehensive Cancer Center, and Department of Medicine, Case Medical Center, Case Western Reserve University, Cleveland, OH 44106; Department of Pathology.

We used whole-exome and targeted sequencing to characterize somatic mutations in 103 colorectal cancers (CRC) from African Americans, identifying 20 new genes as significantly mutated in CRC. Resequencing 129 Caucasian derived CRCs confirmed a 15-gene set as a preferential target for mutations in African American CRCs. Two predominant genes, ephrin type A receptor 6 (EPHA6) and folliculin (FLCN), with mutations exclusive to African American CRCs, are by genetic and biological criteria highly likely African American CRC driver genes. These previously unsuspected differences in the mutational landscapes of CRCs arising among individuals of different ethnicities have potential to impact on broader disparities in cancer behaviors.
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http://dx.doi.org/10.1073/pnas.1417064112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313860PMC
January 2015