Publications by authors named "Christopher A Maher"

80 Publications

Loss of long non-coding RNA NXTAR in prostate cancer augments androgen receptor expression and enzalutamide resistance.

Cancer Res 2021 Nov 5. Epub 2021 Nov 5.

Siteman Cancer Center, Moffitt Cancer Center

Androgen receptor (AR) signaling continues to play a dominant role in all stages of prostate cancer (PC), including castration-resistant prostate cancers (CRPC) that have developed resistance to second-generation AR antagonists such as enzalutamide. In this study, we identified a long non-coding RNA (lncRNA), NXTAR (LOC105373241), that is located convergent with the AR gene and is repressed in human prostate tumors and cell lines. NXTAR bound upstream of the AR promoter and promoted EZH2 recruitment, causing significant loss of AR (and AR-V7) expression. Paradoxically, AR bound the NXTAR promoter, and inhibition of AR by the ACK1/TNK2 small molecule inhibitor (R)-9b excluded AR from the NXTAR promoter. The histone acetyltransferase GCN5 bound and deposited H3K14 acetylation marks, enhancing NXTAR expression. Application of an oligonucleotide derived from NXTAR exon 5 (NXTAR-N5) suppressed AR/AR-V7 expression and prostate cancer cell proliferation, indicating the translational relevance of the negative regulation of AR. In addition, pharmacological restoration of NXTAR using (R)-9b abrogated enzalutamide-resistant prostate xenograft tumor growth. Overall, this study uncovers a positive feedback loop, wherein NXTAR acts as a novel prostate tumor-suppressing lncRNA by inhibiting AR/AR-V7 expression, which in turn upregulates NXTAR levels, compromising enzalutamide-resistant prostate cancer. The restoration of NXTAR could serve as a new therapeutic modality for patients who have acquired resistance to second-generation AR antagonists.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3845DOI Listing
November 2021

Phase 1 study combining alisertib with nab-paclitaxel in patients with advanced solid malignancies.

Eur J Cancer 2021 09 10;154:102-110. Epub 2021 Jul 10.

Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, US. Electronic address:

Aim: Aurora kinase A (AURKA) is a pleiotropic serine/threonine kinase that orchestrates mitotic progression. Paclitaxel stabilises microtubules and disrupts mitotic spindle assembly. The combination of AURKA inhibitor (alisertib) plus paclitaxel may be synergistic in rapidly proliferative cancers. We evaluated the safety and maximum tolerated dose (MTD) of alisertib in combination with nab-paclitaxel and its preliminary efficacy in patients with refractory high-grade neuroendocrine tumours (NETs).

Method: This is a two-part, Phase 1 study. In Part A (dose escalation), a standard 3 + 3 design was used to determine MTD. In Part B (dose expansion), patients with predominantly refractory high-grade NETs were enrolled.

Results: In total, 31 patients were enrolled and treated (16 in Part A and 15 in Part B). The MTD of alisertib was 40 mg BID on D1-3 per week and nab-paclitaxel 100mg/m weekly: 3 weeks, 1 week off. Dose-limiting toxicity was neutropenia, and other common side-effects included fatigue, mucositis, and diarrhoea. In Part A, a patient with small-cell lung cancer with partial response (PR) was treated for more than 2 years, whereas four other patients with pancreatic ductal adenocarcinoma (one patient), small cell lung cancer (SCLC) (two patients), or high-grade NET (one patient) achieved stable disease (SD). In Part B, 13 of 15 enrolled patients had high-grade NETs. Of these, one had PR, and four had SD for more than 10 months.

Conclusions: The combination of alisertib and nab-paclitaxel has manageable side-effect profile and showed promising preliminary efficacy in high-grade NETs, warranting further testing.

Trial Registration: ClinicalTrials.gov identifier: NCT01677559.
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http://dx.doi.org/10.1016/j.ejca.2021.06.012DOI Listing
September 2021

ctDNA MRD Detection and Personalized Oncogenomic Analysis in Oligometastatic Colorectal Cancer From Plasma and Urine.

JCO Precis Oncol 2021 12;5. Epub 2021 Feb 12.

Division of Cancer Biology, Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO.

We hypothesized that circulating tumor DNA (ctDNA) molecular residual disease (MRD) analysis without prior mutational knowledge could be performed after neoadjuvant chemotherapy to assess oligometastatic colorectal cancer (CRC) treated surgically with curative intent. We also investigated urine as an alternative analyte for ctDNA MRD detection in this nongenitourinary setting.

Patients And Methods: We applied AVENIO targeted next-generation sequencing to plasma, tumor, and urine samples acquired on the day of curative-intent surgery from 24 prospectively enrolled patients with oligometastatic CRC. Age-related clonal hematopoiesis was accounted for by removing variants also present in white blood cells. Plasma and urine ctDNA MRD were correlated with tumor cells detected in the surgical specimen, and adjuvant treatment strategies were proposed based on ctDNA-inferred tumor mutational burden (iTMB) and targetable alterations.

Results: Seventy-one percent of patients were treated with neoadjuvant chemotherapy. Tumor-naive plasma ctDNA analysis detected MRD at a median level of 0.62% with 95% sensitivity and 100% specificity, and 94% and 77% sensitivity when only considering patients treated with neoadjuvant chemotherapy and putative driver mutations, respectively. In urine, ctDNA MRD detection specificity remained high at 100%, but sensitivity decreased to 64% with median levels being 11-fold lower than in plasma ( < .0001). Personalized ctDNA MRD oncogenomic analysis revealed 81% of patients might have been candidates for adjuvant immunotherapy based on high iTMB or targeted therapy based on actionable mutations.

Conclusion: Tumor-naive plasma ctDNA analysis can sensitively and specifically detect MRD in patients with oligometastatic CRC after neoadjuvant chemotherapy. Urine-based ctDNA MRD detection is also feasible; however, it is less sensitive than plasma because of significantly lower levels. Oligometastatic patients with detectable MRD may benefit from additional personalized treatment based on ctDNA-derived oncogenomic profiling.
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http://dx.doi.org/10.1200/PO.20.00276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232837PMC
February 2021

A community challenge to evaluate RNA-seq, fusion detection, and isoform quantification methods for cancer discovery.

Cell Syst 2021 08 18;12(8):827-838.e5. Epub 2021 Jun 18.

Biomedical Engineering, Oregon Health and Science University, Portland, OR 97239, USA. Electronic address:

The accurate identification and quantitation of RNA isoforms present in the cancer transcriptome is key for analyses ranging from the inference of the impacts of somatic variants to pathway analysis to biomarker development and subtype discovery. The ICGC-TCGA DREAM Somatic Mutation Calling in RNA (SMC-RNA) challenge was a crowd-sourced effort to benchmark methods for RNA isoform quantification and fusion detection from bulk cancer RNA sequencing (RNA-seq) data. It concluded in 2018 with a comparison of 77 fusion detection entries and 65 isoform quantification entries on 51 synthetic tumors and 32 cell lines with spiked-in fusion constructs. We report the entries used to build this benchmark, the leaderboard results, and the experimental features associated with the accurate prediction of RNA species. This challenge required submissions to be in the form of containerized workflows, meaning each of the entries described is easily reusable through CWL and Docker containers at https://github.com/SMC-RNA-challenge. A record of this paper's transparent peer review process is included in the supplemental information.
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http://dx.doi.org/10.1016/j.cels.2021.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376800PMC
August 2021

Long noncoding RNAs in cancer metastasis.

Nat Rev Cancer 2021 07 5;21(7):446-460. Epub 2021 May 5.

Department of Internal Medicine, Washington University in St Louis, St Louis, MO, USA.

Metastasis is a major contributor to cancer-associated deaths. It is characterized by a multistep process that occurs through the acquisition of molecular and phenotypic changes enabling cancer cells from a primary tumour to disseminate and colonize at distant organ sites. Over the past decade, the discovery and characterization of long noncoding RNAs (lncRNAs) have revealed the diversity of their regulatory roles, including key contributions throughout the metastatic cascade. Here, we review how lncRNAs promote metastasis by functioning in discrete pro-metastatic steps including the epithelial-mesenchymal transition, invasion and migration and organotrophic colonization, and by influencing the metastatic tumour microenvironment, often by interacting within ribonucleoprotein complexes or directly with other nucleic acid entities. We discuss well-characterized lncRNAs with in vivo phenotypes and highlight mechanistic commonalities such as convergence with the TGFβ-ZEB1/ZEB2 axis or the nuclear factor-κB pathway, in addition to lncRNAs with controversial mechanisms and the influence of methodologies on mechanistic interpretation. Furthermore, some lncRNAs can help identify tumours with increased metastatic risk and spur novel therapeutic strategies, with several lncRNAs having shown potential as novel targets for antisense oligonucleotide therapy in animal models. In addition to well-characterized examples of lncRNAs functioning in metastasis, we discuss controversies and ongoing challenges in lncRNA biology. Finally, we present areas for future study for this rapidly evolving field.
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http://dx.doi.org/10.1038/s41568-021-00353-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288800PMC
July 2021

Long, Noncoding RNA Dysregulation in Glioblastoma.

Cancers (Basel) 2021 03 31;13(7). Epub 2021 Mar 31.

Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.

Transcription occurs across more than 70% of the human genome and more than half of currently annotated genes produce functional noncoding RNAs. Of these transcripts, the majority-long, noncoding RNAs (lncRNAs)-are greater than 200 nucleotides in length and are necessary for various roles in the cell. It is increasingly appreciated that these lncRNAs are relevant in both health and disease states, with the brain expressing the largest number of lncRNAs compared to other organs. Glioblastoma (GBM) is an aggressive, fatal brain tumor that demonstrates remarkable intratumoral heterogeneity, which has made the development of effective therapies challenging. The cooperation between genetic and epigenetic alterations drives rapid adaptation that allows therapeutic evasion and recurrence. Given the large repertoire of lncRNAs in normal brain tissue and the well-described roles of lncRNAs in molecular and cellular processes, these transcripts are important to consider in the context of GBM heterogeneity and treatment resistance. Herein, we review the general mechanisms and biological roles of lncRNAs, with a focus on GBM, as well as RNA-based therapeutics currently in development.
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http://dx.doi.org/10.3390/cancers13071604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037018PMC
March 2021

Targeted Therapy to β3 Integrin Reduces Chemoresistance in Breast Cancer Bone Metastases.

Mol Cancer Ther 2021 06 30;20(6):1183-1198. Epub 2021 Mar 30.

Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri.

Breast cancer bone metastases are common and incurable. Tumoral integrin β3 (β3) expression is induced through interaction with the bone microenvironment. Although β3 is known to promote bone colonization, its functional role during therapy of established bone metastases is not known. We found increased numbers of β3 tumor cells in murine bone metastases after docetaxel chemotherapy. β3 tumor cells were present in 97% of post-neoadjuvant chemotherapy triple-negative breast cancer patient samples ( = 38). High tumoral β3 expression was associated with worse outcomes in both pre- and postchemotherapy triple-negative breast cancer groups. Genetic deletion of tumoral β3 had minimal effect , but significantly enhanced docetaxel activity, particularly in the bone. Rescue experiments confirmed that this effect required intact β3 signaling. Ultrastructural, transcriptomic, and functional analyses revealed an alternative metabolic response to chemotherapy in β3-expressing cells characterized by enhanced oxygen consumption, reactive oxygen species generation, and protein production. We identified mTORC1 as a candidate for therapeutic targeting of this β3-mediated, chemotherapy-induced metabolic response. mTORC1 inhibition in combination with docetaxel synergistically attenuated murine bone metastases. Furthermore, micelle nanoparticle delivery of mTORC1 inhibitor to cells expressing activated αvβ3 integrins enhanced docetaxel efficacy in bone metastases. Taken together, we show that β3 integrin induction by the bone microenvironment promotes resistance to chemotherapy through an altered metabolic response that can be defused by combination with αvβ3-targeted mTORC1 inhibitor nanotherapy. Our work demonstrates the importance of the metastatic microenvironment when designing treatments and presents new, bone-specific strategies for enhancing chemotherapeutic efficacy.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442608PMC
June 2021

Antibody profiling of patients with prostate cancer reveals differences in antibody signatures among disease stages.

J Immunother Cancer 2020 12;8(2)

Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA

Background: Previous studies of prostate cancer autoantibodies have largely focused on diagnostic applications. So far, there have been no reports attempting to more comprehensively profile the landscape of prostate cancer-associated antibodies. Specifically, it is unknown whether the quantity of antibodies or the types of proteins recognized change with disease progression.

Methods: A peptide microarray spanning the amino acid sequences of the gene products of 1611 prostate cancer-associated genes was synthesized. Serum samples from healthy male volunteers (n=15) and patients with prostate cancer (n=85) were used to probe the array. These samples included patients with various clinical stages of disease: newly diagnosed localized prostate cancer (n=15), castration-sensitive non-metastatic prostate cancer (nmCSPC, n=40), castration-resistant non-metastatic prostate cancer (n=15) and castration-resistant metastatic disease (n=15). The patients with nmCSPC received treatment with either standard androgen deprivation therapy (ADT) or an antitumor DNA vaccine encoding prostatic acid phosphatase. Serial sera samples from these individuals were also used to probe the array, to secondarily determine whether this approach could be used to detect treatment-related changes.

Results: We demonstrated that this peptide array yielded highly reproducible measurements of serum IgG levels. We found that the overall number of antibody responses did not increase with disease burden. However, the composition of recognized proteins shifted with clinical stage of disease. Our analysis revealed that the largest difference was between patients with castration-sensitive and castration-resistant disease. Patients with castration-resistant disease recognized more proteins associated with nucleic acid binding and gene regulation compared with men in other groups. Our longitudinal data showed that treatments can elicit antibodies detectable by this array, and notably vaccine-treated patients developed increased responses to more proteins over the course of treatment than did ADT-treated patients.

Conclusions: This study represents the largest survey of prostate cancer-associated antibodies to date. We have been able to characterize the classes of proteins recognized by patients and determine how they change with disease burden. Our findings further demonstrate the potential of this platform for measuring antigen spread and studying responses to immunomodulatory therapies.
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http://dx.doi.org/10.1136/jitc-2020-001510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745697PMC
December 2020

SV-HotSpot: detection and visualization of hotspots targeted by structural variants associated with gene expression.

Sci Rep 2020 09 28;10(1):15890. Epub 2020 Sep 28.

McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Whole genome sequencing (WGS) has enabled the discovery of genomic structural variants (SVs), including those targeting intergenic and intronic non-coding regions that eluded previous exome focused strategies. However, the field currently lacks an automated tool that analyzes SV candidates to identify recurrent SVs and their targeted sites (hotspot regions), visualizes these genomic events within the context of various functional elements, and evaluates their potential effect on gene expression. To address this, we developed SV-HotSpot, an automated tool that integrates SV candidates, copy number alterations, gene expression, and genome annotations (e.g. gene and regulatory elements) to discover, annotate, and visualize recurrent SVs and their targeted hotspot regions that may affect gene expression. We applied SV-HotSpot to WGS and matched transcriptome data from metastatic castration resistant prostate cancer patients and rediscovered recurrent SVs targeting coding and non-coding functional elements known to promote prostate cancer progression and metastasis. SV-HotSpot provides a valuable resource to integrate SVs, gene expression, and genome annotations for discovering biologically relevant SVs altering coding and non-coding genome. SV-HotSpot is available at https://github.com/ChrisMaherLab/SV-HotSpot .
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http://dx.doi.org/10.1038/s41598-020-71168-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522247PMC
September 2020

Cell-free DNA alterations in the enhancer and locus predict resistance to AR-directed therapy in patients with metastatic prostate cancer.

JCO Precis Oncol 2020 18;4:680-713. Epub 2020 Jun 18.

Siteman Cancer Center, Barnes Jewish Hospital and Washington University School of Medicine, St. Louis, MO, USA.

Purpose: Cell-free DNA (cfDNA) and circulating tumor cell (CTC) based liquid biopsies have emerged as potential tools to predict responses to androgen receptor (AR)-directed therapy in metastatic prostate cancer. However, due to complex mechanisms and incomplete understanding of genomic events involved in metastatic prostate cancer resistance, current assays (e.g. CTC AR-V7) demonstrate low sensitivity and remain underutilized. The recent discovery of enhancer amplification in >80% of metastatic patients and its association with disease resistance presents an opportunity to improve upon current assays. We hypothesized that tracking /enhancer genomic alterations in plasma cfDNA would detect resistance with high sensitivity and specificity.

Methods: We developed a targeted sequencing and analysis method as part of a new assay called Enhancer and neighboring loci of Androgen Receptor Sequencing (EnhanceAR-Seq). We applied EnhanceAR-Seq to plasma collected from 40 patients with metastatic prostate cancer treated with AR-directed therapy to monitor /enhancer genomic alterations and correlate these events with therapy resistance, progression-free survival (PFS) and overall survival (OS).

Results: EnhanceAR-Seq identified genomic alterations in the /enhancer locus in 45% of cases, including a 40% rate of enhancer amplification. Patients with /enhancer alterations had significantly worse PFS and OS than those without (6-month PFS: 30% vs. 71%, ; 6-month OS: 59% vs. 100%, ). /enhancer alterations in plasma cfDNA detected 18 of 23 resistant cases (78%) and outperformed the CTC AR-V7 assay which was also run on a subset of patients.

Conclusion: cfDNA-based locus alterations, including of the enhancer, are strongly associated with resistance to AR-directed therapy and significantly worse survival. cfDNA analysis using EnhanceAR-Seq may enable more precise risk stratification and personalized therapeutic approaches for metastatic prostate cancer.
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http://dx.doi.org/10.1200/po.20.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446541PMC
June 2020

Pan-cancer proteogenomic analysis reveals long and circular noncoding RNAs encoding peptides.

NAR Cancer 2020 Sep 11;2(3):zcaa015. Epub 2020 Aug 11.

McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA.

Recent studies show that annotated long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) encode for stable, functional peptides that contribute to human development and disease. To systematically discover lncRNAs and circRNAs encoding peptides, we performed a comprehensive integrative analysis of mass spectrometry-based proteomic and transcriptomic sequencing data from >900 patients across nine cancer types. This enabled us to identify 19,871 novel peptides derived from 8,903 lncRNAs. Further, we exploited open reading frames overlapping the backspliced region of circRNAs to identify 3,238 peptides that are uniquely derived from 2,834 circRNAs and not their corresponding linear RNAs. Collectively, our pan-cancer proteogenomic analysis will serve as a resource for evaluating the coding potential of lncRNAs and circRNAs that could aid future mechanistic studies exploring their function in cancer.
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http://dx.doi.org/10.1093/narcan/zcaa015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418880PMC
September 2020

The DNA methylation landscape of advanced prostate cancer.

Nat Genet 2020 08 13;52(8):778-789. Epub 2020 Jul 13.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer.
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http://dx.doi.org/10.1038/s41588-020-0648-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454228PMC
August 2020

The clonal evolution of metastatic colorectal cancer.

Sci Adv 2020 Jun 10;6(24):eaay9691. Epub 2020 Jun 10.

The Alvin J. Siteman Comprehensive Cancer Center, Washington University in St. Louis, St. Louis, MO, USA.

Tumor heterogeneity and evolution drive treatment resistance in metastatic colorectal cancer (mCRC). Patient-derived xenografts (PDXs) can model mCRC biology; however, their ability to accurately mimic human tumor heterogeneity is unclear. Current genomic studies in mCRC have limited scope and lack matched PDXs. Therefore, the landscape of tumor heterogeneity and its impact on the evolution of metastasis and PDXs remain undefined. We performed whole-genome, deep exome, and targeted validation sequencing of multiple primary regions, matched distant metastases, and PDXs from 11 patients with mCRC. We observed intricate clonal heterogeneity and evolution affecting metastasis dissemination and PDX clonal selection. Metastasis formation followed both monoclonal and polyclonal seeding models. In four cases, metastasis-seeding clones were not identified in any primary region, consistent with a metastasis-seeding-metastasis model. PDXs underrepresented the subclonal heterogeneity of parental tumors. These suggest that single sample tumor sequencing and current PDX models may be insufficient to guide precision medicine.
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http://dx.doi.org/10.1126/sciadv.aay9691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286679PMC
June 2020

Long non-coding RNA RAMS11 promotes metastatic colorectal cancer progression.

Nat Commun 2020 05 1;11(1):2156. Epub 2020 May 1.

Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Colorectal cancer (CRC) is the most common gastrointestinal malignancy in the U.S.A. and approximately 50% of patients develop metastatic disease (mCRC). Despite our understanding of long non-coding RNAs (lncRNAs) in primary colon cancer, their role in mCRC and treatment resistance remains poorly characterized. Therefore, through transcriptome sequencing of normal, primary, and distant mCRC tissues we find 148 differentially expressed RNAs Associated with Metastasis (RAMS). We prioritize RAMS11 due to its association with poor disease-free survival and promotion of aggressive phenotypes in vitro and in vivo. A FDA-approved drug high-throughput viability assay shows that elevated RAMS11 expression increases resistance to topoisomerase inhibitors. Subsequent experiments demonstrate RAMS11-dependent recruitment of Chromobox protein 4 (CBX4) transcriptionally activates Topoisomerase II alpha (TOP2α). Overall, recent clinical trials using topoisomerase inhibitors coupled with our findings of RAMS11-dependent regulation of TOP2α supports the potential use of RAMS11 as a biomarker and therapeutic target for mCRC.
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http://dx.doi.org/10.1038/s41467-020-15547-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195452PMC
May 2020

Long non-coding RNA is associated with lung adenocarcinoma prognosis.

Heliyon 2020 Mar 5;6(3):e03521. Epub 2020 Mar 5.

Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Background: More than half of non-small cell lung cancer (NSCLC) patients present with metastatic disease at initial diagnosis with an estimated five-year survival rate of ~5%. Despite advances in understanding primary lung cancer oncogenesis metastatic disease remains poorly characterized. Recent studies demonstrate important roles of long non-coding RNAs (lncRNAs) in tumor physiology and as prognostic markers. Therefore, we present the first transcriptome analysis to identify lncRNAs altered in metastatic lung adenocarcinoma leading to the discovery and characterization of the lncRNA as a prognostic biomarker.

Patients And Methods: RNA-Seq, microarray, nanoString expression, and clinical data from 1,116 LUAD patients across six independent cohorts and 83 LUAD cell lines were used to discover and evaluate the survival association of metastasis associated lncRNAs. Coexpression and gene set enrichment analyses were used to establish gene regulatory networks and implicate metastasis associated lncRNAs in specific biological processes.

Results: Our integrative analysis discovered as the most down-regulated lncRNA in metastasis. Further low expression promoted aggressive phenotypes and regulated genes associated with metastasis (such as metastasis repressor ). Low expression corresponded to poor overall patient survival across five independent lung adenocarcinoma cohorts ( = 881) including our own nanoString validation cohort.

Conclusion: We discovered that was down-regulated in lung cancer progression to promote invasive phenotypes, and lower expression was significantly associated with poor patient outcome and aggressive lung adenocarcinoma.
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http://dx.doi.org/10.1016/j.heliyon.2020.e03521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062942PMC
March 2020

Heparin-based hydrogel scaffolding alters the transcriptomic profile and increases the chemoresistance of MDA-MB-231 triple-negative breast cancer cells.

Biomater Sci 2020 May 24;8(10):2786-2796. Epub 2020 Feb 24.

Graduate Program in Translational Biology, Medicine and Health, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.

The tumor microenvironment plays a critical role in the proliferation and chemoresistance of cancer cells. Growth factors (GFs) are known to interact with the extracellular matrix (ECM) via heparin binding sites, and these associations influence cell behavior. In the present study, we demonstrate the ability to define signals presented by the scaffold by pre-mixing growth factors, such as epidermal growth factor, into the heparin-based (HP-B) hydrogel prior to gelation. In the 3D biomimetic microenvironment, breast cancer cells formed spheroids within 24 hours of initial seeding. Despite higher number of proliferating cells in 2D cultures, 3D spheroids exhibited a higher degree of chemoresistance after 72 hours. Further, our RNA sequencing results highlighted the phenotypic changes influenced by solid-phase GF presentation. Wnt/β-catenin and TGF-β signaling were upregulated in the cells grown in the hydrogel, while apoptosis, IL2-STAT5 and PI3K-AKT-mTOR signaling were downregulated. With emerging technologies for precision medicine in cancer, this nature of fine-tuning the microenvironment is paramount for cultivation and downstream characterization of primary cancer cells and rare circulating tumor cells (CTCs), and effective screening of chemotherapeutic agents.
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http://dx.doi.org/10.1039/c9bm01481kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497406PMC
May 2020

Diverse Gene Rearrangements Mediate Resistance to Androgen Receptor Inhibitors in Metastatic Prostate Cancer.

Clin Cancer Res 2020 04 13;26(8):1965-1976. Epub 2020 Jan 13.

Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.

Purpose: Prostate cancer is the second leading cause of male cancer deaths. Castration-resistant prostate cancer (CRPC) is a lethal stage of the disease that emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. The purpose of this study was to identify genomic mechanisms that contribute to the development and progression of CRPC.

Experimental Design: We used whole-genome and targeted DNA-sequencing approaches to identify mechanisms underlying CRPC in an aggregate cohort of 272 prostate cancer patients. We analyzed structural rearrangements at the genome-wide level and carried out a detailed structural rearrangement analysis of the locus. We used genome engineering to perform experimental modeling of gene rearrangements and long-read RNA sequencing to analyze effects on expression of AR and truncated AR variants (AR-V).

Results: was among the most frequently rearranged genes in CRPC tumors. gene rearrangements promoted expression of diverse AR-V species. gene rearrangements occurring in the context of amplification correlated with AR overexpression. Cell lines with experimentally derived gene rearrangements displayed high expression of tumor-specific AR-Vs and were resistant to endocrine therapies, including the AR antagonist enzalutamide.

Conclusions: gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165042PMC
April 2020

Gene Fusion Discovery with INTEGRATE.

Methods Mol Biol 2020 ;2079:41-68

Division of Oncology, Department of Internal Medicine, Siteman Cancer Center, McDonell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.

Next-generation sequencing (NGS) has become the primary technology for discovering gene fusions. Decreasing NGS costs have resulted in a growing quantity of patients with whole transcriptome sequencing (RNA-seq) and whole genome sequencing (WGS) data. We developed a gene fusion discovery tool, INTEGRATE, that leverages both RNA-seq and WGS data to reconstruct gene fusion junctions and genomic breakpoints by split-read alignment. INTEGRATE has become widely adopted by the larger cancer research community to discover biologically and clinically relevant gene fusions. Here we explain the rationale driving the development of the INTEGRATE tool and describe the detailed practical procedures for applying INTEGRATE to discover gene fusions using NGS data. INTEGRATE can be applied to both combined data and RNA-seq only data.
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http://dx.doi.org/10.1007/978-1-4939-9904-0_4DOI Listing
December 2020

Sclerosing epithelioid mesenchymal neoplasm of the pancreas - a proposed new entity.

Mod Pathol 2020 03 5;33(3):456-467. Epub 2019 Aug 5.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

We have encountered pancreatic tumors with unique histologic features, which do not conform to any of the known tumors of the pancreas or other anatomical sites. We aimed to define their clinicopathologic features and whether they are characterized by recurrent molecular signatures. Eight cases were identified; studied histologically and by immunohistochemistry. Selected cases were also subjected to whole-exome sequencing (WES; n = 4), RNA-sequencing (n = 6), Archer FusionPlex assay (n = 5), methylation profiling using the Illumina MethylationEPIC (850k) array platform (n = 6), and TERT promoter sequencing (n = 5). Six neoplasms occurred in females. The mean age was 43 years (range: 26-75). Five occurred in the head/neck of the pancreas. All patients were treated surgically; none received neoadjuvant/adjuvant therapy. All patients are free of disease after 53 months of median follow-up (range: 8-94). The tumors were well-circumscribed, and the median size was 1.8 cm (range: 1.3-5.8). Microscopically, the unencapsulated tumors had a geographic pattern of epithelioid cell nests alternating with spindle cell fascicles. Some areas showed dense fibrosis, in which enmeshed tumor cells imparted a slit-like pattern. The predominant epithelioid cells had scant cytoplasm and round-oval nuclei with open chromatin. The spindle cells displayed irregular, hyperchromatic nuclei. Mitoses were rare. No lymph node metastases were identified. All tumors were positive for vimentin, CD99 and cytokeratin (patchy), while negative for markers of solid pseudopapillary neoplasm, neuroendocrine, acinar, myogenic/rhabdoid, vascular, melanocytic, or lymphoid differentiation, gastrointestinal stromal tumor as well as MUC4. Whole-exome sequencing revealed no recurrent somatic mutations or amplifications/homozygous deletions in any known oncogenes or tumor suppressor genes. RNA-sequencing and the Archer FusionPlex assay did not detect any recurrent likely pathogenic gene fusions. Single sample gene set enrichment analysis revealed that these tumors display a likely mesenchymal transcriptomic program. Unsupervised analysis (t-SNE) of their methylation profiles against a set of different mesenchymal neoplasms demonstrated a distinct methylation pattern. Here, we describe pancreatic neoplasms with unique morphologic/immunophenotypic features and a distinct methylation pattern, along with a lack of abnormalities in any of key genetic drivers, supporting that these neoplasms represent a novel entity with an indolent clinical course. Given their mesenchymal transcriptomic features, we propose the designation of "sclerosing epithelioid mesenchymal neoplasm" of the pancreas.
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http://dx.doi.org/10.1038/s41379-019-0334-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000300PMC
March 2020

Novel RB1-Loss Transcriptomic Signature Is Associated with Poor Clinical Outcomes across Cancer Types.

Clin Cancer Res 2019 Jul 22;25(14):4290-4299. Epub 2019 Apr 22.

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.

Purpose: Rb-pathway disruption is of great clinical interest, as it has been shown to predict outcomes in multiple cancers. We sought to develop a transcriptomic signature for detecting biallelic loss (RBS) that could be used to assess the clinical implications of loss on a pan-cancer scale.

Experimental Design: We utilized data from the Cancer Cell Line Encyclopedia ( = 995) to develop the first pan-cancer transcriptomic signature for predicting biallelic loss (RBS). Model accuracy was validated using The Cancer Genome Atlas (TCGA) Pan-Cancer dataset ( = 11,007). RBS was then used to assess the clinical relevance of biallelic loss in TCGA Pan-Cancer and in an additional metastatic castration-resistant prostate cancer (mCRPC) cohort.

Results: RBS outperformed the leading existing signature for detecting biallelic loss across all cancer types in TCGA Pan-Cancer (AUC, 0.89 vs. 0.66). High RBS ( biallelic loss) was associated with promoter hypermethylation ( = 0.008) and gene body hypomethylation ( = 0.002), suggesting RBS could detect epigenetic gene silencing. TCGA Pan-Cancer clinical analyses revealed that high RBS was associated with short progression-free ( < 0.00001), overall ( = 0.0004), and disease-specific ( < 0.00001) survival. On multivariable analyses, high RBS was predictive of shorter progression-free survival in TCGA Pan-Cancer ( = 0.03) and of shorter overall survival in mCRPC ( = 0.004) independently of the number of DNA alterations in .

Conclusions: Our study provides the first validated tool to assess biallelic loss across cancer types based on gene expression. RBS can be useful for analyzing datasets with or without DNA-sequencing results to investigate the emerging prognostic and treatment implications of Rb-pathway disruption..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883384PMC
July 2019

Genomic Drivers of Poor Prognosis and Enzalutamide Resistance in Metastatic Castration-resistant Prostate Cancer.

Eur Urol 2019 11 28;76(5):562-571. Epub 2019 Mar 28.

Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.

Background: Metastatic castration-resistant prostate cancer (mCRPC) is the lethal form of the disease. Several recent studies have identified genomic alterations in mCRPC, but the clinical implications of these genomic alterations have not been fully elucidated.

Objective: To use whole-genome sequencing (WGS) to assess the association between key driver gene alterations and overall survival (OS), and to use whole-transcriptome RNA sequencing to identify genomic drivers of enzalutamide resistance.

Design, Setting, And Participants: We performed survival analyses and gene set enrichment analysis (GSEA) on WGS and RNA sequencing results for a cohort of 101 mCRPC patients.

Outcome Measurements And Statistical Analysis: OS was the clinical endpoint for all univariate and multivariable survival analyses. Candidate drivers of enzalutamide resistance were identified in an unbiased manner, and mutations of the top candidate were further assessed for enrichment among enzalutamide-resistant patients using Fisher's exact test.

Results And Limitations: Harboring two DNA alterations in RB1 was independently predictive of poor OS (median 14.1 vs 42.0mo; p=0.007) for men with mCRPC. GSEA identified the Wnt/β-catenin pathway as the top differentially modulated pathway among enzalutamide-resistant patients. Furthermore, β-catenin mutations were exclusive to enzalutamide-resistant patients (p=0.01) and independently predictive of poor OS (median 13.6 vs 41.7mo; p=0.025).

Conclusions: The presence of two RB1 DNA alterations identified in our WGS analysis was independently associated with poor OS among men with mCRPC. The Wnt/β-catenin pathway plays an important role in enzalutamide resistance, with differential pathway expression and enrichment of β-catenin mutations in enzalutamide-resistant patients. Moreover, β-catenin mutations were predictive of poor OS in our cohort.

Patient Summary: We observed a correlation between genomic findings for biopsy samples from metastases from men with metastatic castration-resistant prostate cancer (mCRPC) and clinical outcomes. This work sheds new light on clinically relevant genomic alterations in mCRPC and provides a roadmap for the development of new personalized treatment regimens in mCRPC.
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http://dx.doi.org/10.1016/j.eururo.2019.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764911PMC
November 2019

Clinical and Genomic Implications of Luminal and Basal Subtypes Across Carcinomas.

Clin Cancer Res 2019 04 20;25(8):2450-2457. Epub 2018 Dec 20.

Department of Radiation Oncology, University of California San Francisco, San Francisco, California.

Purpose: Carcinomas originate from epithelial tissues, which have apical (luminal) and basal orientations. The degree of luminal versus basal differentiation in cancer has been shown to be biologically important in some carcinomas and impacts treatment response.

Experimental Design: Although prior studies have focused on individual cancer types, we used a modified clinical-grade classifier (PAM50) to subtype 8,764 tumors across 22 different carcinomas into luminal A, luminal B, and basal-like tumors.

Results: We found that all epithelial tumors demonstrated similar gene expression-based luminal/basal subtypes. As expected, basal-like tumors were associated with increased expression of the basal markers KRT5/6 and KRT14, and luminal-like tumors were associated with increased expression of the luminal markers KRT20. Luminal A tumors consistently had improved outcomes compared with basal across many tumor types, with luminal B tumors falling between the two. Basal tumors had the highest rates of TP53 and RB1 mutations and copy number loss. Luminal breast, cervical, ovarian, and endometrial tumors had increased ESR1 expression, and luminal prostate, breast, cervical, and bladder tumors had increased androgen receptor (AR) expression. Furthermore, luminal B tumors had the highest rates of AR and ESR1 mutations and had increased sensitivity to bicalutamide and tamoxifen. Luminal B tumors were more sensitive to gemcitabine, and basal tumors were more sensitive to docetaxel.

Conclusions: This first pan-carcinoma luminal/basal subtyping across epithelial tumors reveals global similarities across carcinomas in the transcriptome, genome, clinical outcomes, and drug sensitivity, emphasizing the biological and translational importance of these luminal versus basal subtypes.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3121DOI Listing
April 2019

CD4+ T cells induce rejection of urothelial tumors after immune checkpoint blockade.

JCI Insight 2018 12 6;3(23). Epub 2018 Dec 6.

Department of Internal Medicine, Division of Oncology.

Immune checkpoint blockade (ICB) provides clinical benefit to a minority of patients with urothelial carcinoma (UC). The role of CD4+ T cells in ICB-induced antitumor activity is not well defined; however, CD4+ T cells are speculated to play a supportive role in the development of CD8+ T cells that kill tumor cells after recognition of tumor antigens presented by MHC class I. To investigate the mechanisms of ICB-induced activity against UC, we developed mouse organoid-based transplantable models that have histologic and genetic similarity to human bladder cancer. We found that ICB can induce tumor rejection and protective immunity with these systems in a manner dependent on CD4+ T cells but not reliant on CD8+ T cells. Evaluation of tumor infiltrates and draining lymph nodes after ICB revealed expansion of IFN-γ-producing CD4+ T cells. Tumor cells in this system express MHC class I, MHC class II, and the IFN-γ receptor (Ifngr1), but none were necessary for ICB-induced tumor rejection. IFN-γ neutralization blocked ICB activity, and, in mice depleted of CD4+ T cells, IFN-γ ectopically expressed in the tumor microenvironment was sufficient to inhibit growth of tumors in which the epithelial compartment lacked Ifngr1. Our findings suggest unappreciated CD4+ T cell-dependent mechanisms of ICB activity, principally mediated through IFN-γ effects on the microenvironment.
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http://dx.doi.org/10.1172/jci.insight.121062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328023PMC
December 2018

Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer.

Cell Rep 2018 08;24(6):1434-1444.e7

Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.

RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1-6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective.
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http://dx.doi.org/10.1016/j.celrep.2018.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171747PMC
August 2018

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer.

Cell 2018 07 19;174(3):758-769.e9. Epub 2018 Jul 19.

Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA.

While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.
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http://dx.doi.org/10.1016/j.cell.2018.06.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425931PMC
July 2018

Proteogenomic Analysis of Surgically Resected Lung Adenocarcinoma.

J Thorac Oncol 2018 10 11;13(10):1519-1529. Epub 2018 Jul 11.

Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. Electronic address:

Introduction: Despite apparently complete surgical resection, approximately half of resected early-stage lung cancer patients relapse and die of their disease. Adjuvant chemotherapy reduces this risk by only 5% to 8%. Thus, there is a need for better identifying who benefits from adjuvant therapy, the drivers of relapse, and novel targets in this setting.

Methods: RNA sequencing and liquid chromatography/liquid chromatography-mass spectrometry proteomics data were generated from 51 surgically resected non-small cell lung tumors with known recurrence status.

Results: We present a rationale and framework for the incorporation of high-content RNA and protein measurements into integrative biomarkers and show the potential of this approach for predicting risk of recurrence in a group of lung adenocarcinomas. In addition, we characterize the relationship between mRNA and protein measurements in lung adenocarcinoma and show that it is outcome specific.

Conclusions: Our results suggest that mRNA and protein data possess independent biological and clinical importance, which can be leveraged to create higher-powered expression biomarkers.
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http://dx.doi.org/10.1016/j.jtho.2018.06.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135954PMC
October 2018

INTEGRATE-Vis: a tool for comprehensive gene fusion visualization.

Sci Rep 2017 12 19;7(1):17808. Epub 2017 Dec 19.

McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, 63110, USA.

Despite the increasing quantity of tools for accurately predicting gene fusion candidates from sequencing data, we are still faced with the critical challenge of visualizing the corresponding gene fusion products to infer their biological consequence (i.e. novel protein and increased gene expression). This is currently accomplished by manually inspecting and inferring the biological consequence of top scoring gene fusion candidates. This labor-intensive process could be made easier by automating the annotation of gene fusion products and generating easily interpretable visualizations. We developed a gene fusion visualization tool, called INTEGRATE-Vis, that generates comprehensive, highly customizable, publication-quality graphics focused on annotating each gene fusion at the transcript- and protein-level and assessing expression within an individual sample or across a patient cohort. INTEGRATE-Vis is the first comprehensive gene fusion visualization tool to help a user infer the potential consequence of a gene fusion event. It has potential utility in both research and clinical settings. INTEGRATE-Vis is available at https://github.com/ChrisMaherLab/INTEGRATE-Vis .
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http://dx.doi.org/10.1038/s41598-017-18257-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736641PMC
December 2017

Genomic and transcriptomic heterogeneity in metaplastic carcinomas of the breast.

NPJ Breast Cancer 2017 1;3:48. Epub 2017 Dec 1.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA.

Metaplastic breast cancer (MBC) is a rare special histologic type of triple-negative breast cancer, characterized by the presence of neoplastic cells showing differentiation towards squamous epithelium and/or mesenchymal elements. Here we sought to define whether histologically distinct subgroups of MBCs would be underpinned by distinct genomic and/or transcriptomic alterations. Microarray-based copy number profiling identified limited but significant differences between the distinct MBC subtypes studied here, despite the limited sample size ( = 17). In particular, we found that, compared to MBCs with chondroid or squamous cell metaplasia, MBCs with spindle cell differentiation less frequently harbored gain of 7q11.22-23 encompassing and , consistent with their lower expression of claudins and their association with the claudin-low molecular classification. Microarray-based and RNA-sequencing-based gene expression profiling revealed that MBCs with spindle cell differentiation differ from MBCs with chondroid or squamous cell metaplasia on the expression of epithelial-to-mesenchymal transition-related genes, including down-regulation of and . In addition, RNA-sequencing revealed that the histologic patterns observed in MBCs are unlikely to be underpinned by a highly recurrent expressed fusion gene or a pathognomonic expressed mutation in cancer genes. Loss of PTEN expression or mutations affecting or observed in 8/17 MBCs support the contention that PI3K pathway activation plays a role in the development of MBCs. Our data demonstrate that despite harboring largely similar patterns of gene copy number alterations, MBCs with spindle cell, chondroid and squamous differentiation are distinct at the transcriptomic level but are unlikely to be defined by specific pathognomonic genetic alterations.
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http://dx.doi.org/10.1038/s41523-017-0048-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711926PMC
December 2017

Increased breast tissue receptor activator of nuclear factor-κB ligand (RANKL) gene expression is associated with higher mammographic density in premenopausal women.

Oncotarget 2017 Sep 17;8(43):73787-73792. Epub 2017 May 17.

The McDonnell Genome Institute, and Department of Medicine, Washington University, St. Louis, MO, USA.

Increased mammographic breast density is associated with a 4-6-fold increased risk of breast cancer, yet lifestyle factors that can reduce dense breasts are yet to be identified, and viable prevention strategies to reduce breast density-associated breast cancer development are yet to be developed. We investigated the associations of breast tissue receptor activator of nuclear factor-κB (RANK) pathway gene expression with mammographic density in 48 premenopausal women, with no previous history of cancer. Gene expression levels were measured in total RNA isolated from formalin-fixed paraffin-embedded breast tissue samples, using the NanoString nCounter platform. Mammographic density was classified based on the American College of Radiology Breast Imaging Reporting and Data (BI-RADS). Linear regression was used to evaluate associations between gene expression and mammographic density. The mean age of participants was 44.4 years. Women with higher breast tissue RANKL () (-value = 0.0076), and TNF (-value = 0.007) gene expression had higher mammographic density. Our finding provides mechanistic support for a breast cancer chemoprevention trial with a RANKL inhibitor among high-risk premenopausal women with dense breasts.
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http://dx.doi.org/10.18632/oncotarget.17909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650300PMC
September 2017
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