Publications by authors named "Qing Kay Li"

79 Publications

Proteogenomic and metabolomic characterization of human glioblastoma.

Cancer Cell 2021 Feb 11. Epub 2021 Feb 11.

Department of Medicine, Washington University in St. Louis, St. Louis, MO 63130, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63130, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63130, USA; Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63130, USA. Electronic address:

Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM is driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identify specific lipid distributions across subtypes and distinct global metabolic changes in IDH-mutated tumors. This work highlights biological relationships that could contribute to stratification of GBM patients for more effective treatment.
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http://dx.doi.org/10.1016/j.ccell.2021.01.006DOI Listing
February 2021

Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma.

Cancer Cell 2021 Jan 7. Epub 2021 Jan 7.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

We present a proteogenomic study of 108 human papilloma virus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs). Proteomic analysis systematically catalogs HNSCC-associated proteins and phosphosites, prioritizes copy number drivers, and highlights an oncogenic role for RNA processing genes. Proteomic investigation of mutual exclusivity between FAT1 truncating mutations and 11q13.3 amplifications reveals dysregulated actin dynamics as a common functional consequence. Phosphoproteomics characterizes two modes of EGFR activation, suggesting a new strategy to stratify HNSCCs based on EGFR ligand abundance for effective treatment with inhibitory EGFR monoclonal antibodies. Widespread deletion of immune modulatory genes accounts for low immune infiltration in immune-cold tumors, whereas concordant upregulation of multiple immune checkpoint proteins may underlie resistance to anti-programmed cell death protein 1 monotherapy in immune-hot tumors. Multi-omic analysis identifies three molecular subtypes with high potential for treatment with CDK inhibitors, anti-EGFR antibody therapy, and immunotherapy, respectively. Altogether, proteogenomics provides a systematic framework to inform HNSCC biology and treatment.
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http://dx.doi.org/10.1016/j.ccell.2020.12.007DOI Listing
January 2021

Proteomic signatures of 16 major types of human cancer reveal universal and cancer-type-specific proteins for the identification of potential therapeutic targets.

J Hematol Oncol 2020 12 7;13(1):170. Epub 2020 Dec 7.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, 21231, USA.

Background: Proteomic characterization of cancers is essential for a comprehensive understanding of key molecular aberrations. However, proteomic profiling of a large cohort of cancer tissues is often limited by the conventional approaches.

Methods: We present a proteomic landscape of 16 major types of human cancer, based on the analysis of 126 treatment-naïve primary tumor tissues, 94 tumor-matched normal adjacent tissues, and 12 normal tissues, using mass spectrometry-based data-independent acquisition approach.

Results: In our study, a total of 8527 proteins were mapped to brain, head and neck, breast, lung (both small cell and non-small cell lung cancers), esophagus, stomach, pancreas, liver, colon, kidney, bladder, prostate, uterus and ovary cancers, including 2458 tissue-enriched proteins. Our DIA-based proteomic approach has characterized major human cancers and identified universally expressed proteins as well as tissue-type-specific and cancer-type-specific proteins. In addition, 1139 therapeutic targetable proteins and 21 cancer/testis (CT) antigens were observed.

Conclusions: Our discoveries not only advance our understanding of human cancers, but also have implications for the design of future large-scale cancer proteomic studies to assist the development of diagnostic and/or therapeutic targets in multiple cancers.
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http://dx.doi.org/10.1186/s13045-020-01013-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720039PMC
December 2020

Integrated Proteomic and Glycoproteomic Characterization of Human High-Grade Serous Ovarian Carcinoma.

Cell Rep 2020 Oct;33(3):108276

Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287, USA. Electronic address:

Many gene products exhibit great structural heterogeneity because of an array of modifications. These modifications are not directly encoded in the genomic template but often affect the functionality of proteins. Protein glycosylation plays a vital role in proper protein functions. However, the analysis of glycoproteins has been challenging compared with other protein modifications, such as phosphorylation. Here, we perform an integrated proteomic and glycoproteomic analysis of 83 prospectively collected high-grade serous ovarian carcinoma (HGSC) and 23 non-tumor tissues. Integration of the expression data from global proteomics and glycoproteomics reveals tumor-specific glycosylation, uncovers different glycosylation associated with three tumor clusters, and identifies glycosylation enzymes that were correlated with the altered glycosylation. In addition to providing a valuable resource, these results provide insights into the potential roles of glycosylation in the pathogenesis of HGSC, with the possibility of distinguishing pathological outcomes of ovarian tumors from non-tumors, as well as classifying tumor clusters.
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http://dx.doi.org/10.1016/j.celrep.2020.108276DOI Listing
October 2020

Multimodal genomic features predict outcome of immune checkpoint blockade in non-small-cell lung cancer.

Nat Cancer 2020 Jan 13;1(1):99-111. Epub 2020 Jan 13.

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Despite progress in immunotherapy, identifying patients that respond has remained a challenge. Through analysis of whole-exome and targeted sequence data from 5,449 tumors, we found a significant correlation between tumor mutation burden (TMB) and tumor purity, suggesting that low tumor purity tumors are likely to have inaccurate TMB estimates. We developed a new method to estimate a corrected TMB (cTMB) that was adjusted for tumor purity and more accurately predicted outcome to immune checkpoint blockade (ICB). To identify improved predictive markers together with cTMB, we performed whole-exome sequencing for 104 lung tumors treated with ICB. Through comprehensive analyses of sequence and structural alterations, we discovered a significant enrichment in activating mutations in receptor tyrosine kinase (RTK) genes in nonresponding tumors in three immunotherapy treated cohorts. An integrated multivariable model incorporating cTMB, RTK mutations, smoking-related mutational signature and human leukocyte antigen status provided an improved predictor of response to immunotherapy that was independently validated.
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http://dx.doi.org/10.1038/s43018-019-0008-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7514475PMC
January 2020

Submucosal Tunneling Endoscopic Resection for the Management of Heterotopic Pancreas With Cystic Degeneration.

ACG Case Rep J 2020 Jul 9;7(7):e00419. Epub 2020 Jul 9.

Division of Gastroenterology and Hepatology, Johns Hopkins Medical Institutions, Baltimore, MD.

Heterotopic pancreas is pancreatic tissue present outside of the normal location of the pancreas. In the presence of cystic degeneration, heterotopic pancreas is clinically significant because of the symptoms it causes and its physical resemblance to cancerous growth. A diagnosis of heterotopic pancreas is achieved with the aid of various endoscopic techniques for tissue removal. Submucosal tunneling endoscopic resection has proven successful for the resection of gastric subepithelial masses. We present a 53-year-old woman undergoing submucosal tunneling endoscopic resection for the resection of a subepithelial gastric cyst caused by heterotopic pancreas with cystic degeneration.
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http://dx.doi.org/10.14309/crj.0000000000000419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357709PMC
July 2020

Proteomic Analysis of the Air-Way Fluid in Lung Cancer. Detection of Periostin in Bronchoalveolar Lavage (BAL).

Front Oncol 2020 3;10:1072. Epub 2020 Jul 3.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.

Bronchoalveolar lavage (BAL) is a specific type of air-way fluid. It is a commonly used clinical specimen for the diagnosis of benign diseases and cancers of the lung. Although previous studies have identified several disease-associated proteins in the BAL, the potential utility of BAL in lung cancer is still not well-studied. Based upon the fact that the majority of secreted proteins are glycoproteins, we have profiled -glycoproteins in BAL collected from lung cancers, and investigated the expression of glycoproteins such as the matrix glycoprotein, periostin, in lung cancers. BAL specimens ( = 16) were collected from lung cancer patients, and analyzed using mass spectrometry-based quantitative -glycoproteomic technique. Additional BAL specimens ( = 39) were independently collected to further evaluate the expression of periostin by using an enzyme-linked immunosorbent assay (ELISA). A total of 462 glycoproteins were identified in BAL samples using -glycoproteomic technique, including 290 in lung adenocarcinoma (ADC, = 5), 376 in squamous cell carcinoma (SQCC, = 4), 309 in small cell lung carcinoma (SCLC, = 4), and 316 in benign lung disease ( = 3). The expressions of several glycoproteins were elevated, including 8 in ADC, 12 in SQCC, and 17 in SCLC, compared to benign BALs. The expression of periostin was detected in all subtypes of lung cancers. To further investigate the expression of periostin, an ELISA assay was performed using additional independently collected BALs ( = 39) The normalized levels of periostin in benign disease, ADC, SQCC, and SCLC were 255 ± 104 (mean ± SE) and 4,002 ± 2,181, 3,496 ± 1,765, and 1,772 ± 1,119 ng/mg of total BAL proteins. Our findings demonstrate that proteomic analysis of BAL can be used for the study of cancer-associated extracellular proteins in air-way fluid from lung cancer patients.
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http://dx.doi.org/10.3389/fonc.2020.01072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350406PMC
July 2020

Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma.

Cell 2020 07;182(1):200-225.e35

Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA. Electronic address:

To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas.
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http://dx.doi.org/10.1016/j.cell.2020.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373300PMC
July 2020

A Comprehensive Analysis of FUT8 Overexpressing Prostate Cancer Cells Reveals the Role of EGFR in Castration Resistance.

Cancers (Basel) 2020 Feb 18;12(2). Epub 2020 Feb 18.

Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.

The emergence of castration-resistance is one of the major challenges in the management of patients with advanced prostate cancer. Although the spectrum of systemic therapies that are available for use alongside androgen deprivation for treatment of castration-resistant prostate cancer (CRPC) is expanding, none of these regimens are curative. Therefore, it is imperative to apply systems approaches to identify and understand the mechanisms that contribute to the development of CRPC. Using comprehensive proteomic approaches, we show that a glycosylation-related enzyme, alpha (1,6) fucosyltransferase (FUT8), which is upregulated in CRPC, might be responsible for resistance to androgen deprivation. Mechanistically, we demonstrated that overexpression of FUT8 resulted in upregulation of the cell surface epidermal growth factor receptor (EGFR) and corresponding downstream signaling, leading to increased cell survival in androgen-depleted conditions. We studied the coregulatory mechanisms of EGFR and FUT8 expression in CRPC xenograft models and found that castration induced FUT8 overexpression associated with increased expression of EGFR. Taken together, our findings suggest a crucial role played by FUT8 as a mediator in switching prostate cancer cells from nuclear receptor signaling (androgen receptor) to the cell surface receptor (EGFR) mechanisms in escaping castration-induced cell death. These findings have clinical implication in understanding the role of FUT8 as a master regulator of cell surface receptors in cancer-resistant phenotypes.
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http://dx.doi.org/10.3390/cancers12020468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072180PMC
February 2020

An Integrated Workflow for Global, Glyco-, and Phospho-proteomic Analysis of Tumor Tissues.

Anal Chem 2020 01 3;92(2):1842-1849. Epub 2020 Jan 3.

Department of Pathology , Johns Hopkins University School of Medicine , Baltimore , Maryland 21231 , United States.

Recently, the rapid development and application of mass spectrometry (MS)-based technologies have markedly improved the comprehensive proteomic characterization of global proteome and protein post-translational modifications (PTMs). However, the current conventional approach for global proteomic analysis is often carried out separately from PTM analysis. In our study, we developed an integrated workflow for multiplex analysis of global, glyco-, and phospho-proteomics using breast cancer patient-derived xenograft (PDX) tumor samples. Our approach included the following steps: trypsin-digested tumor samples were enriched for phosphopeptides through immobilized metal ion affinity chromatography (IMAC), followed by enrichment of glycopeptides through mixed anion exchange (MAX) method, and then the flow-through peptides were analyzed for global proteomics. Our workflow demonstrated an increased identification of peptides and associated proteins in global proteome, as compared to those using the peptides without PTM depletion. In addition to global proteome, the workflow identified phosphopeptides and glycopeptides from the PTM enrichment. We also found a subset of glycans with unique distribution profiles in the IMAC flow-through, as compared to those enriched directly using the MAX method. Our integrated workflow provided an effective platform for simultaneous global proteomic and PTM analysis of biospecimens.
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http://dx.doi.org/10.1021/acs.analchem.9b03753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725359PMC
January 2020

Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma.

Cell 2019 10;179(4):964-983.e31

Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA. Electronic address:

To elucidate the deregulated functional modules that drive clear cell renal cell carcinoma (ccRCC), we performed comprehensive genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic characterization of treatment-naive ccRCC and paired normal adjacent tissue samples. Genomic analyses identified a distinct molecular subgroup associated with genomic instability. Integration of proteogenomic measurements uniquely identified protein dysregulation of cellular mechanisms impacted by genomic alterations, including oxidative phosphorylation-related metabolism, protein translation processes, and phospho-signaling modules. To assess the degree of immune infiltration in individual tumors, we identified microenvironment cell signatures that delineated four immune-based ccRCC subtypes characterized by distinct cellular pathways. This study reports a large-scale proteogenomic analysis of ccRCC to discern the functional impact of genomic alterations and provides evidence for rational treatment selection stemming from ccRCC pathobiology.
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http://dx.doi.org/10.1016/j.cell.2019.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331093PMC
October 2019

Transthoracic fine-needle aspiration diagnosis of solid, subsolid, and partially calcified lung nodules: A retrospective study from a single academic center.

Cytojournal 2019 22;16:16. Epub 2019 Aug 22.

Address: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Background: The large-scale National Lung Cancer Screening Trial demonstrated an increased detection of early-stage lung cancers using low-dose computed tomography scan in the screening population. It also demonstrated a 20% reduction of lung cancer-related deaths in these patients.

Aims: Although both solid and subsolid lung nodules are evaluated in studies, subsolid and partially calcified lung nodules are often overlooked.

Materials And Methods: We reviewed transthoracic fine-needle aspiration (FNA) cases from lung nodule patients in our clinics and correlated cytological diagnoses with radiologic characteristics of lesions. A computer search of the pathology archive was performed over a period of 12 months for transthoracic FNAs, including both CT- and ultrasound-guided biopsies.

Results: A total of 111 lung nodule cases were identified. Lesions were divided into three categories: solid, subsolid, and partially calcified nodules according to radiographic findings. Of 111 cases, the average sizes of the solid (84 cases), subsolid (22 cases), and calcified (5 cases) lesions were 1.952 ± 2.225, 1.333 ± 1.827, and 1.152 ± 1.984 cm, respectively. The cytological diagnoses of three groups were compared. A diagnosis of malignancy was made in 64.28% (54 cases) in solid, 22.72% (5 cases) in subsolid, and 20% (1 case) in partially calcified nodules. Among benign lesions, eight granulomatous inflammations were identified, including one case of solid, five cases of subsolid, and two cases of calcified nodules.

Conclusions: Our study indicates that solid nodules have the highest risk of malignancy. Furthermore, the cytological evaluation of subsolid and partially calcified nodules is crucial for the accurate diagnosis and appropriate clinical management of lung nodule patients.
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http://dx.doi.org/10.4103/cytojournal.cytojournal_43_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712899PMC
August 2019

Pathologic Complete Response After Chemoradiation of a Massive Primary Urethral Carcinoma.

Adv Radiat Oncol 2019 Jul-Sep;4(3):487-491. Epub 2019 Mar 14.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland.

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http://dx.doi.org/10.1016/j.adro.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639762PMC
March 2019

Expression of p16 and p53 in non-small-cell lung cancer: clinicopathological correlation and potential prognostic impact.

Biomark Med 2019 06 3;13(9):761-771. Epub 2019 Jun 3.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA.

p16 and p53 are frequently altered intracellular pathways in cancers. We investigated the aberrant expression of p16 and its relationship with p53 and HPV status in primary non-small-cell lung carcinoma. Lung tumor tissue microarray (n = 163), immunohistochemical study of p16 and p53, and HPV hybridization were analyzed. p16 and p53 were detected in 50.7 and 57.3% of adenocarcinoma (ADCs; n = 75), and 35.2 and 63.6% of squamous cell carcinoma (n = 88). HPV was detected in 16 and 10.2% of ADC and squamous cell carcinoma. In ADCs, p16 positive tumors demonstrated a favorable median overall survival time of 60.9 months, compared with p16 negative tumors of 46.9 months (p < 0.05). Furthermore, we did not find significant relationships between p16 expression and HPV status, nor with p53 expression. p16 play an unique role in lung cancer survival. The mechanism of p16 needs to be further studied.
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http://dx.doi.org/10.2217/bmm-2018-0441DOI Listing
June 2019

Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer.

Cancer Res 2019 03 12;79(6):1214-1225. Epub 2018 Dec 12.

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients ( = 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57-18.35; = 0.007 and HR 6.91; 95% CI, 1.37-34.97; = 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non-small cell lung cancer ( = 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies. Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer..
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432636PMC
March 2019

Mapping the O-glycoproteome using site-specific extraction of O-linked glycopeptides (EXoO).

Mol Syst Biol 2018 11 20;14(11):e8486. Epub 2018 Nov 20.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Protein glycosylation is one of the most abundant post-translational modifications. However, detailed analysis of O-linked glycosylation, a major type of protein glycosylation, has been severely impeded by the scarcity of suitable methodologies. Here, a chemoenzymatic method is introduced for the site-specific extraction of O-linked glycopeptides (EXoO), which enabled the mapping of over 3,000 O-linked glycosylation sites and definition of their glycans on over 1,000 proteins in human kidney tissues, T cells, and serum. This large-scale localization of O-linked glycosylation sites demonstrated that EXoO is an effective method for defining the site-specific O-linked glycoproteome in different types of sample. Detailed structural analysis of the sites identified revealed conserved motifs and topological orientations facing extracellular space, the cell surface, the lumen of the Golgi, and the endoplasmic reticulum (ER). EXoO was also able to reveal significant differences in the O-linked glycoproteome of tumor and normal kidney tissues pointing to its broader use in clinical diagnostics and therapeutics.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6243375PMC
http://dx.doi.org/10.15252/msb.20188486DOI Listing
November 2018

Detection of RAS and RAS-associated alterations in primary lung adenocarcinomas. A correlation between molecular findings and tumor characteristics.

Hum Pathol 2019 02 25;84:18-25. Epub 2018 Sep 25.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA; Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA. Electronic address:

Rat sarcoma (RAS) and RAS-associated pathways play important roles in the pathogenesis of lung cancers and in the development of targeted therapies. However, the clinical significance of RAS pathways is still not fully understood. We investigated the RAS-associated molecular aberrations in primary lung adenocarcinomas and correlated molecular findings with clinicopathological characteristics of tumors. A total of 220 surgically resected tumors were identified for which a lung cancer molecular panel (testing 7 genes by next-generation sequencing and 3 genes for rearrangement by fluorescence in situ hybridization) had been performed. The overall molecular alterations were detected in 143 cases (65.00%), including 58 cases (26.36%) of KRAS, 40 cases (18.18%) of EGFR, 24 cases (10.91%) of BRAF, 8 cases (3.64%) of PIK3CA, 7 cases (3.18%) of NRAS, 6 cases (2.73%) of ALK alterations. KRAS, BRAF, NRAS, and PIK3CA mutations were more commonly seen in smokers and occurred with much higher rates than previously published data. BRAF mutations were commonly seen in female smokers, whereas, BRAF mutations were seen in both male and female smokers with moderately to poorly differentiated tumors. PIK3CA mutations were predominantly occurred in p.E545K and p.E542K on exon 9 in moderately to poorly differentiated tumors.
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http://dx.doi.org/10.1016/j.humpath.2018.09.004DOI Listing
February 2019

Challenges and opportunities in the proteomic characterization of clear cell renal cell carcinoma (ccRCC): A critical step towards the personalized care of renal cancers.

Semin Cancer Biol 2019 04 25;55:8-15. Epub 2018 Jul 25.

Department of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21224, United States.

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, comprising approximately 75% of all kidney tumors. Recent the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) studies have significantly advanced the molecular characterization of RCC and facilitated the development of targeted therapies. Such advances have improved the median survival of patients with advanced disease from less than 10 months prior to 2004 to 30 months by 2011. However, approximately 30% of localized ccRCC patients will nevertheless develop recurrence or metastasis after surgical resection of their tumor. Therefore, it is critical to further analyze potential tumor-associated proteins and their profiles during disease progression. Over the past decade, tremendous effort has been focused on the study of molecular pathways, including genomics, transcriptomics, and proteomics in order to identify potential molecular biomarkers, as well as to facilitate early detection, monitor tumor progression and uncover potentially therapeutic targets. In this review, we focus on recent advances in the proteomic analysis of ccRCC, current strategies and challenges, and perspectives in the field. This insight will highlight the discovery of tumor-associated proteins, and their potential clinical impact on personalized precision-based care in ccRCC.
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http://dx.doi.org/10.1016/j.semcancer.2018.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624650PMC
April 2019

De novo lipogenesis represents a therapeutic target in mutant Kras non-small cell lung cancer.

FASEB J 2018 Jun 15:fj201800204. Epub 2018 Jun 15.

Department of Pathology, Stony Brook School of Medicine, Stony Brook, New York, USA.

Oncogenic Kras mutations are one of the most common alterations in non-small cell lung cancer and are associated with poor response to treatment and reduced survival. Driver oncogenes, such as Kras are now appreciated for their ability to promote tumor growth via up-regulation of anabolic pathways. Therefore, we wanted to identify metabolic vulnerabilities in Kras-mutant lung cancer. Using the Kras lung cancer model, we show that mutant Kras drives a lipogenic gene-expression program. Stable-isotope analysis reveals that mutant Kras promotes de novo fatty acid synthesis in vitro and in vivo. The importance of fatty acid synthesis in Kras-induced tumorigenesis was evident by decreased tumor formation in Kras mice after treatment with a fatty acid synthesis inhibitor. Importantly, with gain and loss of function models of mutant Kras, we demonstrate that mutant Kras potentiates the growth inhibitory effects of several fatty acid synthesis inhibitors. These studies highlight the potential to target mutant Kras tumors by taking advantage of the lipogenic phenotype induced by mutant Kras.-Singh, A., Ruiz, C., Bhalla, K., Haley, J. A., Li, Q. K., Acquaah-Mensah, G., Montal, E., Sudini, K. R., Skoulidis, F., Wistuba, I. I., Papadimitrakopoulou, V., Heymach, J. V., Boros, L. G., Gabrielson, E., Carretero, J., Wong, K.-k., Haley, J. D., Biswal, S., Girnun, G. D. De novo lipogenesis represents a therapeutic target in mutant Kras non-small cell lung cancer.
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http://dx.doi.org/10.1096/fj.201800204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219836PMC
June 2018

PET and CT features differentiating infectious/inflammatory from malignant mediastinal lymphadenopathy: A correlated study with endobronchial ultrasound-guided transbronchial needle aspiration.

Radiol Infect Dis 2018 Mar 1;5(1):7-13. Epub 2018 Feb 1.

Department of Radiology & Radiological Sciences, The Johns Hopkins University Hospital, Phipps B-125, 600 North Wolfe Street, Baltimore, MD 21287, USA.

Purpose: To explore the advantages of differentiating inflammatory from malignant thoracic lymph nodes by integrating their features on positron emission tomography (PET) and computed tomography (CT).

Material And Method: Following institutional review board approval, PET and CT parameters of thoracic lymph nodes were examined based on their pathologic diagnosis via endobronchial ultrasound-guided transbronchial needle aspiration. The standardized uptake value (SUV) of PET and CT findings of the long- and short-axis diameters, axial short to long diameter ratios (S/L), and measured nodal CT values of the lymph nodes were compared and analyzed statistically.

Results: A total of 124 lymph nodes from 70 patients were studied. The inflammatory and malignant lymph nodes differed significantly in their SUV (P = 0.008), short-axis diameters (SAD, p < 0.001), long-axis diameters (LAD, p = 0.002) and S/L ratios (p < 0.001). They did not differ significantly in non-contrast enhanced CT values (p = 0.304). The sensitivities, specificities, positive predictive values, negative predictive values, diagnostic accuracies and diagnostic odds ratios (DOR) were: 1) elevated SUV alone - 95.31% (61/64), 20% (12/60), 55.96% (61/109), 80% (12/15), 58.87% (73/124), and 5; 2) combined SUV + SAD - 89.06%, 53.33%, 67.06%, 82.05%, 71.77%, and 9.31; 3) combined SUV + S/L ratio - 87.5%, 93.33%, 93.33%, 87.5%, 90.32%, and 98, respectively.

Conclusion: Increased SUV, SAD, LAD, and S/L ratio are accurate PET/CT parameters to characterize inflammatory or malignant lymph nodes. SUV has high sensitivity but low specificity, low positive and negative predictive values, and low DOR. The SUV + SAD and SUV + S/L ratios have higher specificity, positive and negative predictive values, diagnostic accuracy and DOR.
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http://dx.doi.org/10.1016/j.jrid.2018.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831101PMC
March 2018

Intranuclear Inclusions in Conventional Clear Cell Renal Cell Carcinoma (ccRCC): Diagnosis and Differential Diagnosis.

Arch Urol Res 2018 24;2(1):5-7. Epub 2018 Oct 24.

The Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21224.

Intranuclear inclusions are important diagnostic features in many benign and malignant neoplasms. It has also been identified in major epithelial subtypes of renal cell carcinomas (RCCs), particularly in the chromophobe RCC. However, the finding in ccRCC has not been well studied. The finding of intranuclear inclusions may cause diagnostic difficulty, particularly in metastatic lesions. Herein, we reported a case of ccRCC with prominent intranuclear inclusions. The tumor also metastasized to local lymph nodes. Furthermore, in contrast to previous publications, we also found that intranuclear inclusions were immunoreactive with anti-PAX8 (paired box8) antibody. The potential diagnostic and clinical implications of intranuclear inclusions in ccRCC need to be addressed.
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http://dx.doi.org/10.17352/aur.000003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764522PMC
October 2018

Primary parotid adenocarcinoma metastasis to the spleen with mutation: cytological findings and review of the literature.

Int J Clin Exp Pathol 2017 15;10(5):5999-6005. Epub 2017 May 15.

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore 21224, America.

Background: Primary solid tumor metastasis to the spleen is a rare event, and often presents as an incidental finding without clinical symptoms of the patient. The most common primary tumors that metastasize to the spleen are colorectal, ovarian, and lung carcinomas. Parotid tumor metastasis to the spleen is extremely rare. We report an unusual case of metastatic parotid adenocarcinoma NOS (not otherwise specified) to the spleen.

Case Report: The patient presented with primary parotid carcinoma and underwent left parotidectomy. On pathological examination of the primary parotid tumor, no vascular or perineural invasion was found; all surgical resection margins and neck lymph nodes were also uninvolved by the tumor. No other therapy was given after the surgery. Four years later, the patient developed a solitary splenic lesion detected by a routine follow-up computed tomography (CT) scan. The subsequent fine needle aspiration (FNA) and splenectomy showed a metastatic adenocarcinoma consistent with the parotid primary. Immunohistochemical (IHC) staining of the metastatic tumor also showed a similar pattern as that of the primary tumor, including positivity for pancytokeratin, S-100 and SOX10, supporting the diagnosis. Furthermore, A (phosphatidylinositol 3-kinase catalytic subunit) mutation was also detected in the splenic metastasis.

Conclusion: Based on our review of the literature, we believe that this is the first report of such a case. Accurate diagnosis and molecular characterization of the splenic metastasis have a critical impact on the clinical management of the patient.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733716PMC
July 2018

Current WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma (NSCLC): Moving from targeted therapy to immunotherapy.

Semin Cancer Biol 2018 10 26;52(Pt 1):103-109. Epub 2017 Nov 26.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21224, United States. Electronic address:

Recent large scale genomic studies from the Clinical Lung Cancer Genome Project have identified different driver gene mutations in the subtypes of non-small cell lung carcinoma (NSCLC). These findings not only lead to remarkable progress in targeted therapies for lung cancer patients, but also provide fundamental knowledge for the subclassification of NSCLC. More recently, the advancement and clinical application of immunotherapy have reinforced the need for the accurate subclassification of NSCLC. In 2015, the World Health Organization (WHO) and the International Association for the Study of Lung Cancer (IASLC) updated their guidelines for the subclassification of lung cancers. These guidelines emphasize: (1) the subclassification of NSCLC, (2) the critical role of molecular characterization of tumors for targeted therapy, (3) the unique terminology for subclassifying NSCLC using small biopsy specimens, and (4) the utility of IHC biomarkers in the accurate diagnosis and subclassification of lung cancer. The guidelines have significant prognostic impact on oncologic practice and patient care. In this review, we summarize the current WHO guidelines for the classification of lung cancer, discuss advancements of targeted therapy and immunotherapy, and address the utility and limitation of immunomarkers in the subclassification of NSCLC, as well as the prospective future of the field.
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http://dx.doi.org/10.1016/j.semcancer.2017.11.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970946PMC
October 2018

Bronchoscopy with endobronchial ultrasound guided transbronchial needle aspiration . transthoracic needle aspiration in lung cancer diagnosis and staging.

J Thorac Dis 2017 Jul;9(7):2178-2185

Section of Interventional Pulmonology, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

Background: In evaluating patients with suspected lung cancer, it is important to not only obtain a tissue diagnosis, but also to obtain enough tissue for both histologic and molecular analysis in order to appropriately stage the patient with a safe and efficient strategy. The diagnostic approach may often be dependent on local resources and practice patterns rather than current guidelines. We Describe lung cancer staging at two large academic medical centers to identify the impact different procedural approaches have on patient outcomes.

Methods: We conducted a retrospective cohort study of all patients undergoing a lung cancer diagnostic evaluation at two multidisciplinary centers during a 1-year period. Identifying complication rates and the need for multiple biopsies as our primary outcomes, we developed a multivariate regression model to determine features associated with complications and need for multiple biopsies.

Results: Of 830 patients, 285 patients were diagnosed with lung cancers during the study period. Those staged at the institution without an endobronchial ultrasound (EBUS) program were more likely to require multiple biopsies (OR 3.62, 95% CI: 1.71-7.67, P=0.001) and suffer complications associated with the diagnostic procedure (OR 10.2, 95% CI: 3.08-33.58, P<0.001). Initial staging with transthoracic needle aspiration (TTNA) and conventional bronchoscopy were associated with greater need for subsequent biopsies (OR 8.05 and 14.00, 95% CI: 3.43-18.87 and 5.17-37.86, respectively) and higher complication rates (OR 37.75 and 7.20, 95% CI: 10.33-137.96 and 1.36-37.98, respectively).

Conclusions: Lung cancer evaluation at centers with a dedicated EBUS program results in fewer biopsies and complications than at multidisciplinary counterparts without an EBUS program.
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http://dx.doi.org/10.21037/jtd.2017.07.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542941PMC
July 2017

Protein signatures of molecular pathways in non-small cell lung carcinoma (NSCLC): comparison of glycoproteomics and global proteomics.

Clin Proteomics 2017 15;14:31. Epub 2017 Aug 15.

Department of Pathology, Johns Hopkins Medicine, Smith Bldg 4013, 400 N. Broadway, Baltimore, MD 21287 USA.

Background: Non-small cell lung carcinoma (NSCLC) remains the leading cause of cancer deaths in the United States. More than half of NSCLC patients have clinical presentations with locally advanced or metastatic disease at the time of diagnosis. The large-scale genomic analysis of NSCLC has demonstrated that molecular alterations are substantially different between adenocarcinoma (ADC) and squamous cell carcinoma (SqCC). However, a comprehensive analysis of proteins and glycoproteins in different subtypes of NSCLC using advanced proteomic approaches has not yet been conducted.

Methods: We applied mass spectrometry (MS) technology featuring proteomics and glycoproteomics to analyze six primary lung SqCCs and eleven ADCs, and we compared the expression level of proteins and glycoproteins in tumors using quantitative proteomics. Glycoproteins were analyzed by enrichment using a chemoenzymatic method, solid-phase extraction of glycopeptides, and quantified by iTRAQ-LC-MS/MS. Protein quantitation was further annotated via Ingenuity Pathway Analysis.

Results: Over 6000 global proteins and 480 glycoproteins were quantitatively identified in both SqCC and ADC. ADC proteins (8337) consisted of enzymes (22.11%), kinases (5.11%), transcription factors (6.85%), transporters (6.79%), and peptidases (3.30%). SqCC proteins (6967) had a very similar distribution. The identified glycoproteins, in order of relative abundance, included membrane (42%) and extracellular matrix (>33%) glycoproteins. Oncogene-coded proteins (82) increased 1.5-fold among 1047 oncogenes identified in ADC, while 124 proteins from SqCC were up-regulated in tumor tissues among a total of 827 proteins. We identified 680 and 563 tumor suppressor genes from ADC and SqCC, respectively.

Conclusion: Our systematic analysis of proteins and glycoproteins demonstrates changes of protein and glycoprotein relative abundance in SqCC (TP53, U2AF1, and RXR) and in ADC (SMARCA4, NOTCH1, PTEN, and MST1). Among them, eleven glycoproteins were upregulated in both ADC and SqCC. Two glycoproteins (ELANE and IGFBP3) were only increased in SqCC, and six glycoproteins (ACAN, LAMC2, THBS1, LTBP1, PSAP and COL1A2) were increased in ADC. Ingenuity Pathway Analysis (IPA) showed that several crucial pathways were activated in SqCC and ADC tumor tissues.
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http://dx.doi.org/10.1186/s12014-017-9166-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557576PMC
August 2017

Direct detection of early-stage cancers using circulating tumor DNA.

Sci Transl Med 2017 Aug;9(403)

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing. We have used this approach to examine 58 cancer-related genes encompassing 81 kb. Analysis of plasma from 44 healthy individuals identified genomic changes related to clonal hematopoiesis in 16% of asymptomatic individuals but no alterations in driver genes related to solid cancers. Evaluation of 200 patients with colorectal, breast, lung, or ovarian cancer detected somatic mutations in the plasma of 71, 59, 59, and 68%, respectively, of patients with stage I or II disease. Analyses of mutations in the circulation revealed high concordance with alterations in the tumors of these patients. In patients with resectable colorectal cancers, higher amounts of preoperative circulating tumor DNA were associated with disease recurrence and decreased overall survival. These analyses provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer.
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http://dx.doi.org/10.1126/scitranslmed.aan2415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714979PMC
August 2017

INSM1 Demonstrates Superior Performance to the Individual and Combined Use of Synaptophysin, Chromogranin and CD56 for Diagnosing Neuroendocrine Tumors of the Thoracic Cavity.

Am J Surg Pathol 2017 Nov;41(11):1561-1569

Departments of *Pathology †Oncology ‡Otolaryngology, The Johns Hopkins University School of Medicine, Baltimore, MD.

Despite the importance of recognizing neuroendocrine differentiation when diagnosing tumors of the thoracic cavity, the sensitivity of traditional neuroendocrine markers is suboptimal, particularly for high-grade neuroendocrine carcinomas such as small cell lung carcinoma and large cell neuroendocrine carcinoma. To increase sensitivity, neuroendocrine markers are routinely ordered as panels of multiple immunostains where any single positive marker is regarded as sufficient evidence of neuroendocrine differentiation. Insulinoma-associated protein 1 (INSM1) is a well-validated transcription factor of neuroendocrine differentiation that has only recently been evaluated for diagnostic use. We performed INSM1 immunohistochemistry on a large series of thoracic neuroendocrine and non-neuroendocrine tumors and compared its performance to synaptophysin, chromogranin, and CD56. INSM1 was positive in 94.9% of small cell lung carcinomas and 91.3% of large cell neuroendocrine carcinomas, compared with 74.4% and 78.3% with the combined panel of traditional markers. INSM1 also stained all (100%) of the atypical carcinoids, typical carcinoids and mediastinal paragangliomas, but only 3.3% of adenocarcinomas and 4.2% of squamous cell carcinomas. Overall, INSM1 demonstrated a sensitivity of 96.4% across all grades of thoracic neuroendocrine tumors, significantly more than the 87.4% using the panel of traditional markers (P=0.02). INSM1 is sufficiently sensitive and specific to serve as a standalone first-line marker of neuroendocrine differentiation. A more restrained approach to immunohistochemical analysis of small thoracic biopsies is appropriate given the expanding demand on this limited material for therapeutic biomarker analysis.
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http://dx.doi.org/10.1097/PAS.0000000000000916DOI Listing
November 2017

Biomarkers in the accurate subclassification of non-small-cell lung carcinoma for targeted therapy: issues and prospects.

Biomark Med 2017 05;11(5):405-407

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21224, USA.

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http://dx.doi.org/10.2217/bmm-2017-0059DOI Listing
May 2017