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1. Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgery

Author

Laura M Sipe, Mehdi Chaib, Emily B Korba, Heejoon Jo, Mary Camille Lovely, Brittany R Counts, Ubaid Tanveer, Jeremiah R Holt, Jared C Clements, Neena A John, Deidre Daria, Tony N Marion, Margaret S Bohm, Radhika Sekhri, Ajeeth K Pingili, Bin Teng, James A Carson, D Neil Hayes, Matthew J Davis, Katherine L Cook, Joseph F Pierre, and Liza Makowski

Subjects
immunotherapy, obesity, sleeve gastrectomy, breast cancer, metabolic surgery, PD-L1, Medicine, Science, Biology (General), QH301-705.5
Abstract

Bariatric surgery is a sustainable weight loss approach, including vertical sleeve gastrectomy (VSG). Obesity exacerbates tumor growth, while diet-induced weight loss impairs progression. It remains unknown how bariatric surgery-induced weight loss impacts cancer progression or alters response to therapy. Using a pre-clinical model of obesity followed by VSG or diet-induced weight loss, breast cancer progression and immune checkpoint blockade therapy were investigated. Weight loss by VSG or weight-matched dietary intervention before tumor engraftment protected against obesity-exacerbated tumor progression. However, VSG was not as effective as diet in reducing tumor burden despite achieving similar weight and adiposity loss. Leptin did not associate with changes in tumor burden; however, circulating IL-6 was elevated in VSG mice. Uniquely, VSG tumors displayed elevated inflammation and immune checkpoint ligand PD-L1+ myeloid and non-immune cells. VSG tumors also had reduced T lymphocytes and markers of cytolysis, suggesting an ineffective anti-tumor microenvironment which prompted investigation of immune checkpoint blockade. While obese mice were resistant to immune checkpoint blockade, anti-PD-L1 potently impaired tumor progression after VSG through improved anti-tumor immunity. Thus, in formerly obese mice, surgical weight loss followed by immunotherapy reduced breast cancer burden. Finally, we compared transcriptomic changes in adipose tissue after bariatric surgery from patients and mouse models. A conserved bariatric surgery-associated weight loss signature (BSAS) was identified which significantly associated with decreased tumor volume. Findings demonstrate conserved impacts of obesity and bariatric surgery-induced weight loss pathways associated with breast cancer progression.

Published
2022
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2. Correction: Molecular Subtypes in Head and Neck Cancer Exhibit Distinct Patterns of Chromosomal Gain and Loss of Canonical Cancer Genes.

Author

Vonn Walter, Xiaoying Yin, Matthew D Wilkerson, Christopher R Cabanski, Ni Zhao, Ying Du, Mei Kim Ang, Michele C Hayward, Ashley H Salazar, Katherine A Hoadley, Karen Fritchie, Charles J Sailey, Mark C Weissler, William W Shockley, Adam M Zanation, Trevor Hackman, Leigh B Thorne, William D Funkhouser, Kenneth L Muldrew, Andrew F Olshan, Scott H Randell, Fred A Wright, Carol G Shores, and D Neil Hayes

Subjects
Medicine, Science
Abstract

[This corrects the article DOI: 10.1371/journal.pone.0056823.].

Published
2018
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3. Smoking and alcohol by HPV status in head and neck cancer: a Mendelian randomization study

Author

Abhinav Thakral, John JW. Lee, Tianzhichao Hou, Katrina Hueniken, Tom Dudding, Mark Gormley, Shama Virani, Andrew Olshan, Brenda Diergaarde, Andrew R. Ness, Tim Waterboer, Karl Smith-Byrne, Paul Brennan, D. Neil Hayes, Eleanor Sanderson, M. Catherine Brown, Sophie Huang, Scott V. Bratman, Anna Spreafico, John De Almeida, Joel C. Davies, Laura Bierut, Gary J. Macfarlane, Pagona Lagiou, Areti Lagiou, Jerry Polesel, Antonio Agudo, Laia Alemany, Wolfgang Ahrens, Claire M. Healy, David I. Conway, Mari Nygard, Cristina Canova, Ivana Holcatova, Lorenzo Richiardi, Ariana Znaor, David P. Goldstein, Rayjean J. Hung, Wei Xu, Geoffrey Liu, and Osvaldo Espin-Garcia

Subjects
Science
Abstract

Abstract HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = 0.003). Drinks Per Week is also linked with increased risk of both HPV-negative HNSCC (OR = 7.72, 95%CI:3.63-16.4, P = 1.00E-07) and HPV-positive HNSCC (OR = 2.66, 95%CI:1.06-6.68, P = 0.038). Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. These findings have important implications for understanding the modifying risk factors between HNSCC subtypes.

Published
2024
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4. Combined Targeted DNA Sequencing in Non-Small Cell Lung Cancer (NSCLC) Using UNCseq and NGScopy, and RNA Sequencing Using UNCqeR for the Detection of Genetic Aberrations in NSCLC.

Author

Xiaobei Zhao, Anyou Wang, Vonn Walter, Nirali M Patel, David A Eberhard, Michele C Hayward, Ashley H Salazar, Heejoon Jo, Matthew G Soloway, Matthew D Wilkerson, Joel S Parker, Xiaoying Yin, Guosheng Zhang, Marni B Siegel, Gary B Rosson, H Shelton Earp, Norman E Sharpless, Margaret L Gulley, Karen E Weck, D Neil Hayes, and Stergios J Moschos

Subjects
Medicine, Science
Abstract

The recent FDA approval of the MiSeqDx platform provides a unique opportunity to develop targeted next generation sequencing (NGS) panels for human disease, including cancer. We have developed a scalable, targeted panel-based assay termed UNCseq, which involves a NGS panel of over 200 cancer-associated genes and a standardized downstream bioinformatics pipeline for detection of single nucleotide variations (SNV) as well as small insertions and deletions (indel). In addition, we developed a novel algorithm, NGScopy, designed for samples with sparse sequencing coverage to detect large-scale copy number variations (CNV), similar to human SNP Array 6.0 as well as small-scale intragenic CNV. Overall, we applied this assay to 100 snap-frozen lung cancer specimens lacking same-patient germline DNA (07-0120 tissue cohort) and validated our results against Sanger sequencing, SNP Array, and our recently published integrated DNA-seq/RNA-seq assay, UNCqeR, where RNA-seq of same-patient tumor specimens confirmed SNV detected by DNA-seq, if RNA-seq coverage depth was adequate. In addition, we applied the UNCseq assay on an independent lung cancer tumor tissue collection with available same-patient germline DNA (11-1115 tissue cohort) and confirmed mutations using assays performed in a CLIA-certified laboratory. We conclude that UNCseq can identify SNV, indel, and CNV in tumor specimens lacking germline DNA in a cost-efficient fashion.

Published
2015
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5. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer

Author

Young Seok Ju, Ludmil B Alexandrov, Moritz Gerstung, Inigo Martincorena, Serena Nik-Zainal, Manasa Ramakrishna, Helen R Davies, Elli Papaemmanuil, Gunes Gundem, Adam Shlien, Niccolo Bolli, Sam Behjati, Patrick S Tarpey, Jyoti Nangalia, Charles E Massie, Adam P Butler, Jon W Teague, George S Vassiliou, Anthony R Green, Ming-Qing Du, Ashwin Unnikrishnan, John E Pimanda, Bin Tean Teh, Nikhil Munshi, Mel Greaves, Paresh Vyas, Adel K El-Naggar, Tom Santarius, V Peter Collins, Richard Grundy, Jack A Taylor, D Neil Hayes, David Malkin, ICGC Breast Cancer Group, ICGC Chronic Myeloid Disorders Group, ICGC Prostate Cancer Group, Christopher S Foster, Anne Y Warren, Hayley C Whitaker, Daniel Brewer, Rosalind Eeles, Colin Cooper, David Neal, Tapio Visakorpi, William B Isaacs, G Steven Bova, Adrienne M Flanagan, P Andrew Futreal, Andy G Lynch, Patrick F Chinnery, Ultan McDermott, Michael R Stratton, and Peter J Campbell

Subjects
mitochondrial DNA, somatic mutation, mutational signature, cancer genome, evolution, sequencing, Medicine, Science, Biology (General), QH301-705.5
Abstract

Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.

Published
2014
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6. Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes.

Author

Vonn Walter, Xiaoying Yin, Matthew D Wilkerson, Christopher R Cabanski, Ni Zhao, Ying Du, Mei Kim Ang, Michele C Hayward, Ashley H Salazar, Katherine A Hoadley, Karen Fritchie, Charles J Sailey, Mark C Weissler, William W Shockley, Adam M Zanation, Trevor Hackman, Leigh B Thorne, William D Funkhouser, Kenneth L Muldrew, Andrew F Olshan, Scott H Randell, Fred A Wright, Carol G Shores, and D Neil Hayes

Subjects
Medicine, Science
Abstract

Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal heterogeneous disease. Beyond the role of human papilloma virus (HPV), no validated molecular characterization of the disease has been established. Using an integrated genomic analysis and validation methodology we confirm four molecular classes of HNSCC (basal, mesenchymal, atypical, and classical) consistent with signatures established for squamous carcinoma of the lung, including deregulation of the KEAP1/NFE2L2 oxidative stress pathway, differential utilization of the lineage markers SOX2 and TP63, and preference for the oncogenes PIK3CA and EGFR. For potential clinical use the signatures are complimentary to classification by HPV infection status as well as the putative high risk marker CCND1 copy number gain. A molecular etiology for the subtypes is suggested by statistically significant chromosomal gains and losses and differential cell of origin expression patterns. Model systems representative of each of the four subtypes are also presented.

Published
2013
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7. The LKB1 tumor suppressor as a biomarker in mouse and human tissues.

Author

Yuji Nakada, Thomas G Stewart, Christopher G Peña, Song Zhang, Ni Zhao, Nabeel Bardeesy, Norman E Sharpless, Kwok-Kin Wong, D Neil Hayes, and Diego H Castrillon

Subjects
Medicine, Science
Abstract

Germline mutations in the LKB1 gene (also known as STK11) cause the Peutz-Jeghers Syndrome, and somatic loss of LKB1 has emerged as causal event in a wide range of human malignancies, including melanoma, lung cancer, and cervical cancer. The LKB1 protein is a serine-threonine kinase that phosphorylates AMP-activated protein kinase (AMPK) and other downstream targets. Conditional knockout studies in mouse models have consistently shown that LKB1 loss promotes a highly-metastatic phenotype in diverse tissues, and human studies have demonstrated a strong association between LKB1 inactivation and tumor recurrence. Furthermore, LKB1 deficiency confers sensitivity to distinct classes of anticancer drugs. The ability to reliably identify LKB1-deficient tumors is thus likely to have important prognostic and predictive implications. Previous research studies have employed polyclonal antibodies with limited success, and there is no widely-employed immunohistochemical assay for LKB1. Here we report an assay based on a rabbit monoclonal antibody that can reliably detect endogenous LKB1 protein (and its absence) in mouse and human formalin-fixed, paraffin-embedded tissues. LKB1 protein levels determined through this assay correlated strongly with AMPK phosphorylation both in mouse and human tumors, and with mRNA levels in human tumors. Our studies fully validate this immunohistochemical assay for LKB1 in paraffin-embedded formalin tissue sections. This assay should be broadly useful for research studies employing mouse models and also for the development of human tissue-based assays for LKB1 in diverse clinical settings.

Published
2013
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8. Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation.

Author

Matthew D Wilkerson, Xiaoying Yin, Vonn Walter, Ni Zhao, Christopher R Cabanski, Michele C Hayward, C Ryan Miller, Mark A Socinski, Alden M Parsons, Leigh B Thorne, Benjamin E Haithcock, Nirmal K Veeramachaneni, William K Funkhouser, Scott H Randell, Philip S Bernard, Charles M Perou, and D Neil Hayes

Subjects
Medicine, Science
Abstract

Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors.The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes.The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response.

Published
2012
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9. Integrated analyses of microRNAs demonstrate their widespread influence on gene expression in high-grade serous ovarian carcinoma.

Author

Chad J Creighton, Anadulce Hernandez-Herrera, Anders Jacobsen, Douglas A Levine, Parminder Mankoo, Nikolaus Schultz, Ying Du, Yiqun Zhang, Erik Larsson, Robert Sheridan, Weimin Xiao, Paul T Spellman, Gad Getz, David A Wheeler, Charles M Perou, Richard A Gibbs, Chris Sander, D Neil Hayes, Preethi H Gunaratne, and Cancer Genome Atlas Research Network

Subjects
Medicine, Science
Abstract

The Cancer Genome Atlas (TCGA) Network recently comprehensively catalogued the molecular aberrations in 487 high-grade serous ovarian cancers, with much remaining to be elucidated regarding the microRNAs (miRNAs). Here, using TCGA ovarian data, we surveyed the miRNAs, in the context of their predicted gene targets.Integration of miRNA and gene patterns yielded evidence that proximal pairs of miRNAs are processed from polycistronic primary transcripts, and that intronic miRNAs and their host gene mRNAs derive from common transcripts. Patterns of miRNA expression revealed multiple tumor subtypes and a set of 34 miRNAs predictive of overall patient survival. In a global analysis, miRNA:mRNA pairs anti-correlated in expression across tumors showed a higher frequency of in silico predicted target sites in the mRNA 3'-untranslated region (with less frequency observed for coding sequence and 5'-untranslated regions). The miR-29 family and predicted target genes were among the most strongly anti-correlated miRNA:mRNA pairs; over-expression of miR-29a in vitro repressed several anti-correlated genes (including DNMT3A and DNMT3B) and substantially decreased ovarian cancer cell viability.This study establishes miRNAs as having a widespread impact on gene expression programs in ovarian cancer, further strengthening our understanding of miRNA biology as it applies to human cancer. As with gene transcripts, miRNAs exhibit high diversity reflecting the genomic heterogeneity within a clinically homogeneous disease population. Putative miRNA:mRNA interactions, as identified using integrative analysis, can be validated. TCGA data are a valuable resource for the identification of novel tumor suppressive miRNAs in ovarian as well as other cancers.

Published
2012
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10. SWISS MADE: Standardized WithIn Class Sum of Squares to evaluate methodologies and dataset elements.

Author

Christopher R Cabanski, Yuan Qi, Xiaoying Yin, Eric Bair, Michele C Hayward, Cheng Fan, Jianying Li, Matthew D Wilkerson, J S Marron, Charles M Perou, and D Neil Hayes

Subjects
Medicine, Science
Abstract

Contemporary high dimensional biological assays, such as mRNA expression microarrays, regularly involve multiple data processing steps, such as experimental processing, computational processing, sample selection, or feature selection (i.e. gene selection), prior to deriving any biological conclusions. These steps can dramatically change the interpretation of an experiment. Evaluation of processing steps has received limited attention in the literature. It is not straightforward to evaluate different processing methods and investigators are often unsure of the best method. We present a simple statistical tool, Standardized WithIn class Sum of Squares (SWISS), that allows investigators to compare alternate data processing methods, such as different experimental methods, normalizations, or technologies, on a dataset in terms of how well they cluster a priori biological classes. SWISS uses Euclidean distance to determine which method does a better job of clustering the data elements based on a priori classifications. We apply SWISS to three different gene expression applications. The first application uses four different datasets to compare different experimental methods, normalizations, and gene sets. The second application, using data from the MicroArray Quality Control (MAQC) project, compares different microarray platforms. The third application compares different technologies: a single Agilent two-color microarray versus one lane of RNA-Seq. These applications give an indication of the variety of problems that SWISS can be helpful in solving. The SWISS analysis of one-color versus two-color microarrays provides investigators who use two-color arrays the opportunity to review their results in light of a single-channel analysis, with all of the associated benefits offered by this design. Analysis of the MACQ data shows differential intersite reproducibility by array platform. SWISS also shows that one lane of RNA-Seq clusters data by biological phenotypes as well as a single Agilent two-color microarray.

Published
2010
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11. Identification of a targetable JAK-STAT enriched androgen receptor and androgen receptor splice variant positive triple-negative breast cancer subtype

Author

Sarah Asemota, Wendy Effah, Kirsten L. Young, Jeremiah Holt, Linnea Cripe, Suriyan Ponnusamy, Thirumagal Thiyagarajan, Dong-Jin Hwang, Yali He, Keely Mcnamara, Daniel Johnson, Yinan Wang, Brandy Grimes, Yekta Khosrosereshki, T.J. Hollingsworth, Martin D. Fleming, Frances E. Pritchard, Ashley Hendrix, Farhan Khan, Meiyun Fan, Liza Makowski, Zheng Yin, Hironobu Sasano, D. Neil Hayes, Lawrence M. Pfeffer, Duane D. Miller, and Ramesh Narayanan

Subjects
CP: Cancer, Biology (General), QH301-705.5
Abstract

Summary: Triple-negative breast cancer (TNBC) is an aggressive subtype with no targeted therapeutics. The luminal androgen receptor (LAR) subtype constitutes 15% of TNBC and is enriched for androgen receptor (AR) and AR target genes. Here, we show that a cohort of TNBC not only expresses AR at a much higher rate (∼80%) but also expresses AR splice variants (AR-SVs) (∼20%), further subclassifying LAR-TNBC. Higher AR and AR-SV expression and corresponding aggressive phenotypes are observed predominantly in specimens obtained from African American women. LAR TNBC specimens are enriched for interferon, Janus kinase (JAK)-signal activator and transducer (STAT), and androgen signaling pathways, which are exclusive to AR-expressing epithelial cancer cells. AR- and AR-SV-expressing TNBC cell proliferation and xenograft and patient-tumor explant growth are inhibited by AR N-terminal domain-binding selective AR degrader or by a JAK inhibitor. Biochemical analysis suggests that STAT1 is an AR coactivator. Collectively, our work identifies pharmacologically targetable TNBC subtypes and identifies growth-promoting interaction between AR and JAK-STAT signaling.

Published
2023
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12. Salivary Duct Carcinoma with Rhabdoid Features of the Parotid Gland with No E-Cadherin Expression: A Report with Anti-HER2 Therapy and Review of the Literature

Author

Richa Jain, E. Ritter Sansoni, Jacqueline Angel, John P. Gleysteen, D. Neil Hayes, and Adepitan A. Owosho

Subjects
E-cadherin loss, salivary duct carcinoma, salivary gland neoplasms, immunohistochemistry, Dentistry, RK1-715
Abstract

Salivary duct carcinoma with rhabdoid features (SDC-RF) is a rare form of salivary gland neoplasm that was recently described. We report a case of SDC-RF of the parotid gland with loss of E-cadherin and decreased β-catenin expression in a 73-year-old male who presented with right facial/neck swelling and intermittent pain. Morphologically, the tumor presented with a discohesive infiltrate of isolated and cords of pleomorphic round cells containing moderate amount of eosinophilic to fine-vacuolated cytoplasm and hyperchromatic nuclei infiltrating through fibroadipose tissue and salivary parenchyma. Immunophenotypically, the tumor was positive for Cytokeratins Oscar and 7, GATA3, GCDFP, HER2, and an androgen receptor but negative for CK20, S100, p40, Melan A, CDX2, TTF1, ER, SATB2, DOG1, synaptophysin, and chromogranin. Due to its diffuse infiltrating pattern, involvement of the parapharyngeal space, supraclavicular fat pad, dermis, and skin without a defined surgical target, the tumor was deemed unresectable. Anti-HER2 therapy (Herceptin and Pertuzumab) was utilized. At the last follow-up, the patient is alive, with complete locoregional control and brain metastases. An electronic search was performed in the following registries for papers published up to June 2023: PubMed, Embase, and Web of Science. For the database searches, the keywords searched were “salivary gland”, “salivary duct carcinoma”, and “salivary duct carcinoma with rhabdoid features”. Our review of the literature identified 30 cases of SDC-RF that reveal there is a predilection for males (83%), parotid gland (72%), and patients older than the 6th decade of life (83%). Immunophenotypically, all SDC-RF cases except one were positive for AR and GCDFP (97%), 81% were positive for HER2, and loss or decreased expression of E-cadherin in 93% of cases. In conclusion, we described a rare case of SDF-RF of the parotid gland with no E-cadherin expression, decreased β-catenin expression, and its immunophenotypic profile.

Published
2023
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14. Racial Differences in Androgen Receptor (AR) and AR Splice Variants (AR-SVs) Expression in Treatment-Naïve Androgen-Dependent Prostate Cancer

Author

Farhan Khan, Obianuju Mercy Anelo, Qandeel Sadiq, Wendy Effah, Gary Price, Daniel L. Johnson, Suriyan Ponnusamy, Brandy Grimes, Michelle L. Morrison, Jay H. Fowke, D. Neil Hayes, and Ramesh Narayanan

Subjects
androgen receptor (AR), AR splice variants (AR-SV), prostate cancer, castration-resistant prostate cancer (CRPC), race, African American (AA), Biology (General), QH301-705.5
Abstract

Androgen receptor splice variants (AR-SVs) contribute to the aggressive growth of castration-resistant prostate cancer (CRPC). AR-SVs, including AR-V7, are expressed in ~30% of CRPC, but minimally in treatment-naïve primary prostate cancer (PCa). Compared to Caucasian American (CA) men, African American (AA) men are more likely to be diagnosed with aggressive/potentially lethal PCa and have shorter disease-free survival. Expression of a truncated AR in an aggressively growing patient-derived xenograft developed with a primary PCa specimen from an AA patient led us to hypothesize that the expression of AR-SVs could be an indicator of aggressive growth both in PCa progression and at the CRPC stage in AA men. Tissue microarrays (TMAs) were created from formalin-fixed paraffin-embedded (FFPE) prostatectomy tumor blocks from 118 AA and 115 CA treatment-naïve PCa patients. TMAs were stained with AR-V7-speicifc antibody and with antibodies binding to the N-terminus domain (NTD) and ligand-binding domain (LBD) of the AR. Since over 20 AR-SVs have been identified, and most AR-SVs do not as yet have a specific antibody, we considered a 2.0-fold or greater difference in the NTD vs. LBD staining as indication of potential AR-SV expression. Two AA, but no CA, patient tumors stained positively for AR-V7. AR staining with NTD and LBD antibodies was robust in most patients, with 21% of patients staining at least 2-fold more for NTD than LBD, indicating that AR-SVs other than AR-V7 are expressed in primary treatment-naïve PCa. About 24% of the patients were AR-negative, and race differences in AR expression were not statistically significant. These results indicate that AR-SVs are not restricted to CRPC, but also are expressed in primary PCa at higher rate than previously reported. Future investigation of the relative expression of NTD vs. LBD AR-SVs could guide the use of newly developed treatments targeting the NTD earlier in the treatment paradigm.

Published
2023
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15. NFE2L2Mutations Enhance Radioresistance in Head and Neck Cancer by Modulating Intratumoral Myeloid Cells

Author

Li Guan, Dhanya K. Nambiar, Hongbin Cao, Vignesh Viswanathan, Shirley Kwok, Angela B. Hui, Yuan Hou, Rachel Hildebrand, Rie von Eyben, Brittany J. Holmes, Junfei Zhao, Christina S. Kong, Nathan Wamsley, Weiruo Zhang, Michael B. Major, Seung W. Seol, John B. Sunwoo, D. Neil Hayes, Maximilian Diehn, and Quynh-Thu Le

Subjects
Cancer Research, Oncology
Abstract

Radiotherapy (RT) is one of the primary treatments of head and neck squamous cell carcinoma (HNSCC), which has a high-risk of locoregional failure (LRF). Presently, there is no reliable predictive biomarker of radioresistance in HNSCC. Here, we found that mutations in NFE2L2, which encodes Nrf2, are associated with a significantly higher rate of LRF in patients with oral cavity cancer treated with surgery and adjuvant (chemo)radiotherapy but not in those treated with surgery alone. Somatic mutation of NFE2L2 led to Nrf2 activation and radioresistance in HNSCC cells. Tumors harboring mutant Nrf2E79Q were substantially more radioresistant than tumors with wild-type Nrf2 in immunocompetent mice, whereas the difference was diminished in immunocompromised mice. Nrf2E79Q enhanced radioresistance through increased recruitment of intratumoral polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) and reduction of M1-polarized macrophages. Treatment with the glutaminase inhibitor CB-839 overcame the radioresistance induced by Nrf2E79Q or Nrf2E79K. RT increased expression of PMN-MDSC–attracting chemokines, including CXCL1, CXLC3, and CSF3, in Nrf2E79Q-expressing tumors via the TLR4, which could be reversed by CB-839. This study provides insights into the impact of NFE2L2 mutations on radioresistance and suggests that CB-839 can increase radiosensitivity by switching intratumoral myeloid cells to an antitumor phenotype, supporting clinical testing of CB-839 with RT in HNSCC with NFE2L2 mutations.Significance:NFE2L2 mutations are predictive biomarkers of radioresistance in head and neck cancer and confer sensitivity to glutaminase inhibitors to overcome radioresistance.

Published
2023
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16. A Randomized Multi-institutional Phase II Trial of Everolimus as Adjuvant Therapy in Patients with Locally Advanced Squamous Cell Cancer of the Head and Neck

Author

Cherie-Ann O. Nathan, D. Neil Hayes, Theodore Karrison, Olivier Harismendy, José M. Flores, Tara Moore-Medlin, Everett E. Vokes, J. Silvio Gutkind, Prakash Neupane, Glenn Mills, Zoukaa Sargi, Tanguy Seiwert, Juneko Grilley-Olson, Terry Day, Maura Gillison, James L. Wade, Lawrence Feldman, Gautam Jha, Mark Kozloff, Miriam O'Leary, Francis P. Worden, and Ezra E.W. Cohen

Subjects
Male, Cancer Research, Squamous Cell Carcinoma of Head and Neck, Carcinoma, Clinical Trials and Supportive Activities, Oncology and Carcinogenesis, Evaluation of treatments and therapeutic interventions, Epithelial Cells, Middle Aged, Article, Rare Diseases, Squamous Cell, Oncology, Head and Neck Neoplasms, Clinical Research, 6.1 Pharmaceuticals, Carcinoma, Squamous Cell, Humans, Female, Prospective Studies, Everolimus, Oncology & Carcinogenesis, Dental/Oral and Craniofacial Disease, Cancer
Abstract

Purpose: Investigate whether adjuvant everolimus, an mTOR inhibitor, improves progression-free survival (PFS) in advanced-stage head and neck squamous cell carcinoma (HNSCC) and provide outcomes related to correlative biological factors associated with disease control. Patients and Methods: This was a prospective, randomized, double-blind phase II trial of patients with advanced-stage HNSCC from 13 institutions who were confirmed disease-free post-definitive therapy and enrolled between December 2010 and March 2015. Patients received adjuvant everolimus or placebo daily (10 mg, oral) for a maximum of 1 year. p16 IHC as a surrogate marker for human papillomavirus infection and whole-exome sequencing were performed. Cox proportional hazard models estimated hazard rates. Log-rank tests evaluated differences in survival. The primary endpoint was PFS. Secondary endpoints and objectives included overall survival (OS) and toxicity assessment. Results: 52 patients [median (range) age, 58 (37–76) years; 43 men (83%), 9 women (17%)] were randomized to placebo (n = 24) or everolimus (n = 28). PFS favored everolimus, but was not significant [log-rank P = 0.093; HR = 0.44; 95% confidence interval (CI), 0.17–1.17]. There was no difference in OS (P = 0.29; HR = 0.57; 95% CI, 0.20–16.2). Everolimus resulted in significant improvement in PFS for p16-negative patients (n = 31; P = 0.031; HR = 0.26; 95% CI, 0.07–0.97), although subgroup analysis showed no difference for p16-positive patients (n = 21; P = 0.93). Further, PFS was significantly higher in TP53-mutated (TP53mut) patients treated with everolimus compared with placebo (log-rank P = 0.027; HR = 0.24; 95% CI, 0.06–0.95). No treatment difference was seen in patients with TP53 wild-type tumors (P = 0.79). Conclusions: p16-negative and TP53mut patients may benefit from adjuvant treatment with everolimus.

Published
2022
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18. A multicenter open-label randomized phase II study of cediranib with or without lenalidomide in iodine 131-refractory differentiated thyroid cancer

Author

Ari J. Rosenberg, Chih-Yi Liao, Theodore Karrison, Jonas A. de Souza, Francis P. Worden, Bernadette Libao, Monika K. Krzyzanowska, D. Neil Hayes, Eric Winquist, Vassiliki Saloura, Kevin Prescott, Victoria M. Villaflor, Tanguy Y. Seiwert, Rebecca B. Schechter, Walter M. Stadler, Ezra E.W. Cohen, and Everett E. Vokes

Subjects
Oncology, Hematology
Published
2023
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19. Supplementary figure 3: Cytokines and Chemokines from Concurrent Definitive Immunoradiotherapy for Patients with Stage III–IV Head and Neck Cancer and Cisplatin Contraindication

Author

Benjamin G. Vincent, Bhishamjit S. Chera, Jessica R. Bauman, Mark Christian Weissler, Hsing-Hui Wang, Karen P. McKinnon, Ranee Mehra, Christopher Hilliard, D. Neil Hayes, Colette J. Shen, Adam M. Zanation, Shetal Patel, Thomas J. Galloway, Jeffrey M. Blumberg, Trevor G. Hackman, Samip Patel, Juneko E. Grilley Olson, Allision M. Deal, Siddharth Sheth, and Jared Weiss

Abstract

Cytokines and Chemokines

Published
2023
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20. Supplementary Table ST5 from Tumor Cell Extrinsic Synaptogyrin 3 Expression as a Diagnostic and Prognostic Biomarker in Head and Neck Cancer

Author

Antonio L. Amelio, Chad V. Pecot, Wendell G. Yarbrough, Anthony C. Nichols, Gaorav P. Gupta, Andrew Olshan, D. Neil Hayes, Michele C. Hayward, Ashley H. Salazar, Stephanie Cohen, Bentley R. Midkiff, Travis P. Schrank, Peter YF. Zeng, Sunil Kumar, Alisha R. Coffey, Yi-Hsuan Tsai, Miranda B. Carper, Alessandro Porrello, Jason Tasoulas, and Ryan M. Murphy

Abstract

Descriptive statistics for HNSC patients from the CHANCE study by p16 cytoplasmic/nuclear status.

Published
2023
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21. Figure S3 from Tumor Cell Extrinsic Synaptogyrin 3 Expression as a Diagnostic and Prognostic Biomarker in Head and Neck Cancer

Author

Antonio L. Amelio, Chad V. Pecot, Wendell G. Yarbrough, Anthony C. Nichols, Gaorav P. Gupta, Andrew Olshan, D. Neil Hayes, Michele C. Hayward, Ashley H. Salazar, Stephanie Cohen, Bentley R. Midkiff, Travis P. Schrank, Peter YF. Zeng, Sunil Kumar, Alisha R. Coffey, Yi-Hsuan Tsai, Miranda B. Carper, Alessandro Porrello, Jason Tasoulas, and Ryan M. Murphy

Abstract

Additional multiplex staining coexpression and ROI quantification.

Published
2023
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22. Data from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author

Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak

Abstract

Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options.Significance:Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.See related commentary by Aggarwal and Albelda, p. 1508.This article is highlighted in the In This Issue feature, p. 1494

Published
2023
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23. Data from Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors

Author

Kwok-Kin Wong, Glenn Dranoff, Peter S. Hammerman, Gordon J. Freeman, Scott J. Rodig, Lynette M. Sholl, Takeshi Shimamura, Geoffrey I. Shapiro, D. Neil Hayes, Matthew Meyerson, Pasi A. Janne, Travis J. Cohoon, Margaret Soucheray, Jacob B. Reibel, Mohit Butaney, Peter E. Fecci, Matthew D. Wilkerson, Trevor J. Pugh, Ellen M. Beauchamp, Andrew D. Cherniack, Oliver R. Mikse, Camilla L. Christensen, Jeremy H. Tchaicha, Abigail Altabef, Julian Carretero, Shohei Koyama, and Esra A. Akbay

Abstract

The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non–small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition.Significance: We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non–cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape. Cancer Discov; 3(12); 1355–63. ©2013 AACR.See related commentary by Rech and Vonderheide, p. 1330This article is highlighted in the In This Issue feature, p. 1317

Published
2023
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24. Table S3 from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author

Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak

Abstract

Table S3 contains the karyotypes of 16 genome-wide LOH MPM cases from the BWH cohort.

Published
2023
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26. Data from Gene Silencing Associated with SWI/SNF Complex Loss during NSCLC Development

Author

Bernard E. Weissman, Yanfang Zheng, D. Neil Hayes, Jiren Zhang, Christoph Plass, Christopher D. Sproul, Daniel Serber, Dominic J. Smiraglia, Christopher S. Bartlett, Ying Li, Mehmet Karaca, Vonn Walter, and Shujie Song

Abstract

The SWI/SNF chromatin-remodeling complex regulates gene expression and alters chromatin structures in an ATP-dependent manner. Recent sequencing efforts have shown mutations in BRG1 (SMARCA4), one of two mutually exclusive ATPase subunits in the complex, in a significant number of human lung tumor cell lines and primary non–small cell lung carcinoma (NSCLC) clinical specimens. To determine how BRG1 loss fuels tumor progression in NSCLC, molecular profiling was performed after restoration of BRG1 expression or treatment with a histone deacetylase inhibitor or a DNA methyltransferase (DNMT) inhibitor in a BRG1-deficient NSCLC cells. Importantly, validation studies from multiple cell lines revealed that BRG1 reexpression led to substantial changes in the expression of CDH1, CDH3, EHF, and RRAD that commonly undergo silencing by other epigenetic mechanisms during NSCLC development. Furthermore, treatment with DNMT inhibitors did not restore expression of these transcripts, indicating that this common mechanism of gene silencing did not account for their loss of expression. Collectively, BRG1 loss is an important mechanism for the epigenetic silencing of target genes during NSCLC development.Implications: Inactivation of the SWI/SNF complex provides a novel mechanism to induce gene silencing during NSCLC development. Mol Cancer Res; 12(4); 560–70. ©2014 AACR.

Published
2023
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28. Supplementary Table S1.2 from Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer

Author

Kwok-Kin Wong, Lewis C. Cantley, David E. Root, Nathanael S. Gray, Andrew L. Kung, William Y. Kim, David J. Kwiatkowski, John V. Heymach, Ignacio I. Wistuba, Don L. Gibbons, Lauren A. Byers, Alec Kimmelman, Ralph Scully, John M. Asara, Reuben J. Shaw, Brendan D. Manning, Jeffrey A. Engelman, Nabeel Bardeesy, Pasi A. Janne, Nirali M. Patel, D. Neil Hayes, Norman E. Sharpless, Sean T. Bailey, Jianming Zhang, Edward M. Driggers, Sung Choe, Xiaoxu Wang, Jeremy H. Tchaicha, Abigail B. Altabef, Zhao Chen, Yong Zhang, Peng Gao, Travis J. Cohoon, Chunxiao Xu, Thomas J.F. Nieland, Qingsong Liu, Julian Carretero, Glenn S. Cowley, Kevin Marks, and Yan Liu

Abstract

Top 200 genes by KS.

Published
2023
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31. Supplementary Methods, Figure Legends from Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer

Author

Kwok-Kin Wong, Lewis C. Cantley, David E. Root, Nathanael S. Gray, Andrew L. Kung, William Y. Kim, David J. Kwiatkowski, John V. Heymach, Ignacio I. Wistuba, Don L. Gibbons, Lauren A. Byers, Alec Kimmelman, Ralph Scully, John M. Asara, Reuben J. Shaw, Brendan D. Manning, Jeffrey A. Engelman, Nabeel Bardeesy, Pasi A. Janne, Nirali M. Patel, D. Neil Hayes, Norman E. Sharpless, Sean T. Bailey, Jianming Zhang, Edward M. Driggers, Sung Choe, Xiaoxu Wang, Jeremy H. Tchaicha, Abigail B. Altabef, Zhao Chen, Yong Zhang, Peng Gao, Travis J. Cohoon, Chunxiao Xu, Thomas J.F. Nieland, Qingsong Liu, Julian Carretero, Glenn S. Cowley, Kevin Marks, and Yan Liu

Abstract

Supplementary Methods, Figure Legends

Published
2023
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32. Supplementary Figures S1- S10 from Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer

Author

Kwok-Kin Wong, Lewis C. Cantley, David E. Root, Nathanael S. Gray, Andrew L. Kung, William Y. Kim, David J. Kwiatkowski, John V. Heymach, Ignacio I. Wistuba, Don L. Gibbons, Lauren A. Byers, Alec Kimmelman, Ralph Scully, John M. Asara, Reuben J. Shaw, Brendan D. Manning, Jeffrey A. Engelman, Nabeel Bardeesy, Pasi A. Janne, Nirali M. Patel, D. Neil Hayes, Norman E. Sharpless, Sean T. Bailey, Jianming Zhang, Edward M. Driggers, Sung Choe, Xiaoxu Wang, Jeremy H. Tchaicha, Abigail B. Altabef, Zhao Chen, Yong Zhang, Peng Gao, Travis J. Cohoon, Chunxiao Xu, Thomas J.F. Nieland, Qingsong Liu, Julian Carretero, Glenn S. Cowley, Kevin Marks, and Yan Liu

Abstract

Supplementary Figure S1. Generation of GEMM-derived cell lines. Supplementary Figure S2. QPCR and Western blot analyses of DTYMK expression in 634 cells upon indicated shDtymks transduction. Supplementary Figure S3. Lkb1-wt 634 and Lkb1-null t4 cells transduced with shGFP, shDtymk-1 or shDtymk-3 and then cultured with or without additional 100 microM dTTP in medium for 4 days. Supplementary Figure S4. Lkb1-wt (634, 855, and 857) and Lkb1-null (t2, t4, and t5) cell lines (A) and human LKB1-wt (H358 and Calu-1) and LKB1-deficient H2122 and A549) NSCLC cell lines (B) were treated with CHEK1 inhibitors, AZD7762 and CHIR124, for the indicated dose and time, and then lysed for Western blot analysis of gammaH2AX. Supplementary Figure S5. Immunohistochemical analyses assessing gammaH2AZ. Supplementary Figure S6. QPCR and Western blot analyses of DTYMK expression in LKB1-wt Calu-1 NSCLC cells. Supplementary Figure S7. A schematic model is proposed based on our current data. Supplementary Figure S8. QPCR analyses of Dtymk (A) and Chek1 (B) transcript levels in Lkb1-wt (634, 855, and 857) and Lkb1-null (t2, t4, and t5) cell lines. Supplementary Figure S9. QPCR analysis of TK1 expression in 634 cells upon the indicated shTK1 transduction for 3 days. Supplementary Figure S10. Gene expression levels of DTYMK in normal lung vs. lung adenocarcinoma from the Oncomine Cancer Microarray database.

Published
2023
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33. Supplementary Figures from Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors

Author

Kwok-Kin Wong, Glenn Dranoff, Peter S. Hammerman, Gordon J. Freeman, Scott J. Rodig, Lynette M. Sholl, Takeshi Shimamura, Geoffrey I. Shapiro, D. Neil Hayes, Matthew Meyerson, Pasi A. Janne, Travis J. Cohoon, Margaret Soucheray, Jacob B. Reibel, Mohit Butaney, Peter E. Fecci, Matthew D. Wilkerson, Trevor J. Pugh, Ellen M. Beauchamp, Andrew D. Cherniack, Oliver R. Mikse, Camilla L. Christensen, Jeremy H. Tchaicha, Abigail Altabef, Julian Carretero, Shohei Koyama, and Esra A. Akbay

Abstract

PDF file 2020K, Supplementary figures 1-11. For the mouse experiments tumor bearing lungs were classified as mildly sick and severely sick based on the tumor burden as determined by right lung lobe weights. Oncogene induced immunosuppressive environment manifested as compromised T cell function, elevation in the levels of tumor promoting cytokines, and changes in lung hematopoietic population was observed in the mildy sick mice in addition to the severely sick EGFR mutant mice. Anti PD-1 antibody treatment did not show efficacy in the Kras driven tumors despite the expression of the PD-1 ligand

Published
2023
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35. Supplementary Methods from Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors

Author

Kwok-Kin Wong, Glenn Dranoff, Peter S. Hammerman, Gordon J. Freeman, Scott J. Rodig, Lynette M. Sholl, Takeshi Shimamura, Geoffrey I. Shapiro, D. Neil Hayes, Matthew Meyerson, Pasi A. Janne, Travis J. Cohoon, Margaret Soucheray, Jacob B. Reibel, Mohit Butaney, Peter E. Fecci, Matthew D. Wilkerson, Trevor J. Pugh, Ellen M. Beauchamp, Andrew D. Cherniack, Oliver R. Mikse, Camilla L. Christensen, Jeremy H. Tchaicha, Abigail Altabef, Julian Carretero, Shohei Koyama, and Esra A. Akbay

Abstract

PDF file 306K, MRI tumor volume quantification, lists for all the antibodies used in the experiments, gating method for Flow cytometry analysis, and supplementary references

Published
2023
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36. Supplementary Figure Legends from Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors

Author

Kwok-Kin Wong, Glenn Dranoff, Peter S. Hammerman, Gordon J. Freeman, Scott J. Rodig, Lynette M. Sholl, Takeshi Shimamura, Geoffrey I. Shapiro, D. Neil Hayes, Matthew Meyerson, Pasi A. Janne, Travis J. Cohoon, Margaret Soucheray, Jacob B. Reibel, Mohit Butaney, Peter E. Fecci, Matthew D. Wilkerson, Trevor J. Pugh, Ellen M. Beauchamp, Andrew D. Cherniack, Oliver R. Mikse, Camilla L. Christensen, Jeremy H. Tchaicha, Abigail Altabef, Julian Carretero, Shohei Koyama, and Esra A. Akbay

Abstract

PDF file 92K, Legends to supplementary figures 1-11

Published
2023
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37. Supplementary Figures from Loss of SWI/SNF Chromatin Remodeling Alters NRF2 Signaling in Non–Small Cell Lung Carcinoma

Author

Bernard E. Weissman, Michael B. Major, Yanfang Zheng, D. Neil Hayes, Jiren Zhang, Nisarg Desai, Tess Orvis, Darmood Wei, Vonn Walter, Kathleen Mulvaney, Travis Schrank, Vinh Nguyen, and Shujie Song

Abstract

Supplementary Figure 1 shows BRG1 deficiency activates transcription of a subset of NRF2 target genes in second H358 BRG1 knockdown cell line; Supplementary Figure 2 shows western blot of BRG1 and BRM knockout samples used for RNA-seq.

Published
2023
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38. Supplementary Data from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author

Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak

Abstract

Supplementary materials and methods, as well as supplementary figures S1-S7.

Published
2023
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40. Supplementary Figure 1 from Gene Silencing Associated with SWI/SNF Complex Loss during NSCLC Development

Author

Bernard E. Weissman, Yanfang Zheng, D. Neil Hayes, Jiren Zhang, Christoph Plass, Christopher D. Sproul, Daniel Serber, Dominic J. Smiraglia, Christopher S. Bartlett, Ying Li, Mehmet Karaca, Vonn Walter, and Shujie Song

Abstract

PDF file - 4305K, Validation of gene expression for microarray and RGLS analyses; RGLS analysis of the A427 cell line.

Published
2023
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41. Supplementary Table 1 from Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors

Author

Kwok-Kin Wong, Glenn Dranoff, Peter S. Hammerman, Gordon J. Freeman, Scott J. Rodig, Lynette M. Sholl, Takeshi Shimamura, Geoffrey I. Shapiro, D. Neil Hayes, Matthew Meyerson, Pasi A. Janne, Travis J. Cohoon, Margaret Soucheray, Jacob B. Reibel, Mohit Butaney, Peter E. Fecci, Matthew D. Wilkerson, Trevor J. Pugh, Ellen M. Beauchamp, Andrew D. Cherniack, Oliver R. Mikse, Camilla L. Christensen, Jeremy H. Tchaicha, Abigail Altabef, Julian Carretero, Shohei Koyama, and Esra A. Akbay

Abstract

PDF file 57K, Supplementary table and legend. Evaluation of the PD-L1 expression in tumor samples carrying EGFR mutations

Published
2023
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43. Supplementary Table S1 from A Randomized Multi-institutional Phase II Trial of Everolimus as Adjuvant Therapy in Patients with Locally Advanced Squamous Cell Cancer of the Head and Neck

Author

Ezra E.W. Cohen, Francis P. Worden, Miriam O'Leary, Mark Kozloff, Gautam Jha, Lawrence Feldman, James L. Wade, Maura Gillison, Terry Day, Juneko Grilley-Olson, Tanguy Seiwert, Zoukaa Sargi, Glenn Mills, Prakash Neupane, J. Silvio Gutkind, Everett E. Vokes, Tara Moore-Medlin, José M. Flores, Olivier Harismendy, Theodore Karrison, D. Neil Hayes, and Cherie-Ann O. Nathan

Abstract

List of all observed somatic mutations in TP53.

Published
2023
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44. Data from A Randomized Multi-institutional Phase II Trial of Everolimus as Adjuvant Therapy in Patients with Locally Advanced Squamous Cell Cancer of the Head and Neck

Author

Ezra E.W. Cohen, Francis P. Worden, Miriam O'Leary, Mark Kozloff, Gautam Jha, Lawrence Feldman, James L. Wade, Maura Gillison, Terry Day, Juneko Grilley-Olson, Tanguy Seiwert, Zoukaa Sargi, Glenn Mills, Prakash Neupane, J. Silvio Gutkind, Everett E. Vokes, Tara Moore-Medlin, José M. Flores, Olivier Harismendy, Theodore Karrison, D. Neil Hayes, and Cherie-Ann O. Nathan

Abstract

Purpose:Investigate whether adjuvant everolimus, an mTOR inhibitor, improves progression-free survival (PFS) in advanced-stage head and neck squamous cell carcinoma (HNSCC) and provide outcomes related to correlative biological factors associated with disease control.Patients and Methods:This was a prospective, randomized, double-blind phase II trial of patients with advanced-stage HNSCC from 13 institutions who were confirmed disease-free post-definitive therapy and enrolled between December 2010 and March 2015. Patients received adjuvant everolimus or placebo daily (10 mg, oral) for a maximum of 1 year. p16 IHC as a surrogate marker for human papillomavirus infection and whole-exome sequencing were performed. Cox proportional hazard models estimated hazard rates. Log-rank tests evaluated differences in survival. The primary endpoint was PFS. Secondary endpoints and objectives included overall survival (OS) and toxicity assessment.Results:52 patients [median (range) age, 58 (37–76) years; 43 men (83%), 9 women (17%)] were randomized to placebo (n = 24) or everolimus (n = 28). PFS favored everolimus, but was not significant [log-rank P = 0.093; HR = 0.44; 95% confidence interval (CI), 0.17–1.17]. There was no difference in OS (P = 0.29; HR = 0.57; 95% CI, 0.20–16.2). Everolimus resulted in significant improvement in PFS for p16-negative patients (n = 31; P = 0.031; HR = 0.26; 95% CI, 0.07–0.97), although subgroup analysis showed no difference for p16-positive patients (n = 21; P = 0.93). Further, PFS was significantly higher in TP53-mutated (TP53mut) patients treated with everolimus compared with placebo (log-rank P = 0.027; HR = 0.24; 95% CI, 0.06–0.95). No treatment difference was seen in patients with TP53 wild-type tumors (P = 0.79).Conclusions:p16-negative and TP53mut patients may benefit from adjuvant treatment with everolimus.

Published
2023
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46. Figure S3 from Rapid Clearance Profile of Plasma Circulating Tumor HPV Type 16 DNA during Chemoradiotherapy Correlates with Disease Control in HPV-Associated Oropharyngeal Cancer

Author

Gaorav P. Gupta, William Mendenhall, Joel S. Parker, Xianming M. Tan, Mark Weissler, Samip Patel, Jeffrey M. Blumberg, Trevor Hackman, Adam Zanation, Juneko E. Grilley-Olson, Jared Weiss, D. Neil Hayes, Roi Dagan, Nathan Sheets, Robert Amdur, Emily C. Goldman, Rebecca Green, Stuart Jefferys, David Marron, Brian T. Beaty, Sunil Kumar, and Bhishamjit S. Chera

Abstract

Baseline ctHPV16DNA levels stratified by AJCC 8th edition N staging

Published
2023
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47. Supplemental Figure 2 from NFE2L2 Mutations Enhance Radioresistance in Head and Neck Cancer by Modulating Intratumoral Myeloid Cells

Author

Quynh-Thu Le, Maximilian Diehn, D. Neil Hayes, John B. Sunwoo, Seung W. Seol, Michael B. Major, Weiruo Zhang, Nathan Wamsley, Christina S. Kong, Junfei Zhao, Brittany J. Holmes, Rie von Eyben, Rachel Hildebrand, Yuan Hou, Angela B. Hui, Shirley Kwok, Vignesh Viswanathan, Hongbin Cao, Dhanya K. Nambiar, and Li Guan

Abstract

The relationship between NFE2L2 mutation and radiation resistance in OC cancer. Kaplan-Meier analysis of PFS and OSin OC patients treated with surgery and postoperative (chemo)radiotherapy.

Published
2023
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48. Supplemental Figure 7 from NFE2L2 Mutations Enhance Radioresistance in Head and Neck Cancer by Modulating Intratumoral Myeloid Cells

Author

Quynh-Thu Le, Maximilian Diehn, D. Neil Hayes, John B. Sunwoo, Seung W. Seol, Michael B. Major, Weiruo Zhang, Nathan Wamsley, Christina S. Kong, Junfei Zhao, Brittany J. Holmes, Rie von Eyben, Rachel Hildebrand, Yuan Hou, Angela B. Hui, Shirley Kwok, Vignesh Viswanathan, Hongbin Cao, Dhanya K. Nambiar, and Li Guan

Abstract

CB-839 overcomes the Nrf2E79Q-induced radiation resistance through regulating TLR4-mediated cytokine changes.

Published
2023
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