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Article ; Online: Fast all versus all genotype comparison using DNA/RNA sequencing data: method and workflow.

Eschrich, Steven A / Yu, Xiaoqing / Teer, Jamie K

2023 Volume 24, Issue 1, Page(s) 164

Abstract: Background: Massively parallel sequencing includes many liquid handling steps which introduce the possibility of sample swaps, mixing, and duplication. The unique profile of inherited variants in human genomes allows for comparison of sample identity ... ...

Abstract	Background: Massively parallel sequencing includes many liquid handling steps which introduce the possibility of sample swaps, mixing, and duplication. The unique profile of inherited variants in human genomes allows for comparison of sample identity using sequence data. A comparison of all samples vs. each other (all vs. all) provides both identification of mismatched samples and the possibility of resolving swapped samples. However, all vs. all comparison complexity grows as the square of the number of samples, so efficiency becomes essential. Results: We have developed a tool for fast all vs. all genotype comparison using low level bitwise operations built into the Perl programming language. Importantly, we have also developed a complete workflow allowing users to start with either raw FASTQ sequence files, aligned BAM files, or genotype VCF files and automatically generate comparison metrics and summary plots. The tool is freely available at https://github.com/teerjk/TimeAttackGenComp/ . Conclusions: A fast and easy to use method for genotype comparison as described here is an important tool to ensure high quality and robust results in sequencing studies.
MeSH term(s)	Humans ; Software ; Workflow ; Genotype ; High-Throughput Nucleotide Sequencing/methods ; Sequence Analysis, RNA/methods ; DNA ; Sequence Analysis, DNA/methods
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2023-04-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2041484-5
ISSN	1471-2105 ; 1471-2105
ISSN (online)	1471-2105
ISSN	1471-2105
DOI	10.1186/s12859-023-05288-y
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Towards Data Driven RT Prescription: Integrating Genomics into RT Clinical Practice.

Torres-Roca, Javier F / Grass, G Daniel / Scott, Jacob G / Eschrich, Steven A

Seminars in radiation oncology

2023 Volume 33, Issue 3, Page(s) 221–231

Abstract: The genomic era has significantly changed the practice of clinical oncology. The use of genomic-based molecular diagnostics including prognostic genomic signatures and new-generation sequencing has become routine for clinical decisions regarding ... ...

Abstract	The genomic era has significantly changed the practice of clinical oncology. The use of genomic-based molecular diagnostics including prognostic genomic signatures and new-generation sequencing has become routine for clinical decisions regarding cytotoxic chemotherapy, targeted agents and immunotherapy. In contrast, clinical decisions regarding radiation therapy (RT) remain uninformed about the genomic heterogeneity of tumors. In this review, we discuss the clinical opportunity to utilize genomics to optimize RT dose. Although from the technical perspective, RT has been moving towards a data-driven approach, RT prescription dose is still based on a one-size-fits all approach, with most RT dose based on cancer diagnosis and stage. This approach is in direct conflict with the realization that tumors are biologically heterogeneous, and that cancer is not a single disease. Here, we discuss how genomics can be integrated into RT prescription dose, the clinical potential for this approach and how genomic-optimization of RT dose could lead to new understanding of the clinical benefit of RT.
MeSH term(s)	Humans ; Neoplasms/genetics ; Neoplasms/radiotherapy ; Neoplasms/pathology ; Medical Oncology ; Antineoplastic Agents ; Prognosis ; Genomics
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2023-06-16
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1146999-7
ISSN	1532-9461 ; 1053-4296
ISSN (online)	1532-9461
ISSN	1053-4296
DOI	10.1016/j.semradonc.2023.03.007
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Article: Exploiting convergent phenotypes to derive a pan-cancer cisplatin response gene expression signature.

Scarborough, Jessica A / Eschrich, Steven A / Torres-Roca, Javier / Dhawan, Andrew / Scott, Jacob G

NPJ precision oncology

2023 Volume 7, Issue 1, Page(s) 38

Abstract: Precision medicine offers remarkable potential for the treatment of cancer, but is largely focused on tumors that harbor actionable mutations. Gene expression signatures can expand the scope of precision medicine by predicting response to traditional ( ... ...

Abstract	Precision medicine offers remarkable potential for the treatment of cancer, but is largely focused on tumors that harbor actionable mutations. Gene expression signatures can expand the scope of precision medicine by predicting response to traditional (cytotoxic) chemotherapy agents without relying on changes in mutational status. We present a new signature extraction method, inspired by the principle of convergent phenotypes, which states that tumors with disparate genetic backgrounds may evolve similar phenotypes independently. This evolutionary-informed method can be utilized to produce consensus signatures predictive of response to over 200 chemotherapeutic drugs found in the Genomics of Drug Sensitivity in Cancer (GDSC) Database. Here, we demonstrate its use by extracting the Cisplatin Response Signature (CisSig). We show that this signature can predict cisplatin response within carcinoma-based cell lines from the GDSC database, and expression of the signatures aligns with clinical trends seen in independent datasets of tumor samples from The Cancer Genome Atlas (TCGA) and Total Cancer Care (TCC) database. Finally, we demonstrate preliminary validation of CisSig for use in muscle-invasive bladder cancer, predicting overall survival in a small cohort of patients who undergo cisplatin-containing chemotherapy. This methodology can be used to produce robust signatures that, with further clinical validation, may be used for the prediction of traditional chemotherapeutic response, dramatically increasing the reach of personalized medicine in cancer.
Language	English
Publishing date	2023-04-19
Publishing country	England
Document type	Journal Article
ISSN	2397-768X
ISSN	2397-768X
DOI	10.1038/s41698-023-00375-y
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Article ; Online: An Analysis of Nectin-4 (

Grass, G Daniel / Chahoud, Jad / Lopez, Alex / Dhillon, Jasreman / Eschrich, Steven A / Johnstone, Peter A S / Spiess, Philippe E

European urology open science

2023 Volume 49, Page(s) 1–5

Abstract: Penile squamous cell carcinoma (PSCC) remains a worldwide healthcare concern with poor outcomes and inadequate therapeutic options. Molecular characterization continues to describe the intricacies of PSCC biology, which vary by human papillomavirus (HPV) ...

Abstract	Penile squamous cell carcinoma (PSCC) remains a worldwide healthcare concern with poor outcomes and inadequate therapeutic options. Molecular characterization continues to describe the intricacies of PSCC biology, which vary by human papillomavirus (HPV) infection. Despite these advancements in our understanding, utilization of targeted therapies remains limited and underexplored. In this study, we evaluated the transcript and protein expression of Nectin-4 (PVRL4) in PSCC tumors and evaluated whether this is related to tumor features or clinical outcomes. Using two separate PSCC cohorts, we demonstrate that the majority of tumors have active transcription of Nectin-4. We then validated our findings using immunohistochemistry in a tissue microarray representing 57 patients with PSCC. We identified that Nectin-4 was expressed at higher levels in patients with high-risk HPV infection. No significant differences were identified in tumor characteristics or various clinical endpoints when comparing tumors with high and low Nectin-4 expression. This study demonstrates that Nectin-4 is expressed in PSCC and may represent a novel therapeutic target. Patient summary: In this study, we evaluated the expression of Nectin-4, a cell surface protein, in tumors from patients with nonmetastatic penile squamous cell carcinoma (PSCC). To our knowledge, this is the first study to describe elevated expression of Nectin-4 in PSCC, which may suggest its utility as a therapeutic target.
Language	English
Publishing date	2023-01-10
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	3040546-4
ISSN	2666-1683 ; 2058-4881
ISSN (online)	2666-1683
ISSN	2058-4881
DOI	10.1016/j.euros.2022.12.008
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Article ; Online: Deciphering Phenotypes from Protein Biomarkers for Translational Research with PIPER.

Putty Reddy, Sudhir / Alontaga, Aileen Y / Welsh, Eric A / Haura, Eric B / Boyle, Theresa A / Eschrich, Steven A / Koomen, John M

Journal of proteome research

2023 Volume 22, Issue 6, Page(s) 2055–2066

Abstract: Liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM) has widespread clinical use for detection of inborn errors of metabolism, therapeutic drug monitoring, and numerous other applications. This technique detects proteolytic ... ...

Abstract	Liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM) has widespread clinical use for detection of inborn errors of metabolism, therapeutic drug monitoring, and numerous other applications. This technique detects proteolytic peptides as surrogates for protein biomarker expression, mutation, and post-translational modification in individual clinical assays and in cancer research with highly multiplexed quantitation across biological pathways. LC-MRM for protein biomarkers must be translated from multiplexed research-grade panels to clinical use. LC-MRM panels provide the capability to quantify clinical biomarkers and emerging protein markers to establish the context of tumor phenotypes that provide highly relevant supporting information. An application to visualize and communicate targeted proteomics data will empower translational researchers to move protein biomarker panels from discovery to clinical use. Therefore, we have developed a web-based tool for targeted proteomics that provides pathway-level evaluations of key biological drivers (
MeSH term(s)	Translational Research, Biomedical ; Proteins/analysis ; Peptides/metabolism ; Biomarkers/analysis ; Phenotype
Chemical Substances	Proteins ; Peptides ; Biomarkers
Language	English
Publishing date	2023-05-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.3c00137
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Article: Computational methods and opportunities for phosphorylation network medicine.

Chen, Yian Ann / Eschrich, Steven A

Translational cancer research

2014 Volume 3, Issue 3, Page(s) 266–278

Abstract: Protein phosphorylation, one of the most ubiquitous post-translational modifications (PTM) of proteins, is known to play an essential role in cell signaling and regulation. With the increasing understanding of the complexity and redundancy of cell ... ...

Abstract	Protein phosphorylation, one of the most ubiquitous post-translational modifications (PTM) of proteins, is known to play an essential role in cell signaling and regulation. With the increasing understanding of the complexity and redundancy of cell signaling, there is a growing recognition that targeting the entire network or system could be a necessary and advantageous strategy for treating cancer. Protein kinases, the proteins that add a phosphate group to the substrate proteins during phosphorylation events, have become one of the largest groups of 'druggable' targets in cancer therapeutics in recent years. Kinase inhibitors are being regularly used in clinics for cancer treatment. This therapeutic paradigm shift in cancer research is partly due to the generation and availability of high-dimensional proteomics data. Generation of this data, in turn, is enabled by increased use of mass-spectrometry (MS)-based or other high-throughput proteomics platforms as well as companion public databases and computational tools. This review briefly summarizes the current state and progress on phosphoproteomics identification, quantification, and platform related characteristics. We review existing database resources, computational tools, methods for phosphorylation network inference, and ultimately demonstrate the connection to therapeutics. Finally, many research opportunities exist for bioinformaticians or biostatisticians based on developments and limitations of the current and emerging technologies.
Language	English
Publishing date	2014-12-20
Publishing country	China
Document type	Journal Article
ZDB-ID	2901601-0
ISSN	2219-6803 ; 2218-676X
ISSN (online)	2219-6803
ISSN	2218-676X
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Article: An Assessment of the Penile Squamous Cell Carcinoma Surfaceome for Biomarker and Therapeutic Target Discovery.

Grass, George Daniel / Ercan, Dalia / Obermayer, Alyssa N / Shaw, Timothy / Stewart, Paul A / Chahoud, Jad / Dhillon, Jasreman / Lopez, Alex / Johnstone, Peter A S / Rogatto, Silvia Regina / Spiess, Philippe E / Eschrich, Steven A

Cancers

2023 Volume 15, Issue 14

Abstract: Penile squamous cell carcinoma (PSCC) is a rare malignancy in most parts of the world and the underlying mechanisms of this disease have not been fully investigated. About 30-50% of cases are associated with high-risk human papillomavirus (HPV) infection, ...

Abstract	Penile squamous cell carcinoma (PSCC) is a rare malignancy in most parts of the world and the underlying mechanisms of this disease have not been fully investigated. About 30-50% of cases are associated with high-risk human papillomavirus (HPV) infection, which may have prognostic value. When PSCC becomes resistant to upfront therapies there are limited options, thus further research is needed in this venue. The extracellular domain-facing protein profile on the cell surface (i.e., the surfaceome) is a key area for biomarker and drug target discovery. This research employs computational methods combined with cell line translatomic (n = 5) and RNA-seq transcriptomic data from patient-derived tumors (n = 18) to characterize the PSCC surfaceome, evaluate the composition dependency on HPV infection, and explore the prognostic impact of identified surfaceome candidates. Immunohistochemistry (IHC) was used to validate the localization of select surfaceome markers. This analysis characterized a diverse surfaceome within patient tumors with 25% and 18% of the surfaceome represented by the functional classes of receptors and transporters, respectively. Significant differences in protein classes were noted by HPV status, with the most change being seen in transporter proteins (25%). IHC confirmed the robust surface expression of select surfaceome targets in the top 85% of expression and a superfamily immunoglobulin protein called
Language	English
Publishing date	2023-07-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15143636
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The Prognostic Role of Human Papillomavirus and p16 Status in Penile Squamous Cell Carcinoma-A Systematic Review.

Parza, Kevin / Mustasam, Arfa / Ionescu, Filip / Paravathaneni, Mahati / Sandstrom, Reagan / Safa, Houssein / Grass, G Daniel / Johnstone, Peter A / Eschrich, Steven A / Chadha, Juskaran / Zacharias, Niki / Pettaway, Curtis A / Spiess, Philippe E / Chahoud, Jad

Cancers

2023 Volume 15, Issue 14

Abstract: PSCC is a rare cancer, with approximately half of all cases related to HPV. While HPV and p16 IHC testing have proven their prognostic value for oropharyngeal cancer, this is not yet established for PSCC. The current level of evidence exploring the ... ...

Abstract	PSCC is a rare cancer, with approximately half of all cases related to HPV. While HPV and p16 IHC testing have proven their prognostic value for oropharyngeal cancer, this is not yet established for PSCC. The current level of evidence exploring the relation between PSCC and HPV is moderate, so we conducted a systematic review following PRISMA guidelines to evaluate the prognostic role of HPV and p16 IHC in PSCC clinical outcomes. We searched the PubMed, Embase, and Cochrane databases and identified 34 relevant studies that met our inclusion criteria. Of these, 33 were retrospective cohort studies, and one was a cross-sectional study. Nine studies reported that HPV-positive and p16-positive PSCC had better overall survival (OS) and disease-free survival (DFS). This study highlights the need for a meta-analysis to determine the role of routine HPV status or p16 staining testing as part of the initial diagnosis and staging of PSCC patients worldwide.
Language	English
Publishing date	2023-07-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15143713
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Article: Characteristics and Validation Techniques for PCA-Based Gene-Expression Signatures.

Berglund, Anders E / Welsh, Eric A / Eschrich, Steven A

International journal of genomics

2017 Volume 2017, Page(s) 2354564

Abstract: Background: Uniqueness: the general direction of the data being examined can drive most of the observed signal. Robustness: if a gene signature is designed to measure a single biological effect, then this signal should be sufficiently strong and ... ...

Abstract	Background Uniqueness: the general direction of the data being examined can drive most of the observed signal. Robustness: if a gene signature is designed to measure a single biological effect, then this signal should be sufficiently strong and distinct compared to other signals within the signature. Transferability: the derived PCA gene signature score should describe the same biology in the target dataset as it does in the training dataset.
Language	English
Publishing date	2017-02-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2711883-6
ISSN	2314-4378 ; 2314-436X
ISSN (online)	2314-4378
ISSN	2314-436X
DOI	10.1155/2017/2354564
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Article: Multiplex Immunofluorescence Captures Progressive Immune Exhaustion with Advancing Penile Squamous Cell Cancer Stage.

Cancers

2024 Volume 16, Issue 2

Abstract: Penile squamous cell carcinoma (PSCC) is a rare and deadly malignancy. Therapeutic advances have been stifled by a poor understanding of disease biology. Specifically, the immune microenvironment is an underexplored component in PSCC and the activity of ... ...

Abstract	Penile squamous cell carcinoma (PSCC) is a rare and deadly malignancy. Therapeutic advances have been stifled by a poor understanding of disease biology. Specifically, the immune microenvironment is an underexplored component in PSCC and the activity of immune checkpoint inhibitors observed in a subset of patients suggests immune escape may play an important role in tumorigenesis. Herein, we explored for the first time the immune microenvironment of 57 men with PSCC and how it varies with the presence of human papillomavirus (HPV) infection and across tumor stages using multiplex immunofluorescence of key immune cell markers. We observed an increase in the density of immune effector cells in node-negative tumors and a progressive rise in inhibitory immune players such as type 2 macrophages and upregulation of the PD-L1 checkpoint in men with N1 and N2-3 disease. There were no differences in immune cell densities with HPV status.
Language	English
Publishing date	2024-01-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers16020303
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