Discovering Novel RNA Regions to Develop Biomarkers and Therapeutic Opportunities for Breast Cancer & SARS-CoV-2

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dc.contributor.advisorGunaratne, Preethi H.
dc.contributor.committeeMemberBawa-Khalfe, Tasneem
dc.contributor.committeeMemberBedrosian, Isabelle
dc.contributor.committeeMemberBriggs, James M.
dc.contributor.committeeMemberZhang, Xiaoliu Shaun
dc.creatorMistretta, Brandon
dc.date.accessioned2021-08-04T01:19:57Z
dc.date.createdDecember 2020
dc.date.issued2020-12
dc.date.submittedDecember 2020
dc.date.updated2021-08-04T01:20:00Z
dc.description.abstractBreast cancer accounts for 23% of all cancer deaths and second most related mortality in women. Recently, advances in the field of immuno-oncology have demonstrated therapeutic effects of boosting endogenous T cells to combat human cancers. Fusion junctions in chimeric RNAs provide potential neoantigen peptide regions expand the potential repertoire of targets for therapeutic vaccines. Here we focused on extracting neoantigens from fusion transcripts identified from RNA-sequencing of breast tumors. We present 20 novel fusion transcripts from 75 patients (TNBC, HER2+, and HR+), which are not present in normal breast. We focused on the NSF [Exon 1-12]-LRRC37A3 [Exon 5-13] fusion detected in 24% of the tumor samples. Major ORFs predicted including NSF-Exon 1-12-KFPRKLYFLH (C-terminal truncation) and MISNQ-LRRC37A3 Exon 5-15 (N-terminal truncation) were analyzed through MHC Class I binding predictor (MHCnuggets). A total of 15 different 8-11 mer neoantigen peptides discovered from the NSF and LRRC37A3 truncations were predicted to bind to a total of 35 unique MHC class I alleles with a binding affinity of IC50<500nM. We present here a proof of principle strategy to identify immunogenic neoantigen candidates from fusion transcripts that can serve as reagents for developing tumor vaccines for the prevention and treatment of breast cancer. The COVID-19 pandemic has resulted in > 54.7 M cases and > 1.32 M deaths as of November 16, 2020, due to systemic inflammation and multiorgan dysfunction. We performed Whole Genome Sequencing (WGS) of SARS-CoV-2 RNA genome on 30 patients and found a 40% false negative rate from the FDA N1|N2 qPCR test. WGS reads analyzed through the CLC Genomic Pipeline revealed ‘degradation resistant regions’ from the SARS-CoV-2 genome, which we used to design new primer pairs to significantly improve the sensitivity and specificity of detection. Adding primer sets that capture the host response in relation to cytokine storm, cardiac, and vascular endothelial dysfunction we constructed a combined ‘Viral Infection|Host Response Detection’ panel that could be used to accurately identify asymptomatic super-spreaders and triage patients who are likely to develop severe symptoms from SARS-CoV-2 infections. The goal was to establish a clinical decision making framework to manage the pandemic under limited hospital capacity.
dc.description.departmentBiology and Biochemistry, Department of
dc.format.digitalOriginborn digital
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/10657/7958
dc.language.isoeng
dc.rightsThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).
dc.subjectimmuno-oncology
dc.subjectchimeric RNA
dc.subjectneoantigen peptides
dc.titleDiscovering Novel RNA Regions to Develop Biomarkers and Therapeutic Opportunities for Breast Cancer & SARS-CoV-2
dc.type.dcmiText
dc.type.genreThesis
local.embargo.lift2022-12-01
local.embargo.terms2022-12-01
thesis.degree.collegeCollege of Natural Sciences and Mathematics
thesis.degree.departmentBiology and Biochemistry, Department of
thesis.degree.disciplineBiochemistry
thesis.degree.grantorUniversity of Houston
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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