Summary The role of oncoviral genotype and co-infection driving oncogenesis remains unclear. We have developed a scalable, high throughput tool for sensitive and precise oncoviral genotype deconvolution. Using tumor RNA sequencing data, we applied it to 537 virally infected liver, cervical, and head and neck tumors, providing the first comprehensive integrative landscape of tumor-viral gene expression, viral antigen immunogenicity, patient survival, and mutational profiling organized by tumor oncoviral genotype. We find that HBV and HPV genotype and co-infection serve as significant predictors of patient survival and immune activation. Finally, we demonstrate that HPV genotype is more associated with viral oncogene expression than cancer type, implying that expression may be similar across episomal and stochastic integration-based infections. While oncoviral infections are known risk factors for oncogenesis, viral genotype and co-infection are shown to strongly associate with disease progression, patient survival, mutational signatures, and putative tumor neoantigen immunogenicity, facilitating novel clinical associations with infections.
Supplemental Materials:Supp. Figure 1: Kolmogorov-Smirnov test results ( A ) of randomly subsampled distributions of tumor neoantigen binding affinities compared to HBV antigens across 1,000 iterations. B) Distribution of test p-values strongly support the alternative hypothesis that tumor neoantigen cumulative distributions were significantly less than HBV distributions, indicating better average binding affinity scores are robust to subsampling.
Background Liquid biopsy tests capable of tumor profiling with NGS have recently received FDA approval for companion diagnostic treatment selection and tumor profiling, demonstrating the clinical validity of the identification of druggable variants with such information. As the amount of cfDNA per volume of plasma varies greatly from patient to patient, and whole blood/plasma volumes from advanced cancer patients are often limited, it would be advantageous for a liquid biopsy to be able to operate with minimal input, providing robust results across a broad spectrum of blood sample volumes and resultant cfDNA input. In this study, we evaluate the performance of Guardant360 CDx with as little as 3 mL whole blood and 5 ng cfDNA input. Methods The primary concern with low input like 3 mL whole blood is excess preservative in a blood collection tube (BCT) relative to whole blood. In a simulated short draw experiment, the same advanced cancer patient provided whole blood in BCTs with standard, elevated (2X), and high (3.3X) preservatives. We evaluated the molecule coverage across the panel at key exons and positions of interest, across genes evaluated for copy number amplifications, and at frequent fusion gene breakpoint positions. Precision and limit of detection (LoD) have been demonstrated at 5 ng input (P200010B) the lowest allowable input. For clinical utility of a liquid biopsy with low cfDNA input, we also assessed the cfDNA input of 87,305 samples tested with Guardant360 CDx or LDT from a single 10mL BCT. Results and Discussion Differences in molecule coverage between the high preservative and standard preservative were found to fall within expected technical variation (the median of log10 differences in exon-level DNA molecule coverage between short draw and reference conditions fell within +/- 0.125), indicating no meaningful loss of sensitivity for detecting somatic variants. Among the 87,305 clinical samples tested by Guardant360 CDx or LDT, median cfDNA yield was 25ng, with 98.5% yielding at least 5 ng, 88.4% at least 10ng, 73.5% at least 15 ng, and 17.9% at least 60ng. Clinically actionable biomarkers are detectable in low input samples. Of the Guardant360 CDx samples yielding 5-15ng cfDNA input, an average of 0.64 clinically significant variants was reported per sample. With the robust analytical performance demonstrated at low inputs, Guardant360 CDx (a 5ng cutoff) may provide tumor profiling results to guide therapy decisions for about 34% more patients compared to some liquid biopsies that use 2 BCTs for minimal 30ng cfDNA yield (a 15 ng cutoff). Retrospective studies for pharma research are often performed with as little as 2mL of plasma, meaning Guardant360 CDx can return results on 88.4% of such samples whereas other technologies may only be able to address 17.9% (extrapolated from the cfDNA yield distribution for 10mL whole blood yielding 4mL plasma). Citation Format: Aaron O. Richardson, Aaron Hardin, Soni Shukla, Jing Zhao, Catalin Barbacioru, Hilda Beas, Carin Espenschied, Adrian Bubie, Jamie Hutchins, Han-Yu Chuang, Tingting Jiang, Darya Chudova. The liquid biopsy Guardant360 CDx has robust performance at low inputs allowing for high rate of returning patient results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 572.
Recently proposed tumor fitness measures, based on profiling neoepitopes for reactive viral epitope similarity, have led to improved prediction models of response to immune checkpoint inhibitors in melanoma and small-cell lung cancer.Here we apply these checkpoint based fitness measures in the matched checkpoint-treatment naive TCGA samples where cytolytic activity imparts a known survival benefit. No significant survival predictive power beyond that of overall patient tumor mutational burden is observed in either cohort, and furthermore, there is no observed association between checkpoint based fitness and tumor T-cell infiltration, cytolytic activity (CYT), or abundance (TIL burden).We investigate the key assumption of viral epitope similarity driving immune response in the hepatitis B virally infected liver cancer TCGA cohort, and uncover suggestive evidence that tumor neoepitopes dominate viral epitopes in putative immunogenicity and plausibly drive immune response.Significance: Tumor fitness does not predict patient survival better than tumor mutation burden, unlike a measure of CYT. In checkpoint treatment naive patients, our results suggest TIL recruitment and cytolytic activity are essentially driven by tumor neoepitopes, regardless of the presence of viral epitopes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.