bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 6557: A 6-microbial signature risk score for overall survival prediction in hepatocellular carcinoma: a machine learning approach
Authors: Al-Bzour Nour N. , Al-Bzour Ayah N.
Published: April 2023

Introduction: Hepatocellular carcinoma (HCC) is a severe type of cancer associated with high malignancy and poor prognosis. To reach a better prognosis, several factors affecting HCC patients must be considered. In this study, we aim to investigate the relationship between gut microbiota with the survival of HCC patients, and to build a machine learning (ML) prognostic model based on microbiome signatures.

Methods: Microbial and survival data for HCC patients from The Cancer Genome Atlas Program (TCGA) were obtained using the cBioportal database. The microbiome signatures were screened for prognostic effect using the univariate cox regression. The significant microbial signatures were fitted into the Least Absolute Selection and Shrinkage Operator - Cox (LASSO-Cox) model to reduce multicollinearity. Signatures with non-zero LASSO coefficients were screened for independent effect in the multivariate cox regression analysis.

Results: A total of 1407 microbial signatures were downloaded from TCGA dataset. 63 prognostic microbial signatures were identified using the univariate cox. A total of 30 prognostic microbial signatures were screened out using LASSO and further evaluated using independent effect to obtain microbiome risk score. Six microbial signatures were identified as independent prognostic markers including: Marichromatium (HR: 1.26; 95%CI: [0.01-1.56]), p=0.038), Paraclostridium (HR: 1.45; 95%CI:[1.15-1.82], p=0.002), Pseudorhodoferax (HR: 1.20; 95%CI:[1.01-1.43], p=0.037), Chitinimonas (HR: 1.47 95%CI: [1.10-1.97], p=0.009), Marinobacter (HR: 0.79; 95%CI: [0.65-0.97], p=0.022), Desulfovermiculus (HR: 1.44; 95%CI: [1.16-1.78, p=0.001]). Kaplan-Meier survival plot showed better overall survival (OS) in the low-risk group compared to the high-risk group (median OS: 83.6 vs. 41.8; log-rank p-value <0.0001).

Conclusion: Our results show that the gut microbiota is significantly associated with HCC prognosis, in which 5 of them were associated with poorer prognosis and one was associated with better survival. These microbial signatures provide a potential prognostic marker for HCC survival.

Citation Format: Nour N. Al-Bzour, Ayah N. Al-Bzour. A 6-microbial signature risk score for overall survival prediction in hepatocellular carcinoma: a machine learning approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6557.
Abstract 6563: Glioma stem cell index recapitulates grade, IDH mutation status and correlates with survival of glioma patients
Authors: Simões Renan L. , Marção Maycon , Malta Tathiane M.
Published: April 2023

Adult diffuse gliomas are heterogeneous and the most common primary brain tumors. Gliomas have high tissue invasion, proliferation and therapeutic resistance potential. Although much knowledge has been recently gained regarding glioma biology and evolution, many questions are still open, such as which is the cell of origin, what are its characteristics and how the tumor propagation occurs. The cancer stem cell (CSC) model proposes a population of cells with high self-renew capacity and capable of propagating the tumor with more differentiated cells, generating intratumoral heterogeneity. Based on the CSC model, our work aims to integrate the most advanced techniques available such as scRNAseq and machine learning models to estimate the enrichment of glioma stem cells (GSCs) in tumors, by defining a GSC-Stemness Index (GSCsi). To build the prediction model, we used public scRNA-seq data from glioblastoma (GBM)-enriched GSCs. We used the standard Seurat pipeline for quality control, normalization and downstream analysis. The GSC single cell data was used to train a prediction model using the One Class Logistic Regression (OCLR) algorithm. Several models were tested, including overdispersed genes, differentially expressed genes between GSCs and the whole tumor, GSCs from each patient individually and a model with all GSCs. The prediction models were applied to gene expression data from TCGA, GLASS, and publicly available scRNA-seq data from different glioma subtypes. The model built with all the GSCs and all genes showed the best performance, being able to identify with higher indices grade 4 gliomas and IDHwt in the TCGA and GLASS data. Survival analysis resulted in a hazard ratio greater than 20, indicating a high correlation between increased GSCsi and poor prognosis. By applying the model to scRNA-seq data from gliomas, clusters of high GSCsi were identified. We can partially conclude that the GSCsi obtained with the model is capable of identifying grade 4 gliomas and IDHwt and we are performing analyzes with the genes with the highest correlation (positive and negative) with the GSCsi in the TCGA and GLASS data. The analysis of these genes together with genes differentially expressed in the high GSCsi clusters in scRNA-seq data can elucidate pathways responsible for the therapeutic resistance and propagation of gliomas, in addition to proposing theories about the cell of origin and potential therapeutic targets to improve the diagnosis and treatment of these patients.

Citation Format: Renan L. Simões, Maycon Marção, Tathiane M. Malta. Glioma stem cell index recapitulates grade, IDH mutation status and correlates with survival of glioma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6563.
Abstract 6573: Drug Combo: A unique resource for efficient phase 1 trial design with manually curated MTD and DLT
Authors: Wang Lei , Zhang Shijun , Wei Lai , Zhu Yuxi , Owen Dwight , Li Lang
Published: April 2023

Background: With prior preclinical and clinical knowledge, an effective and efficient cancer drug combinatory trial design could be expected, which will significantly accelerate the translation. However, our internal survey results suggested that some knowledge and data sources were underused or underestimated by researchers. One primary reason is that knowledge of drug combinations is scattered in many distinct databases. Moreover, some essential information, such as MTD and DLT was missed in current databases. Drug Combo (https://drugcombo.shinyapps.io/DrugCombo/) is the first knowledge base that integrates drug toxicity and PK data that may help design an efficient Phase I trial. It is a unique informatics resource that manually curated MTD and DLT are well organized in the knowledgebase.

Methods: Drug Combo integrates various publicly available PK and toxicity knowledge for individual drugs and drug combinations (Table 1). More importantly, it is the unique knowledgebase with MTD and DLT. An expert team manually curated MTD and DLT data from publicly available publications. Some standard healthcare terminologies, e.g., Rx-Norm and MedDRA were applied for concept normalization at the back end. We implemented a User-Centered Design process in the user interface (UI).The UI layout will be simple, consistent, purposeful, comprehensive, easy to navigate and informative with readable or scannable typography. A summary view was provided to inform users of some essential information, e.g., MTD, and Overlapping toxicities. The user can find the details in the “Detail Tab”.

Results: Currently, Drug Combo integrates pharmacological, pharmacokinetics, and toxicity data. Especially, MTD and DLT data from more than 1,600 published Phase I trials results are exclusive in Drug Combo.

Conclusions: Drug Combo is the first knowledge base that provides expert-curated MTD and DLT information. It could help design an effective and efficient drug combination phase 1 trial.

Current knowledge type in Drug Combo Type Source Drug Names DrugBank, RxNorm Target DrugBank, Manual curation Associated Condition RxNorm, Drug Labels PK profiles DrugBank Adverse Drug Event Drug Label, FAERS MTD Manual curation DLT Manual curation DDI DrugBank, Manual curation

Citation Format: Lei Wang, Shijun Zhang, Lai Wei, Yuxi Zhu, Dwight Owen, Lang Li. Drug Combo: A unique resource for efficient phase 1 trial design with manually curated MTD and DLT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6573.
Abstract 6587: Method to increase performance of genome-wide association study using imputation for Asian ancestry
Authors: Ryu GangPyo , Koh Youngil , Yoon Sung-soo
Published: April 2023

The emergence of the large-scale public genomic database facilitates genome-wide association study. An unprecedented number of samples emerged, which enable elucidate valid genetic inferences and contribute to finding novel associations for various phenotypes including cancer. However, most of the genome data is from European-based ancestry, which leads to the disparity in study for relatively minor ethnic groups including Asian. Meanwhile, among public genomic database, TOPMed consortium consists of ~180k participants, over 60% of the 180k samples are of predominantly non-European ancestry, and Asian ancestry consisted of 8 % in total. In addition, 1000 Genomes Project(1KG) contains 2,504 individuals from 26 populations and has sequenced 698 samples in addition. These projects serve as a reference to impute missing variants to improve association power for Genome-Wide Association Study (GWAS) subsequently. We compared the imputation results using those reference panels. Korean Genome Project (Korea1K), including 1094 whole genomes are public datasets consisting of only Korean (East Asian) origin. On GRCh38, Korea1K variants consisting of 59,463,566 variants in total, 99.6% with MAF <1% rare variant, only 35.7% of those rare variants passed from GATK Best Practice VQSR filter. With Korea1K data, we have downsampled the result into the exonic level, imputed with reference panels, and seen the consequences for which reference panel shows the best performances. Using 1KG as a reference, we could identify novel rare variants only in 0.1 to 0.38 fold of filtered rare variant in 1KG phase3 and 1KG phase3 30X respectively. On the other hand, TOPMed imputation resulted in rare variants over 1.65 fold increase. With well-imputed variants R2 over 0.8, all three reference database showed poor conservation which only 0.009 % of rare variant are rescued. The reference panel we commonly use are large but required to have more diversity in a Asian rare variant perspective. Despite increase of the Asian fraction in the public genomic database, our result suggests that the number of reference Asian samples are still low to perform association study. In conclusion, our finding highlights both the utility and limitation of the imputation reference panel for Asian ancestry. Novel variants filled by imputation are promising for adding power to various association studies.

Citation Format: GangPyo Ryu, Youngil Koh, Sung-soo Yoon. Method to increase performance of genome-wide association study using imputation for Asian ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6587.
Abstract 6590: Undergraduate e-mentoring in cancer research: The ACE scholars program
Authors: Baciu Cristina , Zachary Compton , Maley Carlo
Published: April 2023

Only 1 in 4 undergraduate college students report having had access to mentoring while in college. To create community and training opportunities for a diverse body of undergraduate students (incl. online students) interested in cancer research, we developed a well-rounded e-mentoring program that incorporates alternated sessions of scientific mentoring (i.e., design a study, create a poster) and professional development (i.e., graduate school strategy and applications, networking). The theoretical background of our program derives from project and team-based learning, which state that students tend to learn better and be more engaged when working hands-on on a given project, in teams. Our teams are led by experienced undergraduate researchers, which enables them to gain leadership experience before applying to graduate school.

We implemented this e-mentoring program in a research center at a large southwestern public university, where 43 undergraduate research assistants were mentored via Zoom during the Spring of 2022. At the end of the semester, we administered a survey to assess program effectiveness and collect student feedback. 31 students took the survey, which revealed that during Spring 2022, 25% of students were responsible for the care of children or other family member(s), 47% worked part-time and 22% worked full-time, and 56% of students encountered personal and/or professional challenges. Furthermore, we measured program effectiveness using the College Student Mentoring Scale, a comprehensive tool that measures students’ perceived psychological and emotional support, degree and career support, academic knowledge support, and role modeling they received during their time in the program. Findings indicate that 82% of students felt they received psychological and emotional support and degree and career support while in the program. Moreover, 96.3% of students indicated that they felt they received academic knowledge support and benefited from role modeling while in the ACE Scholars Program. Additionally, 85% of students agreed or strongly agreed that the ACE Scholars Program, with its research experience and career and professional development components, has helped them be prepared for their future endeavors. Overall, 86% of the students indicated that they were extremely satisfied with the ACE Scholars Program. We will discuss the implications of this program and its findings for the practice of e-mentoring undergraduate students who are interested in cancer research.

Citation Format: Cristina Baciu, Compton Zachary, Carlo Maley. Undergraduate e-mentoring in cancer research: The ACE scholars program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6590.
Abstract 6608: High-sensitivity detection of specific ultra low-frequency somatic mutations for minimal residual disease monitoring
Authors: Liu Tong , Bocek Michael , Cherry Patrick , Gorda Shawn , Challacombe Jean , Murphy Derek , Toro Esteban
Published: April 2023

Minimal/Molecular residual disease (MRD) refers to the small number of tumor cells which may remain within a patient after therapeutic intervention. The detection of these remnants and monitoring of their abundance is a promising prognostic marker to identify individuals at risk of recurrence or in need of adjuvant therapy. Due to the low abundance of ctDNA present in samples obtained during remission, MRD assays need to be highly sensitive. In addition, each individual will have a different set of somatic variants, requiring personalized solutions for detection. Therefore, personalized NGS assays with high sensitivity and specificity are needed for MRD diagnostics.

To address this need and empower accurate assessments of MRD, Twist Bioscience has developed the MRD Rapid 500 Panels. This product enables customers to design, manufacture and ship fully personalized MRD panels (up to 500 targets) in as little as six days.

To demonstrate the detection sensitivity of Twist Rapid 500 MRD panels, we designed five custom MRD panels which specifically target somatic variants found in Breast, Lung, CRC, Melanoma and Renal Cell Carcinoma. Each of these MRD panels were designed to include 197 targets, with 3-5 variants per tissue origin and a selection of passenger mutations. To create the sample set, we blended synthetic variant sequences with fragmented cell line gDNA (NA12878) to form a contrived specimen which approximates the profile cell-free and circulating tumor DNA. Five frequency levels were created with average VAFs of 0% (WT), 0.01%, 0.05%, 0.1% and 2%. Libraries were prepared with UMI adapters and target enrichment was performed using the MRD panels.

With a sequencing depth of 80,000x, variant calling results revealed that an average of 20 SNV targets can be detected with confidence in the 0.01% VAF samples for each MRD panel, clearly distinguishable from the WT control samples. In addition to demonstrating the accuracy of variant calling, we showcase the utility of targeting a large number of variants for the detection of an MRD signature at very low levels (e.g. 0.01% VAF).

In summary, the performance of the Twist MRD Rapid 500 Panels showed high detection sensitivity of ultra low-frequency somatic mutations while maintaining high specificity for the purposes of MRD monitoring.

*For Research Use Only. Not for use in diagnostic procedures.

Citation Format: Tong Liu, Michael Bocek, Patrick Cherry, Shawn Gorda, Jean Challacombe, Derek Murphy, Esteban Toro. High-sensitivity detection of specific ultra low-frequency somatic mutations for minimal residual disease monitoring. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6608.
Abstract 6609: Detection of rare mutations, copy number variation, and DNA methylation in the same template DNA molecules
Authors: Wang Yuxuan , Douville Christopher , Cohen Joshua , Bettegowda Chetan , Papadopoulos Nick , Kinzler Ken , Vogelstein Bert
Published: April 2023

The analysis of cell-free DNA (cfDNA) from plasma offers great promise for the earlier detection of cancer. At present, changes in DNA sequence, methylation, or copy number are the most sensitive ways to detect the presence of cancer. To increase the sensitivity of such assays, it would be useful to be able evaluate the same template molecules for all these changes. Here we report an approach, called MethylSaferSeqS, that achieves this goal, and can be applied to any standard library preparation method suitable for massively parallel sequencing. The innovative step was to copy both strands of each DNA-barcoded molecule with a primer that allows the subsequent separation of the original strands (retaining their 5-methylcytosine residues) from the copied strands (in which the 5-methylcytosine residues are replaced with unmodified cytosine residues). The original and copied strands are queried for epigenetic and genetic alterations, respectively. We applied this approach to plasma from 265 individuals, including 198 with cancers of the pancreas, ovary, lung or colon, and found the expected patterns of mutations, copy number alterations, and methylation. Furthermore, we could determine which original template DNA molecules were methylated and/or mutated. MethylSaferSeqS should be useful for addressing a variety of questions relating genetics and epigenetics in the future.

Citation Format: Yuxuan Wang, Christopher Douville, Joshua Cohen, Chetan Bettegowda, Nick Papadopoulos, Ken Kinzler, Bert Vogelstein. Detection of rare mutations, copy number variation, and DNA methylation in the same template DNA molecules. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6609.
Abstract 665: Repetitive elements and viral mimicry co-evolve with the immune microenvironment in pancreatic ductal adenocarcinoma
Authors: Sun Siyu
Published: April 2023

Overexpression of repetitive RNA is an emerging hallmark of human cancers. These diverse repetitive elements, including SINEs (Short Interspersed Nuclear Elements) and LINEs (Long Interspersed Nuclear Elements), can mimic viruses by replicating in the genome through retrotransposition and displaying pathogen-associated molecular patterns, potentially triggering inflammatory responses. However, our knowledge of how specific repeats affect tumor evolution and shape the tumor immune microenvironment in a pro- or anti-tumorigenic manner remains incomplete. We integrated evolutionary analysis on whole genome and total RNA sequencing data from a unique cohort of multiregion-sampled human primary and metastatic pancreatic ductal adenocarcinoma (PDAC). We find that the more recently evolved SINEs are more likely to form double-strand RNAs (dsRNAs), a structure known to stimulate innate immune response. Consistently, these younger SINEs are highly associated with a RIG-I associated type-I interferon signature. LINE-1 (L1) retrotransposition activity in these samples tracks with tumor phylogenetic branching and is depended on the status of TP53 mutations, supporting active differential surveillance of L1 mobility by mutant TP53 during tumor evolution. Lastly, we discovered that immunostimulatory SINE expression is anti-correlated with both ADAR1 expressions, exonuclease DIS3 expression, and L1 retrotransposons activity, suggesting a cooperative relationship between ADAR1 and L1 activity in regulating immunogenic SINE expression. We propose that pancreatic tumors modulate immunogenic SINE abundance to their pro-tumorigenic inflammatory advantage through hyperactive L1 activity via accelerated exonuclease degradation when ADAR1 is not activated. Our analysis illustrates for the first time the evolutionary role of dark matter genomic repeats in allowing tumors to actively leverage viral-like innate immune responses to manipulate their immune microenvironment for selective advantage.

Citation Format: Siyu Sun. Repetitive elements and viral mimicry co-evolve with the immune microenvironment in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 665.
Abstract 6650: Cell-based assay to support development and characterization of new drugs in immuno-oncology
Authors: Haque Mohammad , Salam Safnas Abdul , McGinley Shawn , Ma Haiching , Wu jianghong
Published: April 2023

The years since 2009 have seen tremendous progress in unlocking the curative potential of the immune system for the treatment of cancer. Much of that revolution in immuno-oncology has been fueled by the clinical success of immune checkpoint inhibitors, targeting cytokines, antibody dependent cell cytotoxicity and complement dependent cytotoxicity via the T cell activation. Reaction biology has established state-of-art high throughput screening procedures for measuring the ability of new Biologics or compounds to activate T cells. Antibody Dependent Cell Cytotoxicity (ADCC), T cell activation assay (NFAT), immune checkpoint inhibitor assay (PD-1/PD-L1 blockade bioassay), cytokines activation assay and Complement Dependent Cytotoxicity (CDC) are commonly used for drug discovery industry. ADCC is a desirable mechanism for killing target cells using antibody-based drugs. T cell activation assay can be used for the discovery and development of novel biologics and cell therapies aimed at inducing, strengthening and/or engineering T cell response. Blocking of immune inhibitory receptors by their respective ligands on an adjacent cell inhibits TCR mediated proliferation, transcriptional activation and cytokines production. Biologics or compounds designed for measuring the stimulatory or inhibitory function of cytokines are promising in the field of immune oncology. Reaction Biology developed biochemical assays for PD-1/PD-L1, CTLA4/CD80 and CTLA4/CD86 to screen immune checkpoint inhibitors. All of these screening procedures and experimental methods will help to identify new therapeutic biologics or compounds for drug discovery in immune-oncology field.

Citation Format: Mohammad Haque, Safnas Abdul Salam, Shawn McGinley, Haiching Ma, jianghong Wu. Cell-based assay to support development and characterization of new drugs in immuno-oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6650.
Abstract 6666: Multispectral imaging to detect immune phenotypes in pre and post therapy breast cancer patient specimens
Authors: Patel Bhavika , Allen Stephanie , Dennison Brenna , Stapleton Jacob , Archuleta Roni , Rath Mary Lou , Mehra Navi , Talwalkar Sameer S.
Published: April 2023

The immune microenvironment is an important component in cancer therapy. Immune cells can encourage tumor growth, leading to disease progression. A high number of immune cells may be predictive of disease prognosis and response to therapies. Therefore, understanding the immune cell phenotypes present within cancerous tissue can be valuable in developing strategies that aid in the treatment of cancer. In this study, we analyzed pre-and post-therapy samples from breast cancer patients, treated with neoadjuvant chemotherapy, using a 6-plex immunofluorescence assay which included clinically relevant immuno-oncology biomarkers (FoxP3, PD-L1, PanCK, CD4, CD8 and CD163). This assay was developed and optimized in-house prior to testing the cohort. Endpoints for this analysis were characterization of the tumor microenvironment and analysis of the individual immune cell subsets pre and post treatment. Staining was completed on the Leica Bond RX autostainer (Leica Biosystems) and slides were scanned using the PhenoImager™ Fusion (Akoya Biosciences). Using Visiopharm® software, the multiplex phenotyping module was used to analyze the high dimensional human tissue and cell phenotypes were detected using artificial intelligence. Qualitative and quantitative results revealed a change in immune cell phenotypes between pre- and post-therapy samples. These included an increase in intra-tumoral and stromal T cells, no significant difference in PD-L1 positive cells, and an increase in the FOXP3 positive T cells in post-treatment samples. Our data provides insights into the development and application of multispectral imaging for characterization of tumor microenvironment and its dynamics before and after treatment in breast cancer. This can be applied to other cancer types and can aid in making treatment decisions.

Citation Format: Bhavika Patel, Stephanie Allen, Brenna Dennison, Jacob Stapleton, Roni Archuleta, Mary Lou Rath, Navi Mehra, Sameer S. Talwalkar. Multispectral imaging to detect immune phenotypes in pre and post therapy breast cancer patient specimens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6666.
Abstract 6787: Vaccinia virus harboring TRAIL (vTRAIL) for in vivo lung cancer therapy
Authors: Yoo So Young
Published: April 2023

While oncolytic virotherapy has shown promising results for uncured patients with cancer, its effects on lung cancer remain unclear. Lung cancer is mostly unlikely to respond to conventional anticancer drug, therefore, oncolytic virotherapy can be the best option. Herein, we evaluated the anti-cancer activity of the previously developed three oncolytic vaccinia viruses encoding TNF-related apoptosis-inducing ligand (TRAIL), angiopoietin 1 (Ang1) and both genes, especially on killing lung cancer (LC). In this study, we confirmed that our engineered vaccinia viruses showed overall higher anti-cancer activity on lung cancer cells, compared to WT. Vaccinia virus engineered with both Ang1 and TRAIL (vTRAN) showed the highest oncolytic activity and selectivity in vitro (WT < vTRAIL < vAng1 < vTRAN). However, In vivo LLC1 murine lung cancer syngeneic model showed highest attenuated tumor growth when vTRAIL was treated (WT < vAng1 < vTRAN < vTRAIL), which was in accordance with CD8 high PD1 low expression levels in the tissues. It concludes that engineered vaccinia virus harboring TRAIL (vTRAIL) is the promising therapeutic option for in vivo lung cancer therapy.

Citation Format: So Young Yoo. Vaccinia virus harboring TRAIL (vTRAIL) for in vivo lung cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6787.
Abstract 746: Disparities in factors affecting access to palliative care in patients with stage IV breast cancer
Authors: Itani Mira , Sabbagh Saad , Mohanna Mohamed , Dominguez Barbara , Liang Hong , Nahleh Zeina
Published: April 2023

Background: Palliative care is an essential component of cancer care; however, factors hindering its reach to the target population remain understudied. We aim to explore whether an association exists between socioeconomic and geographic factors and access to palliative care (PC) in patients with Stage IV breast cancer in the US.

Methods: This 2004-2017 National Cancer Database analysis includes patients with Stage IV breast cancer who received palliative care. Access to PC is defined as being either at the patient’s primary healthcare facility or at a referral site. Chi-square tests and a multivariate logistic regression were performed to determine the independent factors predicting access to PC. SAS version 9.4 was used to analyze the data.

Results: A total of 18,903 patients were included in the analysis: 15,111 received palliative care services at the same facility and 3,792 were referred elsewhere. Patient age, race, insurance status, Charlson-Deyo score, setting, high school diploma status, median income, facility type, facility location, and distance from healthcare centers were all significantly different between the two groups. On logistic regression, better odds for access to PC were predicted by urban settings (OR: 1.47; 95% CI: 1.30 - 1.67) and being in the Middle Atlantic region (OR: 1.27; 95% CI: 1.07 - 1.52). Distance from the healthcare facility of 4 miles or greater predicted worse odds for access to PC. Comprehensive cancer programs (OR: 1.60; 95% CI: 1.43 - 1.80) and academic/research programs (OR: 2.40; 95% CI: 2.11 - 2.73) held higher odds for access to PC. Having Medicaid/other government insurance (OR: 1.43; 95% CI: 1.24 - 1.65) predicted better odds for access to PC. However, having no insurance was also found to increase access to PC (OR: 1.30; 95% CI: 1.08 - 1.55). Median income and high school diploma status were not significantly associated with the outcome.

Conclusion: PC was positively affected by having access to urban settings, nearby healthcare centers, non-community care centers, Medicaid/other governmental insurance, and by being in the Middle Atlantic region of the US. Having no insurance appears to increase palliative care use, which was unexpected but could be explained if patients with no insurance did not receive standard treatment and were instead offered palliative care. This needs to be investigated in future research.

Citation Format: Mira Itani, Saad Sabbagh, Mohamed Mohanna, Barbara Dominguez, Hong Liang, Zeina Nahleh. Disparities in factors affecting access to palliative care in patients with stage IV breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 746.
Abstract 759: Genome-wide cell-free DNA fragmentation in early detection and disease monitoring of hepatocellular carcinoma
Authors: Lian Shifeng , Fang Fang , Liu Zhiwei , Ji Mingfang , Zheng Zongli
Published: April 2023

Background: Genome-wide cell-free DNA fragmentation profiling was suggested to be useful for early cancer detection. However, it still needed to be evaluated using sample before cancer diagnosis.

Methods: A prospective cohort with hepatitis B virus (HBV)-seropositive participants were enrolled in 2012 and followed-up biannually with blood sample collections till 31 December 2019. A case-control study with hospital hepatocellular carcinoma (HCC) cases were conducted to identify potential biomarkers for HCC detection (Discovery). We adapted the DELFI method (Cristiano et al, Nature, 2019) and evaluated cfDNA fragmentation profile (AdaptDelfi) for detecting HCC at the Discovery phase and validated AdaptDelfi in an independent prospective population cohort (Validation).

Results: Of 18,373 participants, 2,893 were HBV-seropositive and developed 81 incident HCC cases. In Discovery, the AdaptDelfi model distinguished HCC cases from controls excellently (AUC [95% confidence interval] = 0.999 [0.997 - 1.0]), while the serum alpha-fetoprotein (AFP) had an AUC of 0.851 (95% CI = 0.796 - 0.906). High AdaptDelfi was associated with advanced tumor stage (P = 0.038). The hazard of death increased in high AdaptDelfi (hazard ratio 2.43, 95% CI = 1.13 - 5.2) after adjustment for tumor stage. In Validation, AdaptDelfi showed slightly increasing performance using pre-HCC samples collected ≥4 years (AUC = 0.530), 3-4 years (0.615), 2-3 years (0.781), 1-2 years (0.711), and 0-1 year (0.770) before diagnosis. These were comparable with the traditional biomarker - AFP that showed corresponding AUCs of 0.521, 0.525, 0.517, 0.575 and 0.727, respectively. Using a fixed cutoff value from Discovery, AdaptDelfi had a specificity of 88.0% and a sensitivity of 32.5% within one year before diagnosis in detecting early HCC, yielding an estimated positive predict value (PPV) of 1.4% (95% CI = 0.8% - 2.4%) among HBV-seropositive male population.

Conclusions: The genome-wide cell-free DNA fragmentation is correlated with HCC stage and may be a useful biomarker for diagnosing clinical HCC and predict patient survival. However, the low PPV suggests its utility in HCC screening in high-risk populations so far may be limited.

Citation Format: Shifeng Lian, Fang Fang, Zhiwei Liu, Mingfang Ji, Zongli Zheng. Genome-wide cell-free DNA fragmentation in early detection and disease monitoring of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 759.
Abstract 760: Characteristics of fatty liver disease-related hepatocellular carcinoma and genetic background in Japan
Authors: Kogiso Tomomi , Ogasawara Yuri , Horiuchi Kentaro , Taniai Makiko , Tokushige Katsutoshi
Published: April 2023

Aim: A single nucleotide polymorphism (SNP) in PNPLA3 was identified as a disease susceptibility gene for fatty liver disease (FLD) and it’s associated with fibrosis progression and carcinogenesis. Additionally, mutations in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), which encodes hepatic lipid droplet protein, have been found the involvement in various metabolic processes. Loss-of-function mutations in the human HSD17B13 gene may confer a strong protective effect on liver injury, inflammation, fibrosis, and even onset of hepatocellular carcinoma (HCC). Here, we evaluated the characteristics of Japanese patients with FLD- HCC and considered the risk factors of HCC including genetic background.

Methods: We enrolled 402 patients of clinically and pathologically diagnosed with FLD (alcohol: 63, nonalcohol: 339) in our hospital from 1990-2018 (228 males, median age 54.9 [14.6-83.6] years). We analyzed the survival and new-onset HCC rates according to the etiology of FLD (alcohol and nonalcohol), hepatic fibrosis, FIB-4 index, and genetic background of PNPLA3 and HSD17B13 for consideration of the risk factors.

Results: FLD-HCC was observed in 57 cases (14.2%). Comparing to the patients with HSD17B13 wild-type AA (212 cases) and mutant (A/AA or AA/AA, 190 cases), patients with wild type showed significantly increased HCC complication (wild vs. mutant; 39 [18.4%] vs. 18 [9.5%], p = 0.01) and these were tended to be high complication of hypertension (120 [56.6%] vs. 90 [47.4%], p = 0.06). In patients with mutant of HSD17B13, HCC incidence was significantly reduced in alcohol-related FLD, FIB-4 index <2.67, and PNPLA3 CC genotype, however, there was not significant difference in nonalcohol-FLD. Patients with HSD17B13 mutant showed severe steatosis (77% vs. 88.6%). Eleven cases of new HCC were developed during observation period (8.1 [0.5-25.1] years) (n = 370). Five-year incidence of HCC was 3.3% in patients with both PNPLA3 GG/GC and HSD17B13 wild type and it was significantly elevated compared to other SNP profiles (0.6%, p = 0.03). Multivariate analysis identified the risk of FLD-HCC including age, gender, and complication of hypertension.

Conclusions: Genetic background of FLD may associate with onset of HCC. Inhibiting HSD17B13 activity may prevent HCC development, especially in alcohol-related FLD and patients with low risk factors. Therefore, SNPs of gene combination with other risk factors may use for screening tool for FLD-HCC.

Citation Format: Tomomi Kogiso, Yuri Ogasawara, Kentaro Horiuchi, Makiko Taniai, Katsutoshi Tokushige. Characteristics of fatty liver disease-related hepatocellular carcinoma and genetic background in Japan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 760.
Abstract 764: Automated walk away NGS sample preparation for constructing in-line molecular barcoded RNA libraries from Fresh Frozen and FFPE samples
Authors: Bigdeli Saharnaz , Arezi Bahram , Godoski Jan , Rhodes Denise , Aguilar Ryan , William Karen , Buehler Bernd , Zhu Ji , Allen Ronda
Published: April 2023

RNA-Seq is a revolutionary technology for transcriptome analysis, which has been used to quantify transcript levels, confirm gene annotation, identify novel transcripts, splice variants, and fusion detection. Traditionally, the usefulness of RNA-Seq has been limited by pre-analytical (sample availability, low integrity, tumor heterogeneity, complex protocols) and analytical factors (small mRNA fraction, high read duplicate rate), which can lead to higher costs, longer turnaround times, and false negative results. We have developed and automated a streamlined workflow for construction of highly complex RNA Libraries from fresh frozen and FFPE samples that addresses these concerns. We use target enrichment by bait selection with FFPE-derived samples, where rRNA depletion is found to be inconsistent and poly(A) enrichment cannot be used due to degradation of the source material. A fully automated protocol using pre-aliquoted reagents, has been optimized on the Magnis NGS Prep System for a wide range of RNA inputs (10-200 ng), various sample types (Intact and FFPE total RNA) and equipped with 192 Unique Dual sample Indices (UDI) to minimize the effects of possible index hopping and contamination. Addition of in-line molecular barcodes incorporated at the ligation step helps differentiate fragmentation from PCR duplicates, which increases the total number of reads available for further analysis (gene expression and fusion detection). With minimal risk of contamination, this automated protocol delivers up to eight target-enriched NGS Illumina sequencing-ready cDNA libraries from total RNA input per run in about 12 hours without the need of any user intervention. Both catalog and custom probes can be utilized, and PCR cycles can easily be adjusted from the touchscreen to optimize the library yields. For Research Use Only. Not for use in Diagnostic procedures.

Citation Format: Saharnaz Bigdeli, Bahram Arezi, Jan Godoski, Denise Rhodes, Ryan Aguilar, Karen William, Bernd Buehler, Ji Zhu, Ronda Allen. Automated walk away NGS sample preparation for constructing in-line molecular barcoded RNA libraries from Fresh Frozen and FFPE samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 764.
Abstract 766: A genome-wide association study identifies the association of common variants in the major histocompatibility complex with cervical cancer in black South African women
Authors: Kamiza Abram Bunya , Chen Wenlong Carl , Brandenberg Jean-Tristan , Ramsay Michele , Mathew Christopher G.
Published: April 2023

Cervical cancer is the second most common female gynaecological malignancy in sub-Saharan Africa (SSA). Previous genome-wide association studies (GWASs) identified genetic variants associated with cervical cancer in women of European and Asian ancestry, particularly within the major histocompatibility complex (MHC). However, owing to the complexity of linkage disequilibrium and varied environmental exposures in different ancestral populations, regional GWASs are needed to investigate the genetic contribution to the pathogenesis of cervical cancer in continental African populations. A total of 1,637 cervical cancer patients and 761 controls in women of African ancestry were identified from the Johannesburg Cancer Study and the AWI-Gen study, respectively. DNA samples were genotyped on the 2.3 million H3Africa GWAS SNP array and genotyped SNPs imputed to a total of 13,937,308 SNPs. The association between genetic variants and cervical cancer was tested using linear mixed models, adjusting for five principal components and cryptic relatedness. We identified one locus within the MHC region associated with cervical cancer at genome-wide significance, led by rs3129965 (odds ratio [OR] = 0.89, 95% confidence interval [CI] = 0.87-0.92, P = 2.292 x 10-11) near HLA-DRA. Four other loci were strongly associated with cervical cancer (P<5x10-7), including rs575105445 (OR=0.77, 95%CI=0.70-0.85, P = 2.188 x 10-07) near HLA-C,rs184053148 (OR =0.79, 95% CI = 0.72-0.86, P = 4.19 x 10-07) in TRIM31,rs12496921 (OR=0.88, 95%CI = 0.84-0.92, P = 1.32 x 10-07) in ROPN1B and rs114031308 (OR= 1.27, 95% CI =1.16-1.39, P =3.06 x 10-07) near TTC26. The genes in these loci are implicated in numerous pathways including antiviral immunity, DNA repair, the regulation of p53, apoptosis, cell growth and differentiation. These discoveries demonstrate the important contribution of common genetic variants to cervical cancer susceptibility and provide insights into its pathogenesis in women of African ancestry.

Citation Format: Abram Bunya Kamiza, Wenlong Carl Chen, Jean-Tristan Brandenberg, Michele Ramsay, Christopher G. Mathew. A genome-wide association study identifies the association of common variants in the major histocompatibility complex with cervical cancer in black South African women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 766.
Abstract 781: Clinical implications for returning polygenic risk information for skin cancer to ultra-high risk organ transplant recipients
Authors: Seviiri Mathias , Law Matthew H. , Hopkins Peter , Olsen Catherine M. , Whiteman David C. , MacGregor Stuart
Published: April 2023

Introduction: Organ transplant recipients (OTRs) have an elevated risk of developing keratinocyte cancer (KC). We have previously shown that a KC polygenic risk score (PRS) effectively triages OTRs for KC risk, with 50% of transplantees with high genetic risk developing KC within 3 years of follow up. However, readiness for clinical application of the KC PRS, its application to triage OTRs in the clinic and the return of the genetic risk information have not yet been assessed.

Objectives: 1) To evaluate patients’ readiness to receive genetic risk information for KC risk stratification in a lung transplant clinic. 2) To assess whether returning the PRS results to patients influences skin cancer screening, incidence, and sun protection behavior.

Methods: We recruited 100 lung transplantees from the Prince Charles Hospital in Queensland into the ASCOT prospective study. We assessed their attitude, knowledge, and perceptions of genetic testing for KC risk stratification. We also collected genetic data. We developed a KC risk stratification pipeline, and triaged the transplantees. PRS results and KC prevention advice were returned to the high risk group. All transplantees are being followed-up for sun protection and screening behaviors, and skin cancer outcomes.

Results: 50% of OTRs were highly likely to accept genetic testing for KC risk stratification. Following transplantation, there was a drastic change in the perception of KC risk and severity, and the majority of transplantees considered it a major health concern. Using the PRS pipeline, 40 patients were triaged into the high risk category for KC, and received their PRS results and health advice, and we are prospectively assessing whether this will influence skin cancer screening rates, skin cancer incidence, and sun protection behavior in this group. Findings will be shared.

Conclusion: There is positive patient-readiness to receive genetic risk information for KC risk stratification among transplantees. High-risk patients are currently being followed-up for KC outcomes and prevention service uptake including screening, and sun protection behaviors.

Citation Format: Mathias Seviiri, Matthew H. Law, Peter Hopkins, Catherine M. Olsen, David C. Whiteman, Stuart MacGregor. Clinical implications for returning polygenic risk information for skin cancer to ultra-high risk organ transplant recipients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 781.