bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2177: Tumor neoantigen profiling with validated patient-specific TCR characterization to improve neoepitope prediction
Authors: Pan Zheng , Dalmas Olivier , Peng Songming , Jacoby Kyle , Sennino Barbara , Ma Yan , Smith Chad , Momin Amin , Xu Allison , Heeringa Katharine , Johnston Jonathan , An Duo , Quach Boi , Lu William , Nguyen Diana , Conroy Andrew , Purandare Bhamini , Huang Eva , Stawiski Eric , Franzusoff Alex , Mandl Stefanie 
Published: July 2021

Abstract
PACT Pharma has developed an ultra-sensitive approach to validate predicted neoantigens and the cognate T cell receptors (neoTCRs) from tumor specific somatic mutations by capturing neoantigen-specific T cells from peripheral blood. This process is used in clinical trials (NCT03970382) of personalized neoTCR-T therapy for persons with solid cancers.
Using the state of the art prediction pipeline and screening process, more than one hundred twenty neoantigens were predicted from 5 type of solid cancers that were validated by characterizing cognate T cells and their close to 200 unique TCRs captured from the blood of the same individual. These validated neoepitopes of 8 to 11 amino acids represent broad HLA class I coverage with &gt;30 alleles to date. Our analysis revealed that mutations can occur in all positions within the epitopes. Epitope immunogenicity is potentially affected by different mechanisms including mutation position, agretopicity, as well as HLA interacting positions and/or by interactions between mutated residues and its cognate TCRs. It was observed that these validated neoepitopes comprise broad ranges of predicted HLA binding affinities, stability, and neoantigen expression levels. The analysis presented here offers insights to enable machine learning to advance rules for epitope selection and prioritization that may be important for immunological approaches to address a broad range of diseases, including cancer.
Citation Format: Zheng Pan, Olivier Dalmas, Songming Peng, Kyle Jacoby, Barbara Sennino, Yan Ma, Chad Smith, Amin Momin, Allison Xu, Katharine Heeringa, Jonathan Johnston, Duo An, Boi Quach, William Lu, Diana Nguyen, Andrew Conroy, Bhamini Purandare, Eva Huang, Eric Stawiski, Alex Franzusoff, Stefanie Mandl. Tumor neoantigen profiling with validated patient-specific TCR characterization to improve neoepitope prediction [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 2177.
Abstract 219: Identifying genetic interactions resulting form diverse biological mechanisms to inform cancer drug development
Authors: Garcia-Quismondo Manuel , Elemento Olivier , Madhukar Neel , Gilvary Coryandar 
Published: July 2021

Abstract
Identifying gene interactions, such as synthetic lethal relationships, has led to actionable, clinical insights, enabling targeted oncology therapies. However, identifying these interactions has proven difficult, in large part due to the multiple mechanisms by which two genes can interact, such as occurring in the same pathways or conversely occurring in parallel pathways, but involved in the same biological functions. Therefore, experimentally testing all possible sources of gene interactions is costly and time consuming, however a robust computational approach would allow researchers to investigate these interactions efficiently. Here, we describe a machine learning approach that integrates multiple metrics, such as gene-gene pairwise expression correlations, similarity metrics for genetic biological functions, and pathway co-occurrence, to derive a global interaction score. Our model can simultaneously achieve significant predictive performance (Area under the receiver operator curve = 0.8), while also elucidating the underlying mechanism of predicted gene interactions, informing future experimental validation protocols. Additionally, we leveraged transcriptomic and genomic profiles of cancer patients to identify clinically actionable genetic interactions. Our tool provides a novel multi-faceted approach for the detection of gene interactions and can be used to identify biomarkers, novel oncology targets and overall enhance our understanding of biological mechanisms.
Citation Format: Manuel Garcia-Quismondo, Olivier Elemento, Neel Madhukar, Coryandar Gilvary. Identifying genetic interactions resulting form diverse biological mechanisms to inform cancer drug development [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 219.
Abstract 2206: Investigation of DNA damage repair mutated characteristics and correlation with immunogenic biomarker in Chinese head and neck cancer patients
Authors: Chen Yong , Wang Yan , Zheng Yating , Xie Wenzhuan , Huang Mengli 
Published: July 2021

Abstract
Background: DNA damage repair (DDR) pathway have been reported in several cancer, and known as a predictive biomarker of platinum-based chemotherapy, PARP inhibitor therapy, radiotherapy, and immunotherapy. However, the predictive value and mutated characteristics of DDR in patients with head and neck cancer (HNC) is still uncertain. The purpose of this study is to assess the frequency of DDR mutations, and the correlation between DDR mutations and immunogenic biomarker such as tumor mutation burden (TMB), microsatellite instability (MSI) and PD-L1 expression in Chinese HNC patients.
Methods: Genomic profiling of DNA was performed through a next-generation sequencing (NGS) (panel on 381/733-gene) on tissue from Chinese patients with head and neck cancer between January 23, 2017 and April 10 2020. TMB was defined as total number of somatic non-synonymous mutations in coding region. MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was determined by immunohistochemistry staining using Dako 22C3. Germline or somatic mutations of 35 DDR genes were classified as DDR gene mutations.
Result: Genetic mutation of 319 HNC patients were analyzed using NGS, of which 32 (10.03%) harbored alterations in DDR genes. The most frequently mutated DDR genes were BRCA2 (3.23%), followed by FANCA (2.02%), BRCA1 (1.61%), RAD51 (0.81%), RAD50 (0.81%), PMS2 (0.81%), and PLAB2 (0.81%). The frequency of KMT2C, CD274, FBXW7, APC, NOTCH1, PDCD1LG2, RB1, LRP1B, and JAK2 mutations was higher in DDR mutations (DDRmut) than in DDR wild-type (DDRwt) patients. PD-L1 status analysis was performed in 265 HNC patients, including 24 DDRmut patients and 241 DDRwt patients. But there was no significant difference on PD-L1 expression between DDRmut t and DDRwt (P=0.93). 310 HNC patients (including 31 DDRmut patients and 279 DDRwt patients) could be evaluated for TMB, the results showed that DDRmut (10.13Muts/Mb) was associated with higher TMB than DDRwt (5.65Muts/Mb) (P = 0.0031). Of the 308 HNC patients (including 31 DDRmut patients and 277 DDRwt), only 3 (0.97%) were diagnosed as MSI-H, including 2 (6.45%) patients with DDRmut and 1 (0.36%) patient with DDRwt.
Conclusions: The DDR pathway genes alteration characteristics was presented in Chinese HNC patients, and was associated with a higher TMB level. These findings provide a theoretical basis for future investigation of clinical therapy in DDR mutated Chinese HNC patients.
Citation Format: Yong Chen, Yan Wang, Yating Zheng, Wenzhuan Xie, Mengli Huang. Investigation of DNA damage repair mutated characteristics and correlation with immunogenic biomarker in Chinese head and neck cancer patients [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 2206.
Abstract 2227: Pan-cancer shedding patterns of tumor circulating cell free DNA
Authors: Navarro Fabio C. P. , Zhang Simo , Tan Mengyao , Abbott Charles , Northcott Josette , Lyle John , Bartha Gabor , Harris Jason , West John , Chen Richard , Boyle Sean Michael 
Published: July 2021

Abstract
Introduction: Tumor circulating cell-free DNA (ctDNA) comprises DNA molecules cast from tumors that reach and survive in a patient's bloodstream. Given its non-invasive nature, the liquid biopsy of ctDNA has remarkable potential for diagnosis, prognosis, disease progression tracking, and treatment monitoring. Nonetheless, little is known about which tumor features yield higher representation of ctDNA in blood or even which regions in the tumor genome are more inclined to shed and thus be observed as ctDNA.
Typically, studies of ctDNA have focused on a limited and well-established set of genes and recurrent variants. However, these limited gene panels may not capture the breadth of genetic alterations that reflect tumor biology. Their limited footprint hinders a comprehensive understanding of tumor heterogeneity, mechanisms of resistance, and DNA shedding patterns. To address these limitations, we developed a whole-exome scale cfDNA platform, NeXT Liquid Biopsy™, that enables sensitive detection and tracking of mutations in over twenty thousand genes from plasma samples.
Results: Here we profile over 50 tumor, normal, and plasma matched samples using NeXT Liquid Biopsy to investigate pan-cancer patterns of DNA shedding. We observe varying levels of ctDNA shedding in plasma, suggesting that tracking tumors with an exome-scale set of variants, as opposed to with a targeted panel, can benefit greatly from the higher sensitivity and granularity of our enhanced exome sequencing. Next, we sought to investigate the patterns of somatic variants representation in plasma. For this, we integrate shedding ratios with transcriptome and epigenome data from healthy paired tissues and examine variant shedding biases associated with transcription rate and histone modifications in associated nucleosomes.
Conclusion: We sequenced and analyzed one of the largest tumor, normal, and plasma cohorts to date with comprehensive coverage of somatic variants across all human genes. Our results suggest that tracking exome-scale somatic variants adds invaluable information to understand a tumor's biology. Moreover, our comprehensive coverage of the tumor genome can be used to unveil biases of tumor genome shedding patterns. We are able to investigate the shedding ratio across distinct genomic features deriving, to our knowledge, the first exome scale pan-cancer shedding resource of the human genome.
Citation Format: Fabio C. P. Navarro, Simo Zhang, Mengyao Tan, Charles Abbott, Josette Northcott, John Lyle, Gabor Bartha, Jason Harris, John West, Richard Chen, Sean Michael Boyle. Pan-cancer shedding patterns of tumor circulating cell free DNA [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 2227.
Abstract 2253: Comparison of genomic alterations in neuroendocrine tumors originated from different primary sites
Authors: Tang Qiyun , Tian Ye , Li Xiaolin , Bai Jian'an , Liu Min , Hu Ping , Zhang Shanshan , Xu Zanmei , Qu Yueting , Wang Aodi 
Published: July 2021

Abstract
Background: Neuroendocrine tumors (NETs) are heterogeneous, relatively rare tumors derive from neuroendocrine system. Currently, limited therapeutic strategies are available for NETs. Next-generation sequencing (NGS) and target gene-based precision therapy have shown promising efficacy in many tumors, but fare in NETs. Several reports illustrated that the primary sites of NETs were significantly bound up with the clinical response and prognosis. However, characteristics of their genomic alterations are insufficiency nowadays. Methods: A cohort of 94 Chinese NET patients were recruited, and the FFPE tumor tissues and matching blood samples from different primary sites were collected. Targeted next generation sequencing (NGS) of 450 genes was performed in OrigiMed (Shanghai, China) with a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: In all patients, the top 5 most-frequently aberrant genes were TP53 (46.8%, 44/94), RB1 (23.4% 22/94), MEN1 (20.2%, 19/94), KRAS (11.7%, 11/94) and ATRX (9.6%, 9/94). The enrolled NETs contain 7 different primary sites, namely, 37 pancreatic NETs (PNETs), 16 hepatic NETs (HNETs), 11 gastric NETs (GNETs), 10 gallbladder NETs (GB-NETs), 8 esophageal NETs (ENETs), 7 colorectal NETs (CNETs), and 5 small intestine NETs (SI-NETs). Based on origin sites, TP53 is the most widely distributed mutant gene in all sites except for PNETs (Ranked 3rd), while RB1 mutations were significantly higher in ENETs (75.0%, 6/8), GB-NETs (60.0%, 6/10) and GNETs (36.4%, 4/11). Other higher -frequency mutated genes among different sites showed greatly dissimilarity (MEN1, ATRX and DAXX in PNETs; FAT3, MAX, MUC16, GATA4 and OBSCN in HNETs; APC, KRAS and PTEN in GNETs; TERT, ERBB2 and YES1 in GB-NETs; LRP1B and FBXW7 in ENETs; APC, ADGRA2 and FGFR1 in CNETs; NF1 in SI-NETs). Furthermore, signaling pathways involved in potential drug-target genes were analyzed. Results revealed 16.0% (15/94) patients with aberrations in PI3K/AKT/mTOR pathway, 11.7% (11/94) in Cell-Cycle pathway, 9.6% (9/94) in HRD pathway, 9.6% (9/94) in FGF pathway and 16.0% (15/94) in other cancer-related genes (ERBB2, VHL, MET etc.). Conclusions: This study reveals the genomic alteration characteristics of NETs from different primary sites. The profiles obtained in our study may provide evidences for further targeted therapy to improve outcomes of Chinese NETs.
Citation Format: Qiyun Tang, Ye Tian, Xiaolin Li, Jian'an Bai, Min Liu, Ping Hu, Shanshan Zhang, Zanmei Xu, Yueting Qu, Aodi Wang. Comparison of genomic alterations in neuroendocrine tumors originated from different primary sites [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 2253.
Abstract 2255: The impact of primary immunodeficiency informed molecular landscape on the biology and prognosis of refractory malignancies
Authors: Tran Son , Murguia-Favela Luis , Narendran Aru 
Published: July 2021

Abstract
Introduction: Cancer is one of the most common causes of death in patients with primary immunodeficiencies (PIDs). The immune surveillance concept postulates that PIDs are an important contributor to cancer growth and outcomes. Although several immunodeficiency syndromes are known to be associated with malignancies in children and adults, currently, the molecular mechanisms that link immune functions to cancers are poorly understood. Here we describe distinct molecular characteristics in adult cancers with respect to PID-associated genes that impact survival outcomes in affected patients.
Methods: In this study, we integrated transcriptome data of 28 adult cancers from the public database The Cancer Genome Atlas (TCGA) with respective healthy tissues as control from the Genotype-Tissue Expression (GTEx) project. Unified datasets integrating GTEx healthy samples and TCGA cancer data were provided by the Recount2 protocol and differential expression analyses (DEA) were carried out using the integrated limma-voom and edgeR pipelines in the TCGAbiolinks R package. Gene ontology (GO) enrichment analyses were performed using the pathfindR R package. Mutational and clinical data of adult cancer patient samples in TCGA and the AACR Project GENIE were consolidated using cBioPortal and the maftools R package. PID-associated genes were curated from the latest registry by the European Society for Immunodeficiencies (ESID).
Results: Of 307 PID-associated genes, 151 (32.0%) up-regulated and 88 (18.6%) down-regulated genes were identified across the 28 unified TCGA-GTEx datasets. From the identified differentially expressed gene sets, GO analysis revealed enrichment in immunological pathways related to complement and coagulation cascades (27/28 datasets), systemic lupus erythematosus (25/28), in addition to Fanconi anemia (22/28). The greatest frequency of mutations in PID-associated genes from the consolidated TCGA and GENIE datasets were KRAS (14.83%), KMT2D (10.03%), TERT (8.99%), PRKDC (7.59%) and PTEN (6.18%) across all cancer types, with a total of 259 affected PID-associated genes. Survival analyses using Cox proportional-hazards and Kaplan-Meier models will assess the clinical implications of the identified molecular alterations in affected patients.
Conclusion: Our integrative approach aids in the elucidation of molecular mechanisms that bridge PIDs to tumour biology. These data may help identify important biomarkers and potential future targeted therapeutics.
Citation Format: Son Tran, Luis Murguia-Favela, Aru Narendran. The impact of primary immunodeficiency informed molecular landscape on the biology and prognosis of refractory malignancies [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 2255.
Abstract 2256: A population-based mouse model for an experimental basal-like mammary cancer
Authors: French John Edgar , Pressel William , Albright Jody , VerHague Melissa , Hursting Stephen D. 
Published: July 2021

Abstract
The prevalence of obesity, an established risk and prognostic factor for basal-like breast cancer (BLBC), has risen dramatically in the US and many other countries over the past 4 decades. Obesity is also associated with increased resistance to several classes of cancer chemotherapeutic agents used for advanced BLBC. Unfortunately the mechanisms underlying chemotherapy resistance, and the inter-individual differences driving resistance, are poorly understood. Population-based experimental mouse models for determining inter-individual genetic differences in chemotherapy pharmacokinetics and treatment-related efficacy or resistance in mammary gland cancer are not well-defined. Our aim is to develop a population-based experimental model based on outcrosses between 30 different Collaborative Cross line females and hemizygous male B6.FVB-Tg(C3-1-TAg) (greater than N15) congenic mice to produce 30 Collaborative Cross (CC) recombinant inbred line intercross (CC RIX) mouse lines to investigate the interactive effects between diet-induced obesity (DIO) and genetic susceptibility to chemotherapy in a genetically heterogeneous mouse model of BLBC. We report here that thirty genetically-different CCRIL X hemizygous B6.FVB-Tg(C3-1-TAg) congenic female and male CC RIX mice observed longitudinally for occurrence of basal-like mammary tumors showed significant differences in both age at first mammary tumor observation and the fraction of females and males in each RIX bearing tumors. Litter size and the number of females and males of each RIX varied across the 30 CC RIX line. The study was well-powered, with at least X males and Y females for each CC RIX line evaluated longitudinally. We observed that 25 of 30 female CC RIX lines presented with BLMC, with distinct times-to-tumor with each CC RIX. The penetrance of the fraction of each CC RIX line (birth cohort) presenting with BLMC varied greatly in females (25-100%). Surprisingly, 11 of 30 male CC RIX lines presented with BLMC, with penetrance of BLMC varying in males between 10-75%. In conclusion, we present preliminary data to support development of an experimental mouse model for BLBC based on the random mating of 8 genetically-diverse homozygous inbred founder lines followed by in-breeding to greater than 95% homozygosity carrying 45 million single-nucleotide and structural variants. Studies are underway using these CC RIX lines to evaluate the genetic underpinnings of obesity-associated resistance to carboplatin in C3-TAg-driven mammary tumors.
Citation Format: John Edgar French, William Pressel, Jody Albright, Melissa VerHague, Stephen D. Hursting. A population-based mouse model for an experimental basal-like mammary cancer [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 2256.
Abstract 2281: Impact of DNA contaminants on next-generation sequencing data quality
Authors: Dubinsky Amy , Saunders Lauren 
Published: July 2021

Abstract
Nucleic acid purification and clean-up are critical steps for genomics applications, including next-generation sequencing (NGS). Variability in the quality of sample extraction methods can result in differential removal of inhibitors, or reaction contaminants, that diminish NGS experimental data quality. To maximize sample recovery and create more consistent results, efficient removal of inhibitors or contaminants is critical during nucleic acid isolation and purification. In this study, we examine the effect of three common tissue-specific nucleic acid contaminants: (1) collagen, (2) myoglobin, and (3) melanin, on NGS library prep and sequencing metrics. These contaminants are present in skin and muscle tissue and are known to cause inhibition of PCR reactions. In addition, we will extract DNA from both of these samples types and evaluate the performance of two commonly used DNA extraction technologies: (1) magnetic bead-based clean-up; and (2) silica-based columns, for their ability to remove contaminants from DNA extractions and the differential effect of these extraction methods on downstream NGS metrics. These findings demonstrate the importance of the choice of extraction chemistry on NGS metrics and read quality. We also demonstrate that magnetic bead-based- protocols offer a superior reliable, rapid, automatable method to produce high quality DNA and remove contaminants.
Citation Format: Amy Dubinsky, Lauren Saunders. Impact of DNA contaminants on next-generation sequencing data quality [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 2281.