bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5763: Comprehensive characteristics between genomic alterations and tumor differentiation in Chinese patients with colorectal cancer
Authors: Cui Xiaolong , Ren Aigang , Chen Hao , Huo Yaoliang , Zeng Yanwu , Zhang Hao , Hu Meizhen , Huang He , Guo Yuntong 
Published: June 2022

Abstract
Background: Colorectal cancer (CRC) is a malignant tumor that seriously threatens human health. Valuable diagnostic and prognostic biomarkers are urgently needed for colorectal cancer. We aim to analyze the mutational characteristics of Chinese CRC patients with different tumor differentiation degree, in order to improve the diagnosis and prognosis of this population.
Methods: We retrospectively analyzed tumor tissue specimens from colorectal cancer patients who were treated at the First Affiliated Hospital of Shanxi Medical University from 2019 to 2021. Targeted NGS for 450 genes was performed in OrigiMed (Shanghai, China), a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory.
Results: There were 35 males (55.6%) and 28 females (44.4%) with a median age of 60 (range 23-87) years were involved, including 55 moderately and well differentiated and 8 poorly differentiated colorectal tumors. The mutational frequency of BRAF in the poorly differentiated group was significantly higher than that in moderately and well differentiated group(25% vs. 1.8%, p=0.04). The mutational frequencies of the chromosome folding pathway, notch pathway, and PI3K pathway in poorly differentiated group were significantly lower than that in moderately and well differentiated group(p=0.975X10-15,p=0.97 X 10-26,and p=0.00517, respectively). In this study, the mutations of PDCD1 (programmed cell death 1) and TSC2 Significantly associated with tumor mutation burden (p=0.007 and p=0.047, respectively). In addition, high-frequency co-mutations of chromosome folding-related genes and DNA damage repair-related genes, such as co-mutations between ARID1A-MLH1,KMT2D-MSH6,KMT2D-MSH2, KMT2D-BRCA1, ARID1A-CHEK2, were detected in this study.
Conclusions: We compared the genomic alterations between well-differentiated group and poorly-differentiated group in Chinese CRC patients. Our data showed significant differences in mutational frequency of chromosome folding pathways, notch pathways, and PI3K pathways between well-differentiated group and poorly-differentiated group. Meanwhile, we also identified the high-frequency and complex co-mutation characteristics of chromosome folding pathway genes and DNA damage repair genes in Chinese CRC patients.
Citation Format: Xiaolong Cui, Aigang Ren, Hao Chen, Yaoliang Huo, Yanwu Zeng, Hao Zhang, Meizhen Hu, He Huang, Yuntong Guo. Comprehensive characteristics between genomic alterations and tumor differentiation in Chinese patients with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5763.
Abstract 5786: Mitochondrial genome evolution in gliomas under therapy
Authors: Wade Taylor E. , Varn Frederick S. , Johnson Kevin C. , Verhaak Roel G. 
Published: June 2022

Abstract
Gliomas are the most common malignant brain tumors and characterized by high recurrence rate and therapeutic resistance. Gliomas are clinically separated by mutations in isocitrate dehydrogenase (IDH) genes, but all subtypes have an altered energy metabolism. Mitochondria are essential cellular organelles that mediate many biological processes associated with tumorigenesis, such as energy metabolism and cell death, that can be impacted by mitochondrial mutations and copy number. As part of the Glioma Longitudinal AnalyiSiS consortium, we characterized mitochondrial genome evolution in response to treatment, using whole-genome sequencing data and associated RNA sequencing data from 152 paired tumor samples from 76 patients. Mitochondrial mutations are unequally distributed across the mitochondrial glioma genome, with only 4 of 13 mtDNA genes harboring a mutation across the cohort. Previous consortium analyses have investigated nuclear DNA hypermutation and changes in aneuploidy in response to chemotherapy and radiation treatment. Previous findings have identified hypermutation and copy number alterations as mechanisms of therapeutic resistance in glioma, but did not include analyses on mitochondrial DNA. Our analysis identified key differences between mitochondrial genome evolution and nuclear genome evolution. The mitochondrial mutational burden was not correlated with an increase in nuclear mutational burden. Unlike the nuclear DNA, we did not observe any samples with treatment-associated hypermutation. Mitochondrial copy number varied greatly but was increased at recurrence in IDH wild-type tumors. In tumors with a mutation in the IDH1 gene, mitochondrial copy number decreases were associated with an increase in aneuploidy score in samples that received radiation therapy. Expression analyses highlighted key differences in the active repair mechanisms between mtDNA and nuclear DNA. Our findings shed light on the variations in DNA repair mechanisms between the nucleus and the cytoplasm in glioma and lay the foundation for further analyses on the co-evolution of the mitochondrial and nuclear genomes in treatment-resistant tumors.
Citation Format: Taylor E. Wade, Frederick S. Varn, Kevin C. Johnson, Roel G. Verhaak. Mitochondrial genome evolution in gliomas under therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5786.
Abstract 58: Novel enzymatic fragmentation for challenging samples and methods
Authors: Sexton Brittany S. , Heider Maggie , Williams Louise , Langhorst Bradley , Dimalanta Eileen , Apone Lynne 
Published: June 2022

Abstract
Next Generation Sequencing (NGS) requires fragmentation of DNA molecules upstream of sequencing. Current methods for fragmentation include mechanical shearing and enzymatic fragmentation for NGS library preparation. Mechanical shearing requires costly instruments, can be difficult to automate for high throughput labs, and results in sample loss. In comparison, enzymatic fragmentation methods do not require expensive instruments and are automation friendly. However, current enzymatic fragmentation methods on the market can remove DNA modifications such as methylation, cement DNA damage resulting from formalin fixation in final libraries and can introduce sequencing artifacts or bias. Therefore, while many fragmentation methods are commercially available, challenges remain for sequencing samples such as FFPE DNA or for detecting DNA modification (e.g., 5-methylcytosine).
We have developed a novel enzymatic fragmentation method that can be used upstream of library preparation for DNA methylation assessment or FFPE DNA. The novel enzymatic fragmentation method is quick and robust, taking as little as 20 minutes. It is automation-friendly and can be used to generate DNA fragments ranging from as small as 50 bp up to over 1000 bp.
Here we demonstrate the use of the novel enzymatic fragmentation method upstream of 5mC library preparation methods. This fragmentation method maintained the methylation marks. These libraries showed improvements in GC bias, library yield, library complexity and other sequencing metrics over libraries generated with mechanically sheared DNA.
The use of the novel enzymatic fragmentation method with FFPE DNA library preparation resulted in improvements in sequencing metrics (increased proper pairs, etc.). There was reduced FFPE-damage-derived mutations compared to mechanical shearing or other enzymatic fragmentation methods.
Fragmenting DNA to defined sizes for diverse applications and sample types remains a challenging aspect of NGS library preparation. This new, robust enzymatic fragmentation method overcomes the limitations of some traditional mechanical and enzymatic fragmentation methods and improves the library preparation and sequencing for both DNA modification assessment studies and FFPE DNA.
Citation Format: Brittany S. Sexton, Maggie Heider, Louise Williams, Bradley Langhorst, Eileen Dimalanta, Lynne Apone. Novel enzymatic fragmentation for challenging samples and methods [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 58.
Abstract 5800: Germline pathogenic variant of cancer predisposition genes in pancreatic cancer patients
Authors: Kim Yena , Kim Min Kyeong , Ryu Kum Hei , Shim Hyoeun , Han Ji Sun , Chun Jung Won , Kim Yun-Hee , Song Ju Sun , Kim Young-gon , Woo Sang Myung , Kong Sun-Young 
Published: June 2022

Abstract
Purpose: Genetic attribution for pancreatic cancer has been reported as 2-10%. However, the incidence of genetic predisposition and germline pathogenic variants (PVs) in Korean pancreatic cancer patients has not been well investigated. Therefore we studied to identify the clinical characteristics of the causative gene mutations and incidence of PV for future treatment strategies in pancreatic cancer.
Methods: Total of 283 (145 male and 138 female) patients were enrolled in National Cancer Center in Korea (IRB no. NCC2019-0034, NCC2021-0338) and their median age was 67 years (range: 33-90). Resectable (25.1%), borderline resectable or locally advanced (25.5%), and metastatic (46.3%) stages were included. Germline hereditary cancer panel tests with 28 genes and BRCA1/2 gene were done in 97.2% (n=275) and 2.8% (n=8) of patients, respectively.
Results: PVs were detected in 17 patients (median age 64, range 49-80) in ATM (n=5, 29.4%), BRCA1 (n=3, 17.6%), BRCA2 (n=2, 11.8%), RAD51D (n=2, 11.8%), TP53 (n=1, 5.9%), PALB2 (n=1, 5.9%), PMS2 (n=1, 5.9%), RAD50 (n=1, 5.9%), and SPINK1 (n=1, 5.9%). Eight patients (4 ATM PVs, 2 BRCA1 1 BRCA2, 1 PALB2 PV) presented various type of cancers in their families and three patients with ATM PVs showed pancreatic cancer in their first degree relatives. Nine patients without family cancer history represented median age as 66 (49-80) which was not significantly different of those with family history as 63 (51-75).
Conclusions: This study showed 6.0% of incidence of germline PVs in Korean pancreatic cancer patients. Though we still don’t have guidelines for germline predisposition gene test in pancreatic cancer patients in Korea, this result showed that the incidence of PVs were comparable with that of the country which have recommendation to do genetic tests for all pancreatic cancer patients. To expand our knowledge for the incidence and involving genes of cancer predisposition for Korean pancreatic cancer patients, further analysis in larger number of patients is needed. (This study was supported by National cancer center, Korea, Grant no. 2110181).Keywords: Germ-line Mutation; Pancreatic Neoplasms; Incidence
Citation Format: Yena Kim, Min Kyeong Kim, Kum Hei Ryu, Hyoeun Shim, Ji Sun Han, Jung Won Chun, Yun-Hee Kim, Ju Sun Song, Young-gon Kim, Sang Myung Woo, Sun-Young Kong. Germline pathogenic variant of cancer predisposition genes in pancreatic cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5800.
Abstract 5804: The inhibition of PLA2G2A decreases K-ras-driven pancreatic cancer growth and migration through damaging cell membrane and mitochondria function
Authors: zhang Mingquan , huang Peng 
Published: June 2022

Abstract
The activation of oncogenic K-ras by mutations may stimulate multiple cellular processes including lipids modification. However, the mechanisms by which K-ras affects lipid metabolism remain poorly understood. In this study, we found that PLA2G2A, an enzyme that hydrolyzes membrane phospholipids at sn-2 position to release polyunsaturated fatty acids (PUFA), was up-regulated by K-ras activation and its high expression was correlated with poor survival of patients with pancreatic ductal adenocarcinoma (PDAC). Abrogation of PLA2G2A by siRNA silencing or pharmacological inhibition significantly suppressed the proliferation of K-ras-driven cancer cells, as evidenced by inhibition of cell growth and loss of colony formation capacity. Suppression of PLA2G2A could also decrease K-ras-driven PDAC cell migration. Mechanistic study showed that PLA2G2A inhibition rendered cells vulnerability to lipid peroxidation, likely due to accumulation of excessive PUFA in the membranes. Such alterations resulted in membrane damage and mitochondrial dysfunction with elevated ROS, leading to a reduction in energy production and a decrease in acetyl-CoA, which further compromised de novo lipid biosynthesis. Our study suggests that PLA2G2A-mediated cell membrane remodeling plays an important role in cell survival and proliferation in during K-ras-driven cancer, and that PLA2G2 could be a potential therapeutic target for pancreatic cancer treatment.
Citation Format: Mingquan zhang, Peng huang. The inhibition of PLA2G2A decreases K-ras-driven pancreatic cancer growth and migration through damaging cell membrane and mitochondria function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5804.
Abstract 5809: eIF2α O-GlcNAcylation promotes oxidative stress in arginine-starved triple-negative breast cancer cells
Authors: Hung Yu-Wen , Wang Yi-Chang , Ann David K. 
Published: June 2022

Abstract
Redox balance is the critical liaison for cancer homeostasis. Moderate increases in reactive oxygen species (ROS) levels can lead to cancer formation and progression. However, a disproportional increase of ROS levels changes equilibrium in cell redox status and leads to cancer cell death. Therefore, exogenous agents or antioxidant inhibitors which augment ROS generation become a potential new way to target cancer cells. We have found excessive accumulation of cellular proteins during arginine starvation causes stresses on the endoplasmic reticulum (ER) protein folding machinery resulting in elevated ROS levels. In this study, we continue to examine that arginine starvation-attenuated heme oxygenase-1 (HO-1) translation exacerbates the high ROS level to kill the cancer cells. In addition, HO-1 translational downregulation is due to arginine starvation-induced O-GlcNAcylation of eIF2α at S219, T239, and T241 residues. Loss of O-GlcNAcylation at eIF2α significantly rescues arginine starvation-reduced HO-1 protein level, resulting in better recovery and migratory properties from starvation and lower ROS level. In addition, arginine starvation-induced O-GlcNAcylation of eIF2α to suppress HO-1 translation is independent of its phosphorylation at S51, which is another stress-stimuli modification that regulates eIF2 involved protein translation. Arginine starvation exploits O-GlcNAcylation to antagonize eIF2α phosphorylation-induced HO-1 expression. Taken together, arginine starvation is a potential anti-cancer therapy in which induced eIF2α O-GlcNAcylation presents itself as a critical role for metabolic adaptation and tumor growth by dysregulating the antioxidant protein in cancer cells.
Citation Format: Yu-Wen Hung, Yi-Chang Wang, David K. Ann. eIF2α O-GlcNAcylation promotes oxidative stress in arginine-starved triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5809.
Abstract 5827: Increased miR150 expression in tumors enhances lymphocytes infiltration causing immunosuppression through inflammatory chemokines
Authors: Maiti Aparna , Oshi Masanori , Wu Rongrong , Hait Nitai , Takabe Kazuaki 
Published: June 2022

Abstract
Dysregulated miRNAs play key roles in multiple biological processes and cancer. miR-150-5p, a cancer-related miRNA, has been reported to be aberrantly expressed in various cancers. We found that triple-negative and HER2+ breast cancer patients have elevated expression of miR150 in the TCGA and METABRIC patient cohort. Both cohorts showed significantly increased expression of miR150 in grade IV patients. Further studies explained that miR150 is strongly correlated with CD8+ T cells and B cells in accord with increased expression of immune-checkpoint markers PD-1, PDL-1, and CTLA4. We, therefore, hypothesized that higher expression of miR150 in tumors attracted more immune cells in the tumor microenvironment. We use two triple negative breast cancer cell lines MDA-231 and BT-549 cells and overexpressed miR150 followed by co-culture them with Jurkart and B cells. Our data revealed that both jurkart and B cells had increased migration towards cancer cells overexpressed miR150 mimic compared to miR150 mimic negative control. Interestingly, overexpressed miR150 mimic in cancer cells inhibited migration in both triple-negative breast cancer cells. Overexpression of miR150 mimic in cancer cells did not alter cell proliferation. To understand further the role of miR150 in breast cancer, we overexpressed miR150 mimic and its corresponding negative control in MDA-231 and did RNA seq analysis. RNA seq data explained that approximately 4927 genes are upregulated with miR150 mimic overexpression. Interestingly several chemokines and mediators of metastasis (CXCL2, CXCL1 CCL20, IGBP3, and ANGPTL4) are upregulated among the top 50 upregulated genes. In addition, gene enrichment analysis explained that TNF-α signaling pathways, Hypoxia, epithelial-mesenchymal pathways, E2F signaling, and Inflammatory pathways are a few upregulated pathways with miR150 mimic overexpression compared to the negative control. We also found miR150 high tumor enriched correlated with interferon-alpha and gamma signaling, inflammatory response pathways similar with cohort analysis data. In conclusion, miR150 in cancer plays a key role in interferon and inflammatory signaling pathways attracting more immune cells and suppressing the tumor microenvironment.
Citation Format: Aparna Maiti, Masanori Oshi, Rongrong Wu, Nitai Hait, Kazuaki Takabe. Increased miR150 expression in tumors enhances lymphocytes infiltration causing immunosuppression through inflammatory chemokines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5827.
Abstract 5850: p53 gene expression and nitric oxide levels after artemisinin-caffeine treatment in breast, lungs and liver of DMBA-induced tumorigenesis
Authors: Dokunmu Titilope M. , Opara Sandra C. , Awani Omiete U. 
Published: June 2022

Abstract
Background: With increasing incidence of cancers globally and limited resources in some affected countries, repurposing existing drugs for reducing tumorigenesis is highly important. Artemisinin and caffeine have potent anti-oxidative and anti-cancer properties, although they are therapies for other diseases. When p53 is activated, it repairs DNA damage, prevents tumorigenesis and induces apoptosis whereas nitric oxide is a pro-apoptotic modulator which can upregulate p53 thereby reducing tumorigenesis. We evaluated the biochemical and p53 gene modulatory effects of doses of artemisinin-caffeine combination on breast, lung and liver tumors in rats induced with DMBA.
Methods: After due ethical approval, 30 animals were treated with 40mg/kg single dose of 7,12-dimethylbenzene anthracene (DMBA) as a model for DNA damage and induction of carcinogenesis. Five animals each received low dose artemisinin (4mg/kg), low dose caffeine (25mg/kg), low dose combination of Art + Caff (4+25mg/kg), high dose combination of Art + Caff (8+50 mg/kg) or no treatment. All treatment doses were orally administered daily for two weeks post-DMBA treatment, normal control received saline. Nitric oxide levels were assessed and p53 relative gene expression was determined by primer-specific RT-PCR (GAPDH was used as loading control) and amplicons were resolved by gel electrophoresis.
Results: DMBA induced lesions in breast, liver, and lung tissues were evident from histology analysis, compared to untreated group. In all 3 tissues, low dose caffeine and combination of Art + Caff significantly reduced p53 gene expression (p &lt; 0.05), but there was significant increase in of p53 expression in low dose Art and high dose Art + Caff groups, which were similar to DMBA group (p&lt;0.05). There was also decrease in nitric oxide levels in treated groups compared to DMBA group.
Conclusions: This study shows a dose-dependent anticancer effects of caffeine and artemisinin combination on p53 gene and nitric oxide regulation and hence can mitigate against tumorigenesis.
Citation Format: Titilope M. Dokunmu, Sandra C. Opara, Omiete U. Awani. p53 gene expression and nitric oxide levels after artemisinin-caffeine treatment in breast, lungs and liver of DMBA-induced tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5850.
Abstract 5851: Negative regulation of p53 by ZnT1
Authors: Brik Ben , Carino Kathleen , Narrow Wade , Harris Chris R. , Yu Xin , Carpizo Darren R. 
Published: June 2022

Abstract
Rationale and Background: p53 is a powerful tumor suppressor protein that also autorepresses by inducing expression of its own negative regulators, such as MDM2. Here we explore another potential mechanism for p53 autorepression, regulation of zinc metabolism. Proper folding of p53 requires zinc binding and cancer-associated mutations in p53 often lower the affinity of the mutant proteins for zinc. Our previous work showed that ZMC1, a zinc metallochaperone, can reactivate certain p53 mutants by raising intracellular zinc concentrations. Here we show that p53 activates transcription of ZnT1. ZnT1 can then export zinc from the cell, which in turn lowers p53 activity.
Methods: To explore the relationship between ZnT1 and p53, we studied several human cancer cell lines under various conditions, including ZnT1 overexpression, ZnT1 silencing, and p53 activation. For silencing gene expression, we used CRISPR-Cas9 with a lentiviral vector to knock out ZnT1 and also employed shRNAs to knockdown expression of p53 or ZnT1. To analyze the relationship between TP53 and ZnT1 genes in clinical samples, data from cBioPortal were examined.
Results: ZnT1 transcription increased after p53 was activated in several p53+ cell lines but did not increase in isogenic p53-null cell lines, suggesting that ZnT1 transcription is dependent on p53. p53 also bound to the ZnT1 promoter by chromatin immunoprecipitation assay, and activated transcription of a ZnT1/luciferase promoter fusion. Overexpression of ZnT1 decreased p21 transcription, indicating lowered p53 function; conversely, knockdown of ZnT1 increased p21 transcription. By cBioPortal analysis, ZnT1 gene amplifications were mutually exclusive with TP53 gene mutations in breast and lung tumors.
Conclusion: These data suggest that autorepression of p53 occurs in part due to lowered intracellular zinc caused by upregulation of ZnT1.
Citation Format: Ben Brik, Kathleen Carino, Wade Narrow, Chris R. Harris, Xin Yu, Darren R. Carpizo. Negative regulation of p53 by ZnT1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5851.