bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5698: Genome-wide DNA methylation profiling for differentiating synchronous endometrial and ovarian cancer
Authors: Chan Yusanne Yung Sing , Wong Oscar Gee Wan , Cheung Annie Nga Yin 
Published: June 2022

Abstract
Background: Synchronous endometrial and ovarian cancer (SEOC) refers to simultaneously discovered endometrial and ovarian tumours on the same patient. SEOC may represent double primary (DP) tumours that arise independently on the two sites, or clonally related (CR) tumours that arise either on the endometrium or ovary and metastasized to the other site. Accurate differential diagnosis between these two scenarios can implicate on the treatment options and prognostication of SEOC. However, it is difficult to achieve as the histopathological features of DP and CR tumours are often ambiguous. DNA methylation landscape of SEOC may provide markers for differentiating DP and CR tumours but remain largely unexplored.
Methods: The archival tissues of six pairs of SEOC and their accompanied normal uterine tissues were retrieved. The tumours were accessed by conventional histopathological criteria and mitochondrial DNA (mtDNA) sequencing to categorize them into DP or CR. We then analyzed the methylation profiles of &gt;850,000 CpG sites of the tumor samples using the Illumina Infinium MethylationEPIC BeadChip array. Downstream methylation analysis was performed in the R/Bioconductor package ChAMP. Gene ontology (GO) enrichment analysis on the methylation driven genes was done using PANTHER.
Results: mtDNA sequencing revealed that among the 6 cases of SEOC, there are 3 DP and 3 CR. Clustering analysis of differentially methylated CpGs (DMPs) between tumours of the same tissue type effectively distinguished endometrial and ovarian tumours into DP or CR. Thus, DP and CR endometrial tumour showed 50 DMPs and 15 differentially methylated regions (DMRs), but no significantly enriched signaling pathway was identified. On the other hand, there were 1,105 DMPs and 44 DMRs that mapped to 601 known genes between DP and CR ovarian tumours. GO analysis revealed that the hypomethylated genes in CR ovarian tumour were enriched in several metastatic-related processes, including cellular response to stimulus, regulation of cell projection organisation, cell migration and negative regulation of voltage-gated potassium channel activity.
Conclusions: Taken together, our findings demonstrated that DNA methylation profiling can be used for SEOC patient stratification and may enhance our understanding of epigenetic regulation of SEOC pathogenesis.
Citation Format: Yusanne Yung Sing Chan, Oscar Gee Wan Wong, Annie Nga Yin Cheung. Genome-wide DNA methylation profiling for differentiating synchronous endometrial and ovarian 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 5698.
Abstract 5704: IDH2 mutation reduce radiotherapy induced immune response in glioblastoma by affecting micronucleus formation
Authors: Elkashef Sara Mahmoud , Nicholson Shirony , Harding Shane 
Published: June 2022

Abstract
DNA methylation is the most abundant epigenetic modification, it plays a critical role in tissue homeostasis, genomic stability, and mitotic fidelity. Isocitrate dehydrogenase genes (IDH1/2) are non-redundantly mutated in several types of cancers including Glioblastoma (GBM), and their mutation induces a DNA hypermethylation phenotype. Radiotherapy (RT), either alone or in combination with other treatments, forms a primary intervention for GBM but the full scope of how IDH1/2 mutations influence this response are not known. In this work, we demonstrate that IDH2 mutation reduces the formation of post-RT micronuclei (MN), small DNA bodies in the cytoplasm distinct from the primary nucleus. Previously, MN has been found to recruit the pattern recognition receptor cGAS to activate an interferon-mediated signalling cascade via STING. We demonstrate that hypermethylation induced by IDH2 mutation does not impact cGAS localization to MN but instead reduces the overall burden of MN which correlates with decreased cGAS-STING mediated transcriptional activation. Mechanistically, IDH2 mutation drives centromeric hypermethylation which stabilizes kinetochore assembly and the fidelity of mitotic chromosome segregation post radiation. We also demonstrate that a reduction of MN formation in IDH2 mutant tumors reduces synergy between RT and immune checkpoint blockade in murine glioma models. Together our data suggest that metabolic alterations in cancers directly influence mitotic fidelity and response to RT with important implications for combination treatments that capitalize on synergy with the innate cellular signalling toward the adaptive immune system.
Citation Format: Sara Mahmoud Elkashef, Shirony Nicholson, Shane Harding. IDH2 mutation reduce radiotherapy induced immune response in glioblastoma by affecting micronucleus formation [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 5704.
Abstract 5729: Dynamic phase separation of the androgen receptor and its coactivators to regulate gene expression
Authors: Zhang Fan , Biswas Maitree , Lee Joseph , Lingadahalli Shreyas , Wong Samantha , Wells Christopher , Saxena Neetu , Sun Bei , Parra-Nuñez Ana K. , Sanchez Christophe , Foo Jane , Chan Novia , Ung Lauren , Khan Nabeel , Altıntaş Umut Berkay , Bui Jennifer M. , Wang Yuzhuo , Fazli Ladan , Rennie Paul S. , Lack Nathan , Cherkasov Artem , Gleave Martin E. , Gsponer Joerg , Lallous Nada 
Published: June 2022

Abstract
Numerous cancers, including prostate cancer (PCa), have been shown to be addicted to transcription programs driven by specific genomic sites known as superenhancers (SEs). Recently, it has been proposed that the robust transcription of genes at such SEs is enabled by the formation of phase-separated condensates by transcription factors and coactivators with intrinsically disordered regions. The androgen receptor (AR), the main oncogenic driver in PCa, contains large disordered regions and is co-recruited with the transcriptional coactivator MED1 to SEs in androgen-dependent prostate cancer cells, thereby promoting oncogenic transcriptional programs. In this work, we show that AR-rich, liquid-like foci form in prostate cancer models upon androgen stimulation. We reveal that foci formation correlates with AR transcriptional activity, which can be modulated by changing cellular foci content genetically or chemically. We also demonstrate that the transcriptional coactivator MED1 plays an essential role in the formation of transcriptionally active AR-rich foci and that AR antagonists that block cofactor recruitment or DNA binding hinder foci formation and thus AR transcriptional activity. The liquid like properties of the condensates were also validated in-vitro by using recombinant AR protein. Using clinical specimens, we detected the interaction between AR and MED1 in advanced forms of prostate cancer and not in benign tissues. These results suggest that enhanced compartmentalization of AR and coactivators at SEs may play an important role in the activation of oncogenic transcription programs in androgen-dependent PCa. A better understanding of the assembly and the regulation of these AR-rich compartments may provide novel therapeutic options for PCa by targeting downstream events of androgen activation and DNA binding of AR.
Citation Format: Fan Zhang, Maitree Biswas, Joseph Lee, Shreyas Lingadahalli, Samantha Wong, Christopher Wells, Neetu Saxena, Bei Sun, Ana K. Parra-Nuñez, Christophe Sanchez, Jane Foo, Novia Chan, Lauren Ung, Nabeel Khan, Umut Berkay Altıntaş, Jennifer M. Bui, Yuzhuo Wang, Ladan Fazli, Paul S. Rennie, Nathan Lack, Artem Cherkasov, Martin E. Gleave, Joerg Gsponer, Nada Lallous. Dynamic phase separation of the androgen receptor and its coactivators to regulate gene expression [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 5729.
Abstract 5746: Analysis of molecular characteristics of gliomas harboring gene fusions
Authors: Wang Jidong , Han Yushuai , Wang Weiran , Ma Tonghui 
Published: June 2022

Abstract
Background: Genotyping plays an important role in tumor diagnosis and prognosis. The 2016 central nervous system (CNS) WHO added molecular parameters to classify CNS tumors on the basis of routine histological features, but the characteristics of gene fusion variations have not been clarified in CNS tumors.
Methods: In order to identify the characteristics of gene fusions in Chinese patients with CNS malignant tumors, we retrospectively analyzed the next-generation sequencing data of 234 patients (pts) with gene fusions.
Results: According to WHO classification of CNS tumor, 121 pts (51.7%) were low-grade gliomas (LGG, grade I, II), and 113 pts (48.3%) were high-grade gliomas (HGG, grade III, IV). The age of pts with LGG (14.1 ± 16.1) was significantly lower than HGG pts (50.2 ± 17.4) (P&lt;0.0001). There was no significant gender difference between them (P = 0.161). In the fusion map of pts with LGG, gene fusions of KIAA1549-BRAF (n=82, 67.7%) and FGFR3-TACC3 (n=7, 5.8%) occurred frequently. Meanwhile, there were 5.7% pts carrying BRAF fusions with other partners, and some other sporadic fusions. Among HGG cases, the most frequent gene fusion was FGFR3-TACC3 (n=36, 31.9%), followed by fusions in EGFR (n=22, 19.5%), MET (n=16, 14.2%), BRAF (n=8, 7.1%), ROS1 (n=5, 4.4%), and other sporadic genes. It can be seen that gene fusion characteristics varied from gliomas with different malignant degrees. KIAA1549-BRAF fusion tended to occur in LGG (67.7% vs. 2.7%, P &lt; 0.0001) than HGG, and FGFR3-TACC3 tended to occur in HGG ( 31.9% vs. 5.8%, P&lt; 0.0001) than LGG. In addition, FGFR3-TACC3 fusion pts were exclusive with IDH1/2 mutations, but tended to be co-mutate with TERT promoter variants (P&lt;0.0001). IDH-mutation-positive glioma usually exhibit a better clinical result, while TERT promoter-mutated glioma predicts a poor outcome. We also found that 75% (12/16) of MET fusion-positive gliomas pts had TP53 co-coexisting and 56.3% (9/16) of MET fusion-positive gliomas pts co-occurred with MET amplification, while only 0.9% (1/105) of pts harboring other fusions were MET amplification positive. Meanwhile, 95.0% (21/22) of EGFR fusion-positive pts co-occurred with EGFR amplification.
Conclusion: By comprehensively analyzing the gene fusion map of Chinese patients with gliomas, we found the gene fusion characteristics of LGG differed from that of HGG. These fusion features may be important molecular information for judging the grade of malignancy and prognosis of patients.
Citation Format: Jidong Wang, Yushuai Han, Weiran Wang, Tonghui Ma. Analysis of molecular characteristics of gliomas harboring gene fusions [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 5746.
Abstract 5757: Germline and somatic mutational landscape of Chinese early-onset colorectal cancers
Authors: Zeng Xiancheng , Liu Junhao , Luo Yurong , Li Hailiang , Liu Xinyi , Huang Mengli 
Published: June 2022

Abstract
Background: The incidence of colorectal cancer (CRC) in young people, described as early-onset colorectal cancer (EOCRC) has been rising up in decades. Apart from definite familial genetic disease, a considerable proportion of EOCRC remained unknown of the mechanism. Characterizing the difference in genomic features of EOCRC and late-onset CRC (LOCRC) would help us to understand it.
Methods: A total of 1777 Chinese CRC patients diagnosed in 2019-2020 were included. 489 patients under 50 years were defined as EOCRC. A 733-gene panel next-generation sequencing (NGS) testing and measurement of tumor mutational burden (TMB) levels based on the panel were conducted in all patients’ tumor specimen. Lynch syndrome (LS) was defined as patients harboring at least one non-benign germline mutation in four LS MMR genes (MLH1, MSH2, MSH6, PMS2).
Results: 43 of 489(8.8%) cases and 54 of 1288 (4.2%) cases were MSI-H in EOCRC and LOCRC, separately. Excluded 97 LS patients (84.3% in MSI-H EOCRC and 72.0% in MSI-H LOCRC), the proportion of non-LS MSI-H in EOCRC and in LOCRC were 1.8% and 1.7%, separately. Compared to non-LS MSI-H LOCRC, EOCRC has higher germline mutational frequencies in APC, CD74, ATM, BCL2L11, CHEK2, and RECQL4 genes and somatic mutational frequencies in APC, ERCC4, CHD2, ARHGAP5, CASP8, and ATM genes. In non-LS MSS patients, germline mutations in CHEK2, NBN and POLE genes, somatic SNV/indels in RNF43, ATR, AFF3, JAK2, POLG, CHD2 genes and somatic copy number gain in genes on chromosome 8 (ZNF703, FGFR1, MYC, PTK2) occurred more frequently in EOCRC. KEGG enrichment analysis in somatic mutations indicated significant overexpressed MAPK signaling pathway. The TMB level was significantly lower in non-LS MSS EOCRC than in LOCRC.
Conclusions: The proportion of non-LS MSI-H in Chinese EOCRC and LOCRC were approximate. Non-LS MSS EOCRC had marked chromosome 8 somatic copy number gain and MAPK signaling pathway, indicating the potential mechanism. The comparative lower TMB level in EOCRC was concordance with previous studies and the correlations between low TMB level and high CNV burden also corroborate the etiopathogenesis.
Citation Format: Xiancheng Zeng, Junhao Liu, Yurong Luo, Hailiang Li, Xinyi Liu, Mengli Huang. Germline and somatic mutational landscape of Chinese early-onset colorectal cancers [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 5757.
Abstract 5776: Predictors of radioactive iodine refractoriness in papillary thyroid carcinomas
Authors: Masoodi Tariq , Siraj Sarah , Siraj Abdul K. , Azam Saud , Qadri Zeeshan , Parvathareddy Sandeep K. , Al-Kuraya Khawla S. 
Published: June 2022

Abstract
Optimized surgery and radioactive iodine (131I, RAI) are the cornerstone of treatment for papillary thyroid carcinoma (PTC). Although standard treatment is curative for most, 5-20% of PTC patients develop RAI refractory disease – the main cause of thyroid cancer-related deaths. Early predictors indicating therapeutic response to RAI therapy in PTC are yet to be elucidated. We performed whole-exome sequencing (at a median depth of 198x) on 158 patient-matched primary PTCs and germline DNA. Clinical data was used to categorize RAI avidity in the PTC cohort. Whereby, 66 RAI refractory and 92 RAI avid tumors were identified. Clinical data and somatic variants were analyzed to compare the clinicopathological presentation, genomic landscape and mutational signatures between RAI refractory and avid PTCs. RAI refractory tumors were significantly associated with distinct aggressive clinicopathological features, including positive surgical margins (65.5% versus 26.7%; p=0.016) and the presence of lymph node metastases at primary diagnosis (62.5% versus 30.1%; p=0.012); higher nonsilent tumor mutation burden (p=0.011); and the enrichment of APOBEC-related single base substitution (SBS) COSMIC mutational signatures 2 (p=0.03) and 13 (p&lt;0.001). APOBEC mutational signatures were not associated with BRAFV600E mutation. Notably, using multivariate logistic regression analysis only the SBS13 (odds ratio 13.01, 95% confidence intervals 1.20-140.94) APOBEC mutational signature was revealed to be an independent predictor of RAI refractoriness in PTC (p=0.035). Furthermore, using Cox proportional hazards SBS13-positive tumors (hazard ratio 3.52, 95% confidence intervals 1.79-6.91) were also significantly associated with poorer progression-free survival (p&lt;0.001), albeit only in univariate analysis. This study highlights distinct clinical and genomic features in RAI refractory PTC, but above all proposes the APOBEC SBS13 mutational signature as an independent predictor of RAI refractoriness in a more aggressive subgroup of PTC. Where detection of RAI refractory disease following standard surgical PTC removal, and more suitable therapeutic interventions may potentially improve patient outcomes.
Citation Format: Tariq Masoodi, Sarah Siraj, Abdul K. Siraj, Saud Azam, Zeeshan Qadri, Sandeep K. Parvathareddy, Khawla S. Al-Kuraya. Predictors of radioactive iodine refractoriness in papillary thyroid carcinomas [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 5776.
Abstract 5782: Sample management for enabling successful single-cell RNAseq processing
Authors: Halvorsen Priya J. , Britton Caitlin W. , Shaban Hiba , Torres Fernando , Wilson Douglas , Modarelli Joseph 
Published: June 2022

Abstract
Background: Single cell analysis allows the profiling of biomolecules on a cell-by-cell basis, revealing insights into how cellular heterogeneity impacts biological mechanisms. Drug discovery and development have greatly benefited from the comparative, longitudinal, and causal information single cell analysis provides, transforming our ability to understand disease. Many preclinical and clinical studies leveraging single cell resolution have already played a crucial role in target identification and biomarker discovery. From collection through analysis, proper sample management is a crucial and challenging aspect of large-scale clinical research studies and directly influences specimen quality and the ability to interrogate specific cell populations of interest.
Methods: We sought to determine the effect of collection and storage conditions for PBMCs enriched from whole blood prior to downstream processing using our scRNAseq workflow. PBMCs were freshly isolated from whole blood collected in EDTA tubes or following storage at various timepoints and temperatures until PBMC isolation. Samples were then cryopreserved after the conclusion of each isolation stage and later processed to assess impact of cryopreservation. All PBMC samples were processed using the Chromium Single Cell Immune Profiling kit to compare gene expression and immune repertoire profiling across all storage conditions.
Results: We found that gene expression data were highly correlated across all storage conditions tested. We also found that the clustering and annotation of PBMC libraries were comparable across all conditions tested, but certain subsets were more sensitive to these conditions, indicated by an elevation in cell stress and apoptosis markers.
Conclusions: When planning future studies, it is imperative to consider collection and storage conditions in the workflow of processing for enabling high quality samples for single cell analysis, especially with regard to sensitive and rare cell types of interest.
Citation Format: Priya J. Halvorsen, Caitlin W. Britton, Hiba Shaban, Fernando Torres, Douglas Wilson, Joseph Modarelli. Sample management for enabling successful single-cell RNAseq processing [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 5782.
Abstract 5821: Enhanced tumorigenesis in a novel miR-216a knockout/KPC mouse model of pancreatic cancer
Authors: Brock Andrew A. , Powell Katherine , Schmittgen Thomas D. , Sempere Lorenzo F. 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) originates from both ductal and acinar cells of the pancreas. The highly abundant and acinar cell-enriched miR-216a is reduced during in vitro acinar ductal metaplasia (ADM), throughout PanIN progression, during the development of pancreatitis in mice and humans, and during development of mouse and human PDAC. To investigate the contribution of miR-216a in the development of PDAC, we generated a miR-216a germline knockout mouse (216aKO) via CRISPR genetic editing of a minimal and precise deletion of the miR-216a precursor sequence without affecting the host gene. We crossed this 216aKO mouse to the LSL-KrasG12D; LSL-Trp53Flox/+; Pdx1Cre/+ (KPC) mice to produce a transgenic mouse with an activating Kras mutation, p53 deletion, and knockout of miR-216a (referred to here as miR216aKPC). miR216aKPC displayed an increase in tumor progression compared to KPC and had reduced survival - median 15 weeks miR216aKPC vs. 25 weeks for KPC. miR216aKPC produced lung metastasis by 12 weeks of age which were not present in the lungs of similarly aged KPC mice. Transfection of miR-216a mimetic oligo into cell lines derived from KPC or 216aKPC mice did not reduce viability or alter cellular morphology, suggesting that a potential tumor suppressive role of miR-216a functions during the early stages of PDAC development. A three dimensional ADM assay using acinar cells derived from both mouse and human pancreata will be applied to investigate the contributions of miR-216a on the development of ADM and cell polarity. To discover miR-216a target genes that are responsible for the increased tumorigenesis, cell lines derived from miR216aKPC will be transfected with miR-216a mimetic or scrambled control oligo followed by RNA sequencing. Our results thus far suggest a tumor suppressive role for miR-216a in the early development of PDAC and future studies will investigate molecular and cellular mechanisms driving acinar cell-induced PDAC.
Citation Format: Andrew A. Brock, Katherine Powell, Thomas D. Schmittgen, Lorenzo F. Sempere. Enhanced tumorigenesis in a novel miR-216a knockout/KPC mouse model of pancreatic 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 5821.