bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3656: Detecting MSI in plasma: Implications for early detection of lynch associated tumors
Authors: Srinivasan Preethi , Tran Christina , Reichel Jonathan , Patel Juber Ahamad , Hasan Maysun , Meng Fanli , Jing Xiaohong , Middha Sumit , Zehir Ahmet , Yaeger Rona D. , Reidy Diane , Tsui Dana , Stadler Zsofia , Berger Michael F. 
Published: August 2018

Abstract
Lynch Syndrome (LS) is characterized by germline mutations in mismatch repair pathway genes. The increased cancer susceptibility risk in these patients and the association of these tumors with microsatellite instability (MSI) provides a transformative opportunity for early detection of cancer in these patients. The presence of microsatellite unstable DNA fragments or zygosity changes of the MMR mutations in the plasma of LS patients is predictive of the presence of cancer. Here we describe an approach to detect MSI from plasma cell-free DNA (cfDNA) of LS associated cancer patients. First, to determine the background rate of MSI in cfDNA of microsatellite stable patients, we screened plasma samples collected from a large number of advanced cancer patients using MSK-IMPACT, a custom sequencing assay targeting 468 cancer genes encompassing ~1.5 megabases. MSK-IMPACT is approved by the NYS Department of Health and authorized by the FDA for clinical testing, including MSI assessment based on more than 1,000 microsatellite regions covered by the assay, and has been used to profile more than 20,000 patients at our institution. We were also able to confirm the ability to detect MSI in cfDNA in a small cohort of plasma samples collected from patients with MSI High tumors, and determine thresholds to delineate MSI from MSS cases from plasma. Using MSK-IMPACT, we detected MSI in the plasma of four patients with advanced MSI-H cancer, including one with confirmed LS. Three of these were patients with confirmed MSI signature from tumor tissue (one prostate cancer and two colorectal cancers. The fourth patient with prostate cancer had no tissue available for sequencing, though MSI was independently confirmed. To improve the sensitivity to detect MSI in patients with earlier stage disease where the fraction of tumor-derived cfDNA is lower, we have developed a novel targeted panel with optimized sequencing process and informatics, incorporating a set of highly informative microsatellite regions as well as SNPs to assess tumor-specific zygosity changes in mismatch repairs pathway genes. Through this work, we demonstrate the ability of our assay to detect MSI in plasma cfDNA with high sensitivity.
Citation Format: Preethi Srinivasan, Christina Tran, Jonathan Reichel, Juber Ahamad Patel, Maysun Hasan, Fanli Meng, Xiaohong Jing, Sumit Middha, Ahmet Zehir, Rona D. Yaeger, Diane Reidy, Dana Tsui, Zsofia Stadler, Michael F. Berger. Detecting MSI in plasma: Implications for early detection of lynch associated tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3656.
Abstract 366: Association of MLL2/KMT2D and MLL3/KMT2C with chronic myeloid leukemia
Authors: Ramos Doralina do Amaral Rabello , Ferreira Vivian D'Afonseca da Silva , Berzoti-Coelho Maria Gabriela , Burin Sandra Mara , Magro Cíntia Leticia , Cacemiro Maira da Costa , Simões Belinda Pinto , Saldanha-Araujo Felipe , Castro Fabíola Attié , Pittella-Silva Fábio 
Published: August 2018

Abstract
Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm linked to the Philadelphia chromosome presence that generates the BCR-ABL1 fusion oncogene. Tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM) dramatically improved the treatment efficiency and survival of CML patients by targeting BCR-ABL tyrosine kinase. Although patients in the chronic phase respond well to treatment, patients in the accelerated phase or blast crisis usually show therapy resistance and CML relapse. It is crucial, therefore, to identify biomarkers to predict CML genetic evolution and resistance to TKI therapy, considering not only the effects of genetic aberrations but also the role of epigenetic alterations during the disease. Although dysregulations in epigenetic modulators such as histone methyltrasnferases have already been described for some hematologic malignancies, to date very limited data is available for CML, especially when considering the MLL2/KMT2D and MLL3/KMT2C genes of histone methyltrasnferases. Here we investigated the expression profile of both genes in CML patients in different stages of the disease, in patients showing different responses to therapy with IM and in non-neoplastic control samples. Imatinib sensitive and resistant CML cell lines were also used to investigate whether treatment with other tyrosine kinase inhibitors interfered in their expression. Both genes were either upregulated or with basal expression level during the chronic phase compared to controls. Interestingly, MLL3/KMT2C and specially MLL2/KMT2D levels decreased during disease progression correlating with distinct clinical stages. Furthermore, MLL2/KMT2D was decreased in patients resistant to IM treatment. Our results established a new association between MLL2/KMT2D and MLL3/KMT2C genes with CML and suggest that MLL2/KMT2D is associated with disease evolution and may be a potential marker to predict the development of therapy resistance.
Citation Format: Doralina do Amaral Rabello Ramos, Vivian D'Afonseca da Silva Ferreira, Maria Gabriela Berzoti-Coelho, Sandra Mara Burin, Cíntia Leticia Magro, Maira da Costa Cacemiro, Belinda Pinto Simões, Felipe Saldanha-Araujo, Fabíola Attié Castro, Fábio Pittella-Silva. Association of MLL2/KMT2D and MLL3/KMT2C with chronic myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 366.
Abstract 3663: Non-invasive detection of fusion, splicing and mutation events from circulating cell-free RNA in cancers
Authors: Zhao Zhixin 
Published: August 2018

Abstract
Circulating cell-free DNA (cfDNA) and cell-free RNA (cfRNA) in cancer patients are valuable resource of biomarkers for early detection, diagnosis, treatment and monitoring of disease progression. Compared to cfDNA, cfRNA is more labile to degrade and fluctuate, and thus more challenging to be detected in blood. In the present study, we reported PrediSeq, a validated NGS-based liquid biopsy assay to detect fusions, splicing and mutation events using cfRNA. By using Predicine proprietary ultra-sensitive DeepSeaTM (Deterministic, Efficient, Precise, Sensitive Algorithm) variant detection algorithm, pre-analytical study demonstrated RNA-based detection of fusion, RNA splicing, and mutations using reference materials. In a LOD study, PrediSeq NGS assay is more sensitive than the digital PCR based assay in terms of mutation detection. In clinical validation study, tissue and plasma samples from various types of cancer patients (lung, breast, prostate etc) were used, where concordant fusion events with tissue were observed and RNA mutations confirmed variants detected at DNA level. In conclusion, a highly sensitive and accurate RNA-based liquid biopsy test has been developed to complement the use of cfDNA for detection of fusion, splicing and mutations.
Citation Format: Zhixin Zhao. Non-invasive detection of fusion, splicing and mutation events from circulating cell-free RNA in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3663.
Abstract 3667: Technical advances in plasma genomic biomarkers for mutation detection and monitoring in cancer patients
Authors: Fitzgerald Sandra , Lasham Annette , Blenkiron Cherie , Shields Paula , Lawrence Ben , Print Cristin 
Published: August 2018

Abstract
A sea-change is imminent for cancer medicine, due to the use of non-invasive genomic biomarkers in blood to inform screening, diagnosis and the selection of treatment. This technology may be used routinely in oncology within five years. Although numerous studies, including work in our laboratory, have shown that genomic analysis of blood can detect the presence and even the type of cancer, researchers have only scratched the surface of what this technology can do. In our laboratory, we are generating new methods to improve the sensitivity and accuracy of such tests. Cell-free DNA from a metastatic colorectal cancer patient has been used to directly compare the sensitivity of mutation detection across three platforms - a custom QiaSeq Targeted amplicon sequencing panel, droplet digital PCR (ddPCR) and UltraSEEK lung panel. UltraSEEK and ddPCR platforms show better sensitivity for detection of the KRAS G12A mutation, compared to the QiaSeq Targeted DNA sequencing panel. This pilot study shows that when looking to specifically detect a small number of known mutations, UltraSEEK or ddPCR gives the highest sensitivity, but when mutations are not limited to a few or are completely unknown, the QiaSeq Targeted DNA panel allows identification of the entire repertoire of mutations in specific cancer-associated genes.
Citation Format: Sandra Fitzgerald, Annette Lasham, Cherie Blenkiron, Paula Shields, Ben Lawrence, Cristin Print. Technical advances in plasma genomic biomarkers for mutation detection and monitoring in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3667.
Abstract 3669: Assessing the genetic heterogeneity of localized, multifocal prostate cancer via cell-free DNA
Authors: Chen Emmalyn , Cario Clinton L. , Leong Lancelote , Lopez Karen , Simko Jeffry P. , Carroll Peter R. , Tai Caroline , Witte John S. 
Published: August 2018

Abstract
At the time of diagnosis, it is common to find multiple spatially distinct foci within a single prostate gland in men with prostate cancer. Recent studies evaluating the genetic heterogeneity of localized, multifocal prostate cancers through whole-genome sequencing and whole-exome sequencing have only recently been described. These tumors were highly heterogeneous for single-nucleotide variants, copy number alterations, and genomic rearrangements. One exciting use of cfDNA is its potential ability to simultaneously capture all genetically distinct tumor subclones. Currently, the degree to which a cfDNA sample is representative of the entire genetic landscape of localized prostate cancer is unknown. The objective of this study is to determine if somatic mutations identified in tumor tissue are detectable in cfDNA. Tumor tissue and blood samples have been collected from twenty-nine patients undergoing radical prostatectomy. Samples from fourteen patients have already been subjected to whole-exome sequencing with a target sequencing depth of 200X (HiSeq 4000). Preliminary analyses indicate that tumor foci within a single prostate gland in an individual are genetically heterogeneous. Further analysis of mutational concordance between tumor tissue DNA and cfDNA along with clinical data will be performed.
Citation Format: Emmalyn Chen, Clinton L. Cario, Lancelote Leong, Karen Lopez, Jeffry P. Simko, Peter R. Carroll, Caroline Tai, John S. Witte. Assessing the genetic heterogeneity of localized, multifocal prostate cancer via cell-free DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3669.
Abstract 3670: Urine- and blood-based DNA+RNA liquid biopsy tests in prostate, bladder and kidney cancers
Authors: Wang Amy , Zhao Zhixin , Xie Cheng , Cheung Tak , Montesinos Carlos , Zhang Phoebe , Du Pan , Yu Jianjun , Jia Shidong 
Published: August 2018

Abstract
The estimated incidence of genitourinary (GU) cancers (prostate, bladder, and kidney) will be over 2 million worldwide and responsible for ∼800 000 deaths by 2020. Current diagnosis and monitoring methods of GU cancer patients are often invasive and/or lack sensitivity and specificity. The recent tremendous success in cell-free DNA (cfDNA) blood test has laid the groundwork for using body fluids such as blood and urine as minimally invasive “liquid biopsies” to identify RNA- and DNA-based molecular biomarkers in urologic malignancies.
Here we report the development and clinical application of PrediSeq panel, a urine- and blood-based next generation sequencing-based diagnostics assay that offers integrated genomic cfDNA and cell-free RNA (cfRNA) profiling of genitourinary cancers to detect RNA-based splicing variants (e.g. AR-V7) and rearrangement (e.g. TMPRSS2-ERG), DNA/RNA-based point mutation (e.g. p53, PIK3CA, FGFRs), DNA-based copy number change (e.g. AR) as well as tumor mutation burden (TMB) and microsatellite instability (MSI) using a single tube of blood and/or urine sample in prostate, bladder, and kidney cancers, respectively. In addition to NGS-based multiplex test, we also developed a Bio-Rad digital PCR assay measuring drug response and resistance biomarkers including AR-V7 and PD-L1.
Collectively, PrediSeq NGS and ddPCR assays offer comprehensive genomic profiling of both cfDNA and cfRNA using blood and/or urine samples in patients with genitourinary cancers. The successful development and clinical validation of these tests has potential to enable early diagnosis, cancer screening, and precision medicine in genitourinary cancers.
Citation Format: Amy Wang, Zhixin Zhao, Cheng Xie, Tak Cheung, Carlos Montesinos, Phoebe Zhang, Pan Du, Jianjun Yu, Shidong Jia. Urine- and blood-based DNA+RNA liquid biopsy tests in prostate, bladder and kidney cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3670.
Abstract 3673: Targeting the epigenome of small cell hypercalcemic carcinoma of the ovary, hypercalcemic type (SCCOHT)
Authors: Wang Yemin , Chen Shary Yu-ting , Colborne Shane , Orlando Krystal , Lang Jessica , Karnezis Anthony , Hendricks William , Morin Gregg , Weissman Bernard , Trent Jeffrey , Huntsman David 
Published: August 2018

Abstract
Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare and poorly differentiated cancer that impacts young women with an average 2-year survival of less than 35%. We and others have discovered the inactivating mutations of SMARCA4 as the only consistent genetic alternation in SCCOHT genomes. SMARCA4 is the ATPase of the SWI/SNF chromatin-remodeling complex, which modulates chromatin accessibility to regulate transcription and plays critical roles in many biologic processes such as cell cycle control, apoptosis, and differentiation. SCCOHT also lacks the expression of SMARCA2, the alternative ATPase in the complex, contrasting the requirement of SMARCA2 for survival of most SMARCA4-deficient cancer cells. This suggest that the complete loss of chromatin-remodeling activity may rewire the epigenome and create opportunities for synthetic lethal targeting. A rational epigenetic drug screen identified EZH2 inhibitors and HDAC inhibitors as promising therapeutic agents in SCCOHT cells. We confirm that catalytic inhibition of EZH2 selectively suppressed the growth of SCCOHT cells in vitro and in xenograft models through activation of apoptosis and differentiation. Pan-HDAC inhibitors also displayed a more robust anticancer effect in SCCOHT cells than other in other ovarian cancer cell lines. Furthermore, combined treatment of EZH2 inhibitors and pan-HDAC inhibitors increased the global acetylation level at histone H3K27 site and synergistically suppressed the growth of SCCOHT cell lines and xenografts through robust induction of apoptosis. Although EZH2 or HDAC inhibitor treatment led to re-expression of SMARCA2, depletion of SMARCA2 had only minimal effect on drug response. Proteomic analysis identified key signaling pathways underlying the efficacy of epigenetic therapy that are under investigation. Therefore, inactivation of SWI/SNF chromatin remodeling complex may drive SCCOHT development through PRC2-dependent rewiring of the epigenome. Targeting these oncogenic events can be the feasible strategies for treatment of SCCOHT that warrant clinical investigation.
Citation Format: Yemin Wang, Shary Yu-ting Chen, Shane Colborne, Krystal Orlando, Jessica Lang, Anthony Karnezis, William Hendricks, Gregg Morin, Bernard Weissman, Jeffrey Trent, David Huntsman. Targeting the epigenome of small cell hypercalcemic carcinoma of the ovary, hypercalcemic type (SCCOHT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3673.
Abstract 3675: Loss of alveolar type II epithelial and endothelial cell lineages in invasive mucinous adenocarcinoma of the lung (IMA)
Authors: Tomoshige Koichi , Guo Minzhe , Tsuchiya Tomoshi , Fink-Baldauf Iris , Nagayasu Takeshi , McKillip Kelsey Dillehay , Maeda Yutaka 
Published: August 2018

Abstract
Background: Invasive mucinous adenocarcinoma of the lung (IMA) is pathologically characterized as lung tumor cells with goblet cell morphology containing abundant intracytoplasmic mucin. IMA has been reported to account for 2-10% of lung adenocarcinomas. Genetically, the majority of IMA harbor KRAS mutations. Recently, by analyzing RNA-seq data using human IMA cases, we reported mucus-related genes specifically expressed in IMA, which includes MUC5AC, MUC5B, MUC3, SPDEF, FOXA3 and HNF4 (Guo, Tomoshige et al., 2017). Notably, immunohistochemical analyses have determined that NKX2-1 (also known as TTF-1) is reduced in IMA (Travis et al., 2011); however, other than NKX2-1, genes reduced in IMA compared to normal lungs have not been determined.
Methods: In order to further understand the demographic occurrence of IMA, we surveyed the clinical records at the University of Cincinnati College of Medicine in the U.S. and Nagasaki University of School of Medicine in Japan. Genes reduced in IMA compared to normal lungs were identified using the RNA-seq datasets as we have previously reported (Guo, Tomoshige et al., 2017). Using single-cell and sorted RNA-seq datasets (LGEA; Du et al., 2017), genes were further categorized into groups that define different cell types that exist in normal lungs.
Results: IMA occurred in 4.6% (3/65 cases in 2017) and 1.9% (2/105 cases in 2017) of lung adenocarcinomas at the University of Cincinnati College of Medicine and Nagasaki University of School of Medicine, respectively. Importantly, analysis using normal lung cell type specification markers obtained from the single-cell and sorted RNA-seq datasets identified that genes that define alveolar type II epithelial cells (e.g., SFTPC and ABCA3) and endothelial cells (e.g., FOXF1 and SOX17) were significantly reduced in IMA compared to normal lungs.
Conclusion: IMA comprises mucus-producing goblet cell lineage populations devoid of alveolar type II epithelial and endothelial cell-lineage populations, suggesting a unique tumor microenvironment distinct from other lung adenocarcinomas.
Citation Format: Koichi Tomoshige, Minzhe Guo, Tomoshi Tsuchiya, Iris Fink-Baldauf, Takeshi Nagayasu, Kelsey Dillehay McKillip, Yutaka Maeda. Loss of alveolar type II epithelial and endothelial cell lineages in invasive mucinous adenocarcinoma of the lung (IMA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3675.
Abstract 3676: CMS classification of colorectal adenomas
Authors: Komor Malgorzata A. , Bosch Linda J. , Bounova Gergana , Bolijn Anne S. , Diemen Pien Delis-van , Rausch Christian , Hoogstrate Youri , Stubbs Andrew , Jong Mark de , Jenster Guido , Grieken Nicole C. an , Carvalho Beatriz , Wessels Lodewyk , Jimenez Connie R. , Fijneman Remond J. , Meijer Gerrit A. , Consortium NGS-ProToCol 
Published: August 2018

Abstract
Background Consensus molecular subtyping (CMS) is an RNA-expression-based classification of colorectal cancers (CRC). Genomic alterations, resulting in specific RNA-expression patterns, accumulate during CRC pathogenesis, including the premalignant adenoma stage.
Aim This study aimed to investigate whether differentiation of colorectal neoplasia into CMS classes can already be recognized at the adenoma stage, and whether specific CMS classes could be associated with DNA copy number aberrations that mark adenomas at high-risk of progressing to CRC.
Materials and Methods RNA-sequencing was performed on 62 advanced adenomas and 59 CRCs. DNA copy number analysis in adenomas was performed by low-coverage DNA-sequencing (n=30) or array-Comparative Genomic Hybridization (n=32). Microsatellite instability (MSI) status was determined by PCR methods. Adenomas and CRCs were classified into CMS subtypes together with CRCs (n=556) from The Cancer Genome Atlas, using the Random Forest CMS classifier.
Results The majority of the adenomas were classified as CMS3 (n=45; 72%), the 'metabolic subtype', recognized as least common among CRCs. No adenomas were classified as the 'mesenchymal' CMS4 subtype. One adenoma was classified as the 'MSI immune' CMS1 (2%), and 8 adenomas as the 'canonical' CMS2 (13%) type. The remaining 8 (13%) could not be classified. The CMS3 class was enriched with adenomas at low-risk of progression.
Conclusion Most adenomas were successfully classified. The lack of CMS4 adenomas is consistent with the fact that adenomas lack invasion-associated stroma. Adenomas showing cancer-associated chromosomal instability (CIN) or MSI (24%) were mostly classified as CMS2 and CMS1, respectively. The CMS3 subtype appeared to be the predominant adenoma signature.
Citation Format: Malgorzata A. Komor, Linda J. Bosch, Gergana Bounova, Anne S. Bolijn, Pien Delis-van Diemen, Christian Rausch, Youri Hoogstrate, Andrew Stubbs, Mark de Jong, Guido Jenster, Nicole C. an Grieken, Beatriz Carvalho, Lodewyk Wessels, Connie R. Jimenez, Remond J. Fijneman, Gerrit A. Meijer, NGS-ProToCol Consortium. CMS classification of colorectal adenomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3676.