bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3389: Analysis of the hepatocellular carcinoma transcriptome reveals dysregulation in pathways implicated in immunotherapy efficacy
Authors: Li Wei Tse , Honda Christine O. , Qu Yuanhao , Honda Thomas K. , Saad Omar A. , Wang-Rodriguez Jessica , Ongkeko Weg M. 
Published: August 2019

Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality in the world, but current treatment options are very limited in efficacy for patients who are diagnosed late, which often occurs because of limitations in current screening methods. Immunotherapy has emerged in recent years as arguably the most effective treatment for advanced HCC, but the failure of a large percentage of patients to respond to immunotherapy remains the ultimate obstacle to successful treatment. A phase I clinical trial with CTLA-4 checkpoint blockade has only achieved a 17.6% partial response rate in patients with advanced HCC, while another clinical trial using the PD-1 checkpoint inhibitor nivolumab has reported 18% partial response. Etiology-associated dysregulation of immune-associated (IA) genes may be able to explain the development of this differential clinical response. Using large-scale RNA-sequencing data from The Cancer Genome Atlas (TCGA), we identified immune-associated genes potentially dysregulated by alcohol or viral hepatitis B in HCC. Thirty-four dysregulated IA genes exhibiting significant correlation of gene expression to survival data and clinical variables were identified. To investigate the molecular mechanism for their dysregulation and explore the possibility of genome-based patient stratification, we profiled the correlation of all genomic alterations in HCC patients to IA gene expression using the information theory-based algorithm REVEALER. We also studied gene expression regulators and identified multiple microRNAs implicated in HCC pathogenesis that can potentially regulate these IA genes’ expression. Finally, we validated the dysregulation of several genes by alcohol, including the downregulation of NDRG2 and SOCS2, in vitro using HCC cell lines. Our study identified several potentially key pathways, including the IL-7 pathway, TNFRSF4 (OX40)- NF-κB pathway, and IL-10 pathway, that may be targeted in HCC immunotherapy treatments as well as possible sources of dysregulation for pathways known to be implicated in HCC immunotherapy efficacy. Lastly, we present microRNAs as promising therapeutic targets for dysregulated IA genes because of their extensive regulatory roles in the cancer immune landscape.
Citation Format: Wei Tse Li, Christine O. Honda, Yuanhao Qu, Thomas K. Honda, Omar A. Saad, Jessica Wang-Rodriguez, Weg M. Ongkeko. Analysis of the hepatocellular carcinoma transcriptome reveals dysregulation in pathways implicated in immunotherapy efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3389.
Abstract 3391: Dissecting intratumoral cell-cell interactions in myeloid reprogramming by single cell RNA-seq
Authors: Song Qianqian , Hawkins Gregory A. , Wudel Leonard , Chou Ping-Chieh , Forbes Elizabeth , Pullikuth Ashok K. , Liu Liang , Jin Guangxu , Craddock Lou , Topaloglu Umit , Kucera Gregory , O’Neill Stacey , Levine Edward A. , Sun Peiqing , Watabe Kounosuke , Lu Yong , Alexander-Miller Martha A. , Pasche Boris , Miller Lance D. , Zhang Wei 
Published: August 2019

Abstract
Tumor-infiltrating myeloid cells are the most abundant leukocyte population within tumors. Molecular cues from the tumor microenvironment promote the differentiation of immature myeloid cells toward an immunosuppressive phenotype. However, the in situ dynamics of the transcriptional reprogramming underlying this process are poorly understood. Therefore, we applied single cell RNA-seq (scRNAseq) to computationally investigate the cellular composition and transcriptional dynamics of tumor and adjacent normal tissues from 4 early-stage non-small cell lung cancer (NSCLC) patients. Our scRNA-seq analyses identified 11,485 cells that varied in identity and gene expression traits between normal and tumor tissues. Among these, myeloid cell populations exhibited the most diverse changes between tumor and normal tissues, consistent with tumor-mediated reprogramming. Through trajectory analysis, we identified a differentiation path from CD14+ monocytes to M2 macrophages (monocyte-to-M2). This differentiation path was reproducible across patients, accompanied by increased expression of genes (e.g. MRC1/CD206, MSR1/CD204, PPARG, TREM2) with significantly enriched functions (Oxidative phosphorylation and P53 pathway) and decreased expression of genes (e.g. CXCL2, IL1B) with significantly enriched functions (TNFa signaling via NF-kB and inflammatory response). Our analysis further identified a co-regulatory network implicating upstream transcription factors (JUN, NFKBIA) in monocyte-to-M2 differentiation, and activated ligand-receptor interactions (e.g. SFTPA1-TLR2, ICAM1-ITGAM) suggesting intratumoral mechanisms whereby epithelial cells stimulate monocyte-to-M2 differentiation. Overall, our analysis identified the prevalent monocyte-to-M2 differentiation in NSCLC, accompanied by an intricate transcriptional reprogramming mediated by specific transcriptional activators and intercellular crosstalk involving ligand-receptor interactions.
Citation Format: Qianqian Song, Gregory A. Hawkins, Leonard Wudel, Ping-Chieh Chou, Elizabeth Forbes, Ashok K. Pullikuth, Liang Liu, Guangxu Jin, Lou Craddock, Umit Topaloglu, Gregory Kucera, Stacey O’Neill, Edward A. Levine, Peiqing Sun, Kounosuke Watabe, Yong Lu, Martha A. Alexander-Miller, Boris Pasche, Lance D. Miller, Wei Zhang. Dissecting intratumoral cell-cell interactions in myeloid reprogramming by single cell RNA-seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3391.
Abstract 3398: Interaction of STAT proteins with genistein: A computational analysis
Authors: Govardhanagiri Sneha , Bethi Shipra Reddy , Saddala Madhu Sudhana , El-Rayes Bassel F. , Nagaraju Ganji Purnachandra 
Published: August 2019

Abstract
Background: Signal transducer and activator of transcription (STAT) proteins are a seven-member family of cytoplasmic proteins. A conserved SH2 domain facilitates STAT initiation by allowing binding to phosphotyrosine motifs for STAT-receptor interactions and STAT dimerization. STAT proteins (STAT1, STAT2 and STAT3) are promising targets for anti-cancer drugs, because irregular facilitation of STAT initiation may result in cancer, inflammation and auto-immunity.
Methods: The crystal structure of the phosphotyrosine STAT1 and STAT3 dimers bound to DNA was obtained from a protein data bank (PDB), while STAT2 was modelled through Swiss-Model workspace by using 1YVL as a template. The stereochemical quality and integrity of STAT2 was tested by RAMPAGE server, ERRAT, ProSA, and Verify3D programs. The active sites were predicted using CASTp 3.0 with a new algorithm, which identifies and measures surface accessible pockets and interior inaccessible cavities on STAT1, STAT2, and STAT3. MD (molecular dynamics) simulation was conducted with STAT2 protein. Molecular Docking was used to predict the binding modes and approximate binding free energies of genistein to STAT1, STAT2 and STAT3 SH2 dimerization sites. Genistein was docked into the active site with AutoDock Vina in PyRx Virtual Screening tool.
Results: Genistein showed best binding energies. The most successful binding energies were -5.6 (STAT1), -6.7 (STAT2), -6.3 (STAT3) kcal/mol respectively. The binding interactions of this compound with the active site of STAT proteins suggested that amino acid residues (Tyr631, Leu639, Tyr640, Glu643, His647, Met648, Gln649, Ile659, Met660 and LYS16) play a crucial role in anti-cancer activity.
Conclusion: These observations increase the understanding of the functional role of STAT proteins in cancer and allow better development for additional druggable STAT inhibitors with high potency, specificity and outstanding bioavailability.
Citation Format: Sneha Govardhanagiri, Shipra Reddy Bethi, Madhu Sudhana Saddala, Bassel F. El-Rayes, Ganji Purnachandra Nagaraju. Interaction of STAT proteins with genistein: A computational analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3398.
Abstract 340: Development of high affinity anti-CLDN18.2 antibody to treat gastric cancers
Authors: Zhou Zhenhao 
Published: August 2019

Abstract
Claudins are tight junction proteins that regulate epithelial-cell barrier function and polarity. Gastric lineage-specific isoform 2 of CLDN18 (CLDN18.2) has been proposed as therapy target in primary/metastatic gastric cancers and CLDN18.2-ectopically-activated cancers, such as pancreatic, esophageal and lung adenocarcinomas. As demonstrated by Zolbetuximab, a monoclonal chimeric antibody directing CLDN18.2, the median overall survival was prolonged to 16.7 months when treated with Zolbetuximab+EOX (OS of EOX group: 9.0 months) in pre-screened CLDN18.2 highly expressing patients (2+/3+ staining in ≥70% tumor cells). Expression of CLDN18.2 in gastric tumors in Chinese population, however, showed diverse levels of frequency with low-frequency expression in a significant portion of tumor cells. Antibody of high affinity is expected to have advantage in targeting antigen of low-frequency, thus clearing tiny lesions clinically. We developed a high affinity anti-CLDN18.2 antibody, GB7004-09. GB7004-09 binded to human/mouse CLDN18.2 while sparing CLDN18.1. It displayed significantly better binding/ADCC/CDC potency against CLDN18.2 expressing tumor cells comparing to leading clinical drug entity. And its in vitro superiority translated to greater in vivo efficacy. Humanization version of GB7004-09, GB7004-09hu15, has been put into preliminary toxicity and PK study. As we are observing safety, stability and activity of GB7004-09hu15, GB7004-09hu15 is a promising agent for extended clinical exploration in cancer indications mention above
Citation Format: Zhenhao Zhou. Development of high affinity anti-CLDN18.2 antibody to treat gastric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 340.
Abstract 3413: CRIPAK genomic alterations are associated with indolent lung adenocarcinoma and predicts longer survival
Authors: Qian Jun , Chen Heidi , Zou Yong , Massion Pierre 
Published: August 2019

Abstract
Background: Multiple lung screening studies have shown a beneficial reduction in cancers specific mortality with annual low-dose computed tomography (LDCT) screening in high risk patients and resulted in a much improved probability of early stage disease at diagnosis. Nonetheless, still ~30% of such patients have a recurrence within 5 years following surgical resection. This begs the question what are the molecular determinants of cancer behavior between indolent and aggressive tumors.
Methods: A targeted deep sequencing was performed on the DNA samples of 21 adenocarcinoma in situ (AIS), 27 minimally invasive adenocarcinoma (MIA) and 54 fully invasive adenocarcinoma. These cancers were classified based on the tumor size (1.5 cm) as indolent (n=42) and aggressive (n=60) tumors. We analyzed the association between tumor aggressiveness and genomic alterations of these targeted genes including frequency of gene mutations, copy number changes, mutation signatures, tumor clonality as well as overall survival.
Results: Copy number loss of CRIPAK (chr4p16) and copy number gain of NOTCH1 were enriched in indolent tumors and chromosome 19q13 deletion was enriched in aggressive tumors. CRIPAK alterations including both mutations and copy number loss together were further significantly enriched in a subset of indolent tumors (16/25) that only consists of AIS/MIA. CRIPAK alterations were associated with longer survival in all population, after adjusting for histology and age (P=0.02). Interestingly, we found higher CRIPAK mRNA level was also significantly associated with better survival in a combined seven public lung adcarcinoma datasets (n=673, HR=0.37, P=1.1e-05), after adjusting for stage, gender and smoking history. In addition, both APOBEC and MMR mutation signatures were correlated with indolent tumors. Known driver genes such as KRAS, EGFR or TP53 mutations were not distinct between indolent and aggressive tumors, indicating an early role for these genes in the development of lung adenocarcinoma. Finally, we found that mutations of NCOR1, USP9X and NF1 were enriched in indolent tumors while mutations in GNAS and ATM were enriched in aggressive tumors.
Conclusion: Our study suggests the genomic alterations of the chromosome 4p16 harboring a novel cancer gene CRIPAK’s deletions and mutations are predictive of indolent behavior, a finding that warrants further validation. This work was supported by UO1CA196405.
Citation Format: Jun Qian, Heidi Chen, Yong Zou, Pierre Massion. CRIPAK genomic alterations are associated with indolent lung adenocarcinoma and predicts longer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3413.
Abstract 3419: Sex, mutations, and mortality in early stage melanoma
Authors: Schwartz Matthew R. , Luo Li , Berwick Marianne 
Published: August 2019

Abstract
Our goal is to investigate the relationship between sex, tumor mutation burden (TMB) and survival in untreated primary melanoma tumors, using data collected in an ongoing large P01 study on the Integration of Clinical and Molecular Biomarkers for Melanoma Survival (InterMEL). Here we present preliminary findings on sex, survival, and somatic TMB from 60 Stage II and Stage III primary melanoma tumors, none of which have received immunotherapy using the MSK IMPACT™ next generation sequencing assay. Our preliminary analysis includes 30 patients who died within 5 years (median survival of 31 months) and 30 patients who lived for more than 5 years since diagnosis (median follow-up of 86 months). We found the expected relationship between TMB and better survival in a univariate Cox regression analysis (HR=0.43, 95% CI=0.19 to 0.97, P=0.04), but no evidence of association between TMB and sex (Wilcoxon rank-sum test P=0.7) or any relationship between sex and survival (logrank test P=0.42).
Our study is the first to investigate the relationship between sex, tumor mutational burden, and mortality in an early stage primary cohort that has not received immunotherapy. In our small sample, we observed the expected protective effect of TMB on survival, but no evidence of gender differences in TMB or survival. This is surprising given the robust, consistent, and well-documented female survival advantage (Roh et al., 2015; de Vries et al., 2008), and merits further investigation. Our results are an important first step to increasing our understanding of the relationship between mutational burden, survival, and biological sex.
References
Roh, M.R., Eliades, P., Gupta, S., Grant-Kels, J.M., and Tsao, H. (2015). Cutaneous melanoma in women. Int. J. Womens Dermatol. 1, 21–25.
de Vries, E., Nijsten, T.E.C., Visser, O., Bastiaannet, E., van Hattem, S., Janssen-Heijnen, M.L., and Coebergh, J.-W.W. (2008). Superior survival of females among 10
538 Dutch melanoma patients is independent of Breslow thickness, histologic type and tumor site. Ann. Oncol. 19, 583–589.
Citation Format: Matthew R. Schwartz, Li Luo, Marianne Berwick. Sex, mutations, and mortality in early stage melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3419.
Abstract 3423: HER2 amplification and microsatellite status distribution in Chinese gastric cancer patients
Authors: Guo Jun , Jiang Da , Zhang Wei , Deng Ting , Niu Zhaojian , Chen Wenting , Shi Junping , Zhang Shuirong , Zhang Lin 
Published: August 2019

Abstract
Background:Amplification and/or overexpression of human epidermal growth factor receptor-2 (HER2, also known as ERBB2) were present in 6.1-23.0% of gastric cancer. In breast cancer, amplification and overexpression of the HER2 are associated with poor prognosis. Meanwhile, MSI-H patients have an improved prognosis in gastric cancer. However, little is known about the association of these two indicators in gastric cancer.
Method:260 tumor tissues and matched normal from gastric cancer patients were included in this study to reveal HER2 amplification and microsatellite status distribution of Chinese patients with gastric cancer using deep next generation sequencing (NGS) targeting 450 cancer genes. Microsatellite status (MSS or MSI-H) were evaluated according to NGS algorithms.
Result:Male to female ratio was about 2:1 with a mean age of 60 years old. 241 tumors were primary tumors and 19 were metastases. MSI-H was detected in 16 samples (6.2%) and HER2 amplification was detected in 18 samples (6.9%), which were consistent with the previously reported incidences. The proportion of MSI-H in metastatic lesions was higher than that in primary lesions, but the difference was not statistically significant (10.5% vs. 5.8%, P=0.33). The detection of HER2 amplification in metastatic foci and primary tumors had a similar trend as that in MSI-H (15.8% for metastatic foci vs. 6.2% for primary tumors, P=0.13). Interestingly, our study revealed that HER2 amplification was mutually exclusive with MSI-H in both primary and metastatic lesions. MSI-H/HER2amp-, MSS/HER2amp+, and MSS/HER2amp- subgroups accounted for 5.8%, 6.2%, and 88% in primary cancers, while MSI-H/HER2amp-, MSS/HER2amp+ and MSS/HER2amp- subgroups accounted for 10.5%, 15.8% and 73.7% in metastasis, respectively.
Conclusion:We analyzed the distribution of HER2 amplifications and microsatellite status in Chinese patients with gastric cancer. The detection rate of HER2 amplifications and MSI-H was consistent with previous reports. Interestingly, our data showed that both HER2 amplifications and MSI-H have higher detection rate in metastases than that in primary lesions, and the two biomarkers were mutual exclusive in our cohort.
Citation Format: Jun Guo, Da Jiang, Wei Zhang, Ting Deng, Zhaojian Niu, Wenting Chen, Junping Shi, Shuirong Zhang, Lin Zhang. HER2 amplification and microsatellite status distribution in Chinese gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3423.
Abstract 3424: Consensus molecular subtype of triple negative breast cancer to implicate in chemotherapy response
Authors: Kim Jihyun , Yu Doyeong , Noh Jiyoon , Jang Wooyeong , Yang Hanna , Kwon Youngmee , Lee Keun Seok , Sim Sung Hoon , Kong Sun-Young , Park In Hae , Park Charny 
Published: August 2019

Abstract
Objective: The heterogeneity of triple negative breast cancer (TNBC) confers the difficulties in chemotherapy and induces poor outcome. Subtype classification of TNBC using gene expression profile could achieve to identify molecular markers to suggest therapeutic guidance.
Methods: In this study, we collected gene expression profiles of 957 TNBC patients from GEO and integrated into one meta-data using meta analysis. We identified subtypes using nonnegative matrix factorization (NMF) and explored for comprehensive characteristics of consensus molecular subtype (CMS) by investigating key pathway activity, tumor microenvironment, stemness and so on. In addition, we computed the drug response score (DRscore) from MSigDB chemical perturbation signature gene set and examined drug associations with key pathways of CMS. Drug candidates were validated from independent two data sets; our patients’ expression profile (n = 38) and biobank TNBC organoids (n=64).
Results: We classified four different TNBC subtypes displaying gene expression patterns including mesenchymal-like (MSL), luminal-AR (LAR), immunomodulatory (IM), and stem-like (SL). MSL were activated pathways with epithelial-to-mesenchymal (EMT) and TGF-beta signaling whereas SL was up-regulation of cell cycle and WNT signaling pathway. The LAR subtype was activated of androgen and estrogen receptor pathway. Although metastatic TNBC generally shared equal activity of key pathways with primary, coagulation, toll-like receptors, TNF, and Jak-STAT signaling pathways were dysregulated in metastasis. Especially, SPP1 gene expression to induce metastasis was associated with poor prognosis. DRscores were discriminative in CMS of meta-data and biobank expression profile. We found subtype-specific 18 drugs as therapeutic candidates and these drugs were also correlated with key pathways. In a case of cisplatin, DRscores appear resistant in MSL while response in SL. Our patients’ expression profiles were shown to consistent result as well as biobank.
Conclusion: These finding might facilitate understanding heterogeneity of TNBC. Our novel approach to explore drug response suggested functional intervention landscape of drug
response without in-vivo experiment. Taken together, we propose biomarkers for diagnosis and also suggest therapeutic strategy depending on CMS.
Citation Format: Jihyun Kim, Doyeong Yu, Jiyoon Noh, Wooyeong Jang, Hanna Yang, Youngmee Kwon, Keun Seok Lee, Sung Hoon Sim, Sun-Young Kong, In Hae Park, Charny Park. Consensus molecular subtype of triple negative breast cancer to implicate in chemotherapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3424.