bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5724: Loss of SWI/SNF chromatin remodeling alters NRF2 signaling in human cancers
Authors: Nguyen Vinh , Shranck Travis , Hamad Samera , Weissman Bernard 
Published: June 2022

Abstract
Next-generation sequencing studies of lung cancer has shown a significant number of mutations in two previously unrecognized regulatory pathways. Activating mutations, the NF-E2-related factor 2 (NFE2L2, NRF2) transcription factor induces constitutive expression of cytoprotective and redox maintenance genes. Inactivating mutations in members of the SWI/SNF chromatin-remodeling complex, especially SMARCA4 (BRG1) and ARID1A, lead to changes in nucleosome positioning and gene expression. Here, we show that loss of SWI/SNF complex function activated a subset of NRF2-mediated transcriptional targets. Using a series of isogenic NSCLC lines with reduced or depleted BRG1 and/or BRM expression, we observed significantly increased expression and protein levels of the NRF2-target genes HMOX1 and GSTM4. RNA sequencing of BRG1-proficient and -deficient cell lines confirmed changes in KEAP1-NRF2 target gene expression as well as identified novel targets of the SWI/SNF complex. Importantly, low BRG1 expression levels in primary human NSCLC tumors correlated with increased NRF2-target gene expression. In addition to BRG1 levels, we examined loss of ARID1A across primary human tumors and found ARID1A deficiency was associated with altered NRF2 signaling. The tumors with the highest frequency of altered NRF2 signaling were lung squamous (LUSC) and head and neck squamous (HNSCC), cancers strongly associated with environmental toxicants. Interestingly ARID1A loss depressed NRF2 signaling in LUSC while amplifying it in HNSCC, an observation we are exploring mechanistically in cell line knock out models. Our data demonstrate that loss of SWI/SNF in lung cancer results in activation of the NRF2/KEAP1 pathway and increased expression of a subset of its downstream targets. These data provide an additional molecular explanation for why patients harboring SWI/SNF mutations show a poor prognosis. Our results also potentially link mutations in SWI/SNF complex components, that occur in &gt;20% of human cancers, with exposure to environmental toxicants. A better understanding of these mechanism may yield novel insights into the design of targeted treatment modalities for human lung cancers.
Citation Format: Vinh Nguyen, Travis Shranck, Samera Hamad, Bernard Weissman. Loss of SWI/SNF chromatin remodeling alters NRF2 signaling in human 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 5724.
Abstract 5734: The effect of PRAME on retinoid response and cell proliferation in cutaneous and head and neck squamous cell carcinoma
Authors: Ramchatesingh Brandon Liam , Litvinov Ivan 
Published: June 2022

Abstract
As cells undergo terminal differentiation, they adopt their tissue-specific functions and permanently exit the cell cycle. Inducing differentiation of premalignant cells and malignant cells are proposed strategies for cancer prevention and treatment, respectively. Retinoids, compounds related to retinol, drive terminal differentiation of numerous cell types. These compounds exhibit efficacy for the prevention of cutaneous squamous cell carcinomas (cSCC) and head and neck squamous cell carcinomas (HNSCCs), and their incorporation into treatment plans for these cancers is supported by laboratory and clinical studies. Preferentially Expressed Antigen in Melanoma (PRAME) is a cancer-testis antigen that represses retinoid signaling, and is associated with adverse outcomes in a plethora of malignancies. Although PRAME is known to be expressed in subsets of cutaneous SCC (cSCC) and head and neck SCC (HNSCC) tumors, its functions, prognostic and therapeutic significance have never been investigated in these cancers. We hypothesize that PRAME expression in SCC cells confers resistance to the anti-neoplastic effects of retinoids and supports cell proliferation. PRAME expression was evaluated in human cSCC tumors, and in cSCC and HNSCC cell lines by immunoblotting and qRT-PCR. PRAME-overexpressing immortalized keratinocyte, cSCC and HNSCC cell lines were generated. shRNA-mediated knockdown of PRAME was performed in a cSCC and a HNSCC cell line. Cells were treated with all-trans retinoic acid (ATRA) for 24, 48 or 72 hours. Expression of differentiation markers was assessed by immunoblotting and qRT-PCR of markers of differentiation. Cell counting assays, immunoblot analysis of cell cycle genes and Ki67 immunofluorescence staining were used to assess proliferation. PRAME expression is detected in subsets of cSCC tumors and in select SCC cell lines. Overexpression of PRAME in HNSCC cells enhanced cell proliferation compared to control cells. Treatment with ATRA did not promote differentiation of PRAME-expressing cells. Furthermore, PRAME overexpression attenuated the anti-proliferative effect of ATRA in HNSCC cells. We conclude that PRAME enhances proliferation of malignant keratinocytes in vitro and may confer resistance to retinoid-induced differentiation and proliferation arrest. Investigations to assess the prognostic and therapeutic significance of PRAME expression in SCCs are warranted.
Citation Format: Brandon Liam Ramchatesingh, Ivan Litvinov. The effect of PRAME on retinoid response and cell proliferation in cutaneous and head and neck squamous cell carcinoma [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 5734.
Abstract 5739: Genetic characteristics of the early stage Chinese NSCLC patients
Authors: Mao Naiquan , Yao Weishen , Su Liufu , Huang Xiaochun , Huang mengli 
Published: June 2022

Abstract
Background: Lung Cancer, predominantly non-small-cell lung cancer (NSCLC), is the leading cause of cancer-related death in China. Although precision therapies for patients with advanced or metastatic NSCLC have developed over the past two decades, the 5-year survival rate remains low at 0%-26%. Thus, recurrence monitoring and treatment at an early stage are of great significance for improving survival benefits. Here, we explored the genetic characteristics of early stage NSCLC patients to provide additional values to predict recurrence risk and treatment strategies.
Methods: Tumor or plasma samples were collected from 146 Chinese NSCLC patients in stage I-III (127 LUAD, 5 LUSC, 2 LUASC, 12 unknown pathology). 733 cancer-related genes were sequenced on NGS platform for variants analysis. Tumor mutation burden (TMB) was defined by all somatic mutation counts in coding region per megabase. Immunohistochemistry (IHC) was performed using antibodies (clone 22C3 or SP263) to analyze PD-L1 expression. PD-L1 positivity was defined as TPS ≥1%. Online databases, such as cBioPortal, TIMER2.0 and Kaplan-Meier Plotter, were also used for analysis. Statistical analysis was performed using the R Software (v 4.0.5).
Results: Of 146 NSCLC patients, commonly mutated genes were detected, including EGFR (68%), TP53 (40%), KMT2D (10%), MSH3 (9%), RBM10 (9%), ZFHX3 (9%). Six pathogenic or likely pathogenic fusion variants harbored in common driver genes like EGFR, ALK and ROS1 were identified for the first time. EGFR was more frequently mutated in female patients (P &lt; 0.01), while CDH10 mutations occurred more often in male patients (P &lt; 0.05). Correlation analysis showed RBM10, ZFHX3 and CTNNB1 mutations were respectively co-occurrent with CARD11, ARHGAP5 and APC, reflecting the distinct profile of our cohort when compared to cBioPortal. Patients with TP53mut, MSH3mut or LRP1Bmut had significantly higher TMB (P &lt; 0.05). Compared to PD-L1- group, TP53, TIMELESS, FBXW7 were remarkably mutated in PD-L1+ group. In LUAD, SPTA1mut and TIMELESSmut were noticeably related to CD8+T and B cell infiltration, while FBXW7mut and ZFHX3mut with more M1 macrophages infiltration. Prognostic analysis showed that LUAD patients harboring MSH3mut (P &lt; 0.001) and SPENmut (P = 0.0005) at stage II exhibited significantly shorter RFS. Moreover, we found that cases carried somatic mutations in TP53 signaling pathway had more lymph node metastasis.
Conclusion: These findings expanded our understanding of the early stage Chinese NSCLC, hopefully providing valuable guidance for recurrence risk prediction and treatment strategies.
Citation Format: Naiquan Mao, Weishen Yao, Liufu Su, Xiaochun Huang, mengli Huang. Genetic characteristics of the early stage Chinese NSCLC 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 5739.
Abstract 5741: Characterizing isoform switching events in esophageal adenocarcinoma
Authors: Zhang Yun , Weh Katherine M. , Howard Connor L. , Riethoven Jean-Jack , Clarke Jennifer L. , Lagisetty Kiran H. , Lin Jules , Reddy Rishindra M. , Chang Andrew C. , Beer David G. , Kresty Laura A. 
Published: June 2022

Abstract
Esophageal adenocarcinoma (EAC), the major subtype of esophageal cancer in the US, is characterized by increasing incidence rates and high mortality due to ineffective screening, late-stage diagnosis, and poor treatment efficacy. The only known precursor to EAC is Barrett’s Esophagus (BE), but the precise mechanisms and molecular events leading to disease progression are still being unraveled. In recent years, analysis of TCGA data revealed that isoform switching events with predicted functional consequences are common in many cancers, but the characterization of switching events in esophageal adenocarcinoma (EAC) is lacking. Next-generation sequencing was utilized to detect levels of RNA transcripts and specific isoforms in 66 treatment naïve esophageal tissues from 41 patients. Tissues ranged from premalignant Barrett’s esophagus (BE), BE with low or high-grade dysplasia (LGD or HGD) to EAC. Samples were stratified by histopathology, p53 mutation status, and significant isoform switching events with predicted functional consequences, followed by enrichment analysis. Barrett’s with high-grade dysplasia increased risk for EAC progression. Comparing BE with LGD and BE with HGD, isoform switching events were identified in 75 genes including KRAS, APC, RNF-128 and WRAP53. Stratification based on p53 status increased the number of significant isoform switches to 135 suggesting switching events impact cellular functions based on tissue histopathology, as well as p53 status. Analysis of isoforms agnostic to mutant p53, exclusive to mutant p53, and shared between the two groups revealed unique signatures including demethylation, lipid and retinoic acid metabolism, and glucuronidation, respectively. About 25% of isoform switching events were identified without significant alteration of gene-level expression. Importantly, two p53-interacting isoforms, RNF128 and WRAP53, were significantly linked to patient survival. Analysis of global isoform switching consequences and alternative splicing events also revealed significant changes in the fraction of coding transcripts, complete open-reading-frames, signal peptides, alternative 5’ donor sites, and alternative transcription start sites. Thus, analysis of isoform switching events may provide new insight for the identification of prognostic markers and inform new potential therapeutic targets for EAC treatment or prevention.
Citation Format: Yun Zhang, Katherine M. Weh, Connor L. Howard, Jean-Jack Riethoven, Jennifer L. Clarke, Kiran H. Lagisetty, Jules Lin, Rishindra M. Reddy, Andrew C. Chang, David G. Beer, Laura A. Kresty. Characterizing isoform switching events in esophageal adenocarcinoma [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 5741.
Abstract 5754: The molecular characteristics of EGFR co-mutations in lung adenocarcinoma
Authors: Shang Yanhong , Zhang Hao , Zang Aiming , Yuan Shaohua , Li Xiaofang , Zhang Wenpan , Huo Ran , Fang Guotao , Dou Zhengyue , Liu Weiwei , Han Xiao , Zhao Qi , Xi Chenglin 
Published: June 2022

Abstract
Background: With the development of sensitive next-generation sequencing (NGS) techniques that go beyond the genotyping of specific mutations, detection rates for uncommon mutations have risen clinically. Given this rise in mutation identification, discoveries regarding isolation or coexistent mutations with the EGFR mutation (termed a “complex” mutation) are in “uncharted territory” in terms of their biological impacts on oncogenic pathways and their sensitivity or resistance, to EGFR TKIs.
Methods: 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: A cohort of 262 Chinese lung adenocarcinoma patients were recruited. The most common mutated gene was EGFR (63%, 165/262), and followed by TP53 gene (59.2%, 155/262). Beyond single genetic lesions, we found that enriched co-mutations in lung adenocarcinoma were significantly different for TP53 (p &lt; 0.001) and RTK-RAS (p = 0.0012) signaling pathways between the EGFR-positive and EGFR-negative groups. In all EGFR co-mutated patients, the frequency of co-mutation for EGFR/TP53 and the classical EGFR mutation was 106 (64.2%) and 144 (87.3%), respectively. EGFR-only mutations occurred in 50 (30.3%) patients, while co-mutation of EGFR and at least one tumor suppressor gene (TSG) occurred in 84 (50.9%) patients. Patients with EGFR-only mutation had a lower tumor mutational burden (p = 0.026) as compared to patients with only a TSG mutation. Patients with co-mutations of EGFR and at least one TSG also displayed a lower tumor mutational burden, although only a slight difference (p = 0.062) was determined.
Conclusions: Profiles of EGFR co-mutational TSGs should be regarded as a unique subgroup for predictive insights in treatments for patients with co-occurrence of somatic EGFR and TSG mutations. To improve predictions related to drug sensitivity in targeted therapies for oncogenes with diverse mutations, our future studies will include publications dedicated to this topic.
Citation Format: Yanhong Shang, Hao Zhang, Aiming Zang, Shaohua Yuan, Xiaofang Li, Wenpan Zhang, Ran Huo, Guotao Fang, Zhengyue Dou, Weiwei Liu, Xiao Han, Qi Zhao, Chenglin Xi. The molecular characteristics of EGFR co-mutations in lung adenocarcinoma [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 5754.
Abstract 5756: Next-generation sequencing (NGS) reveals different molecular profiles of pediatric sarcoma in children and adults
Authors: Cai Weisong , Liu Fang , Liu Xuejiao , Wang Xiaojuan , Wang Chunyang , Ma Tonghui , Li Shu 
Published: June 2022

Abstract
Background: Pediatric sarcomas represent approximately 12% of all pediatric cancers with over 100 subtypes. Although some molecular detection techniques can be used to assist the diagnosis and treatment of pediatric sarcoma, it still remains challenging due to overlapping morphological features and limited biopsy specimens. Here we performed next generation sequencing (NGS) to analyze the molecular profiles of pediatric and adult sarcomas in China.
Methods: A total of 700 Chinese patients with sarcoma were collected. The tumor tissue and matching blood specimens were tested by the integrative DNA and RNA sequencing panel Onco Panscan plus࣪ at Genetronhealth.
Results: Of the 700 sarcoma patients, there were 224 children (32%) and 476 adults (68%). Difference from the almost same ratio of men to women in adults, there were more males (n = 134) than females (n = 90) in children. Rhabdomyosarcoma was the most common soft tissue tumor in children, accounting for 24.1% (n = 54), followed by Ewing's sarcoma (9.8%, n = 22) and Osteosarcoma (8.5%, n = 34), while Angiosarcoma (3.8%, n = 18) and Fibrosarcoma (3.6%, n = 17) were the most common in adults. Based on mutation types, the frequent alterations were missense mutations (n = 326, 51.2%), fusions (n = 129, 20.3%) and copy number variants (n = 66, 10.4%) in children with a mean of 3 mutations per patient, and missense mutations (n = 1438, 66.8%), fusions (n = 221, 10.3%) and truncating mutations (n = 215, 10.0%) in adults with an average 5 mutations. TP53 (12.9%, n = 29), EWSR1 (8.9%, n = 20) and ALK mutations (6.7%, n = 15) were common in children, which was distinct from TP53 (29.4%, n = 140), NF1 (4.8%, n = 23), CTNNB1 (4.2%, n = 20) and RB1 (4.2%, n = 20) in adults. Based on NGS results, pathological subtypes could be confirmed in 40.2% (90/224) and 48.1% (229/476) of children and of adults sarcoma patients, respectively. In addition, we identified a total of 72 drug-targeted gene mutations in the 57 children patients, of which 35 (48.6%) gene mutations could be targeted by FDA-approved drugs. In adults, 256 drug-targeted gene mutations were detected and the proportion of actionable mutations was up to 78.9% (n = 202).
Conclusion: The genomic landscape of pediatric sarcomas is different from that of adults. NGS aids in the subtype classification and clinical guidance of pediatric sarcomas, providing evidence for personalized treatments with clinical benefit.
Citation Format: Weisong Cai, Fang Liu, Xuejiao Liu, Xiaojuan Wang, Chunyang Wang, Tonghui Ma, Shu Li. Next-generation sequencing (NGS) reveals different molecular profiles of pediatric sarcoma in children and adults [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 5756.
Abstract 576: Shark VNAR single domain-based CAR T cells targeting PD-L1 for cancer therapy
Authors: Li Dan , English Hejiao , Hong Jessica , Liang Tianyuzhou , Merlino Glenn , Day Chi-Ping , Ho Mitchell 
Published: June 2022

Abstract
Background: Chimeric antigen receptor (CAR)-T therapy shows great potency against hematological malignancies, whereas it is difficult to transfer CAR T into solid tumors due to lack of appropriate antigenic targets and immunosuppressive tumor microenvironment. Checkpoint molecule PD-L1 is widely overexpressed on multiple tumor types, and PD-1/PD-L1 interaction is a primary mediator of immunosuppression in the TME. Here, we generated anti-PD-L1-specific shark single domain VNAR-based CAR T cell strategy and explored its anti-tumor efficacy in xenograft mouse models.
Methods: We isolated anti-PD-L1 single domain antibodies from semi-synthetic shark VNAR phage display libraries. The binding of isolated VNARs was validated by ELISA, flow cytometry, and Octet. A peptide library based on human PD-L1 was synthesized to predict the epitope of select VNARs. Anti-tumor efficacy of CAR T cells was determined via cell luciferase-based cell assay as well as xenograft mouse models. Two tumor models, MDA-MB-231 (triple-negative breast cancer) and Hep3B (hepatocellular carcinoma or HCC) were used in the present study. Glypican-3 (GPC3) is a tumor-specific target in the Hep3B model.
Results: We identified three anti-PD-L1 phage binders, B2, A11, and F5 from our shark phage libraries. All three binders showed cross-activity to human, mouse, and canine antigens, whereas only B2 functionally blocked the interaction of human PD-1 to PD-L1. Moreover, CAR (B2) T cells specifically lysed both MDA-MB-231 and Hep3B tumor cells by targeting constitutive and inducible expression of PD-L1. Importantly, the combination of anti-GPC3 CAR (hYP7) T cells with CAR (B2) T cells regress Hep3B tumors synergistically in mice.
Conclusions: PD-L1-targeted shark VNAR single domain-based CAR T cell therapy is a novel strategy to treat breast cancer and liver cancer. This work provides a rationale for a potential use of anti-PD-L1 CAR T cells as a monotherapy or combination with a tumor-specific therapy in clinical studies for solid tumors.
Citation Format: Dan Li, Hejiao English, Jessica Hong, Tianyuzhou Liang, Glenn Merlino, Chi-Ping Day, Mitchell Ho. Shark VNAR single domain-based CAR T cells targeting PD-L1 for cancer 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 576.
Abstract 5764: Genomic profiling of cutaneous, acral and mucosal melanomas in Chinese populations
Authors: Chen Jing , Ye Ting , Fan Li , Zhang Jieying , Cao Rubo , Liu Yanshen 
Published: June 2022

Abstract
Background: Targeted therapies and immunotherapies have significantly improved the survival of patients with cutaneous melanoma. Nevertheless, patients with acral and mucosal melanomas show limited benefit. The proportion of acral and mucosal subtypes are much higher in Chinese populations than Caucasians. Therefore, it is of great interest to detail the genomic features of acral and mucosal melanomas and compare these with cutaneous melanoma.
Methods: A total of 111 Chinese patients with melanoma treated in Union Hospital, Tongji Medical College, Huazhong University of Science and Technology were enrolled in this study, comprising 32 cutaneous(28.8%), 41 acral(36.9%) and 26 mucosal(23.4%) subtypes. NGS-based genomic profiling of major cancer-related genes was performed on formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens with matched blood samples. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations.
Results: The most commonly mutated genes of cutaneous melanoma include BRAF(48%), CDKN2A(41%), CDKN2B(41%), NRAS(22%) and PTEN(22%). In acral melanoma patients, the mutation rate of BRAF was 10% while NRAS(31%), CDKN2A(21%), EMSY(21%), KIT(18%), CCND1(18%)) and NF1(18%) were frequently mutated. Mucosal melanomas were found most commonly to have mutations in CDKN2A(36%), KIT(32%), CDKN2B(28%), PDGFRA(24%), KDR(20%) and BRAF(16%). In acral and mucosal subtypes, the overall mutation rates of BRAF were significantly lower while the relative proportions of non-V600 mutations were higher as compared to cutaneous subtype. These may explain the less significant survival benefit of BRAFi+/-MEKi in acral and mucosal melanomas. In contrast, KIT mutations including SNVs and amplification, were enriched in acral and mucosal melanomas. Acral melanomas had lower mutation load than mucosal melanomas(2.42 Muts/Mb vs 4.84 Muts/Mb, p=0.0002), while cutaneous melanomas(4.03 Muts/Mb) did not differ from other subtypes in mutation burden. Additionally, patients with TERT, APC and FAT1 gene mutations had a significantly higher TMB than patients with wild-type genes respectively, indicating more activated anti-tumor immune profiles and suggesting therapeutic benefit from immune checkpoint inhibitors.
Conclusions: We conducted a direction comparison of comprehensive genomic profiles of different melanoma subtypes among Chinese patients. The genomic alterations identified in our study may provide reference to discover potential strategies for targeted therapy and immunotherapy in acral and mucosal melanomas.
Citation Format: Jing Chen, Ting Ye, Li Fan, Jieying Zhang, Rubo Cao, Yanshen Liu. Genomic profiling of cutaneous, acral and mucosal melanomas in Chinese populations [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 5764.