bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3349: TEAD4 expression in human hepatocellular carcinoma correlates with poor prognosis and promotes tumor growth and migration
Authors: Tosti Nadia , Lanzafame Manuela , Paradiso Viola , Ng Charlotte K. , Piscuoglio Salvatore , Quintavalle Cristina , Terracciano Luigi Maria 
Published: August 2018

Abstract
Background: TEAD family is a group of four transcription factor members, including TEAD1, TEAD2, TEAD3 and TEAD4. These genes are known to be involved in the regulation of different genes associated with cell proliferation, differentiation and apoptosis. TEAD proteins represent the major downstream effectors of the conserved Hippo signalling pathway, known to be deregulated in different cancer entities. In the present study, we sought to explore the expression of TEAD4 in hepatocellular carcinoma (HCC) and its effect in in vitro models. Methods: We evaluated TEAD4 expression at mRNA level using data from The Cancer Genome Atlas (liver dataset) and at protein level using a tissue microarray containing 192 HCCs, 108 cirrhotic tissues and 79 normal liver samples. For in vitro experiments, two liver cancer cell lines were stably overexpressed and downregulated for TEAD4 to characterize its role in in vitro models, in terms of proliferation, migration and anchorage-independent growth. Results: TEAD4 was found overexpressed in a subset of HCCs in the TCGA dataset and its overexpression correlated with worst overall survival (p=0.03). The tissue microarray analysis showed a similar trend not only in the HCCs but also in cirrhotic tissues. The in vitro assays demonstrated that the overexpression of TEAD4 promoted tumour growth and migration as well as increased foci formation capacity. On the other hand, TEAD4 knockdown was able to revert the phenotype, suggesting a putative oncogenic role of TEAD4 in hepatocarcinogenesis. Conclusions: Finally, TEAD4 is frequently overexpressed in HCCs and in cirrhotic tissues and its expression is associated with poor prognosis. Furthermore, in vitro evidence suggests that TEAD4 may act as oncogene and may have a pivotal role in hepatocarcinogenesis.
Citation Format: Nadia Tosti, Manuela Lanzafame, Viola Paradiso, Charlotte K. Ng, Salvatore Piscuoglio, Cristina Quintavalle, Luigi Maria Terracciano. TEAD4 expression in human hepatocellular carcinoma correlates with poor prognosis and promotes tumor growth and migration [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 3349.
Abstract 335: Variable off-target effects of clinically advanced PARP inhibitors
Authors: Wielgos Monica E. , Patibandla Jay , Firlit Michelle , Oudenhove Elke Van , Cybulska Paulina , Jelinic Petar , Levine Douglas A. 
Published: August 2018

Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most common subtype of ovarian cancer with low 5-year survival rates. Inhibitors of poly (ADP-ribose) polymerase (PARP) are promising novel agents that uniquely target HGSOCs with DNA repair deficiencies. The majority of patients with DNA repair proficient HGSOCs do not respond to PARP inhibitor monotherapy, highlighting the need for novel treatment approaches for these women. The goal of this study was to expand the patient population that could benefit from PARP inhibition by identifying the off-target effects that are favorable in combination with CHK1 inhibitors among the five most clinically advanced PARP inhibitors.
Cell cycle and western blot analysis revealed that the four most potent PARP trappers (rucaparib, olaparib, niraparib, and talazoparib) have a strong effect on the cell cycle. The PARP trappers in particular activated CHK1 through phosphorylation at the serine 345 residue, decreased total protein levels of CDC25C, and arrested cells in the S/G2 phase of the cell cycle. These results were not observed after treatment with veliparib, the least potent PARP trapper. We created phospo-CHK1 mutants to confirm CHK1 activation at serine 345 and to further investigate whether potent PARP trappers activate CHK1 on serine 317, another residue that is also phosphorylated in response to replication stress. The data suggest that PARP trappers activate CHK1 at both the serine 317 and 345 phosphorylation sites.
Next, we examined whether PARP inhibition-induced activation of CHK1 is a determinant of synergy between PARP and CHK1 inhibitors. We exposed one of our established BRCA wild-type, TP53 mutant HGSOC patient-derived xenograft models to a PARP1 inhibitor (veliparib or talazoparib) or to the CHK1 inhibitor (MK-8776) or a combination of PARP and CHK1 inhibitors. CHK1 inhibition slightly increased sensitivity to talazoparib compared to single agent therapy. However, the tumor volume was significantly reduced by the combination of CHK1 inhibition and veliparib treatment compared to either single agent alone. This study suggests that there are off-target cell cycle effects that vary among the five most clinically-advanced PARP inhibitors that likely influence the response to combinatorial treatment. We propose the use of PARP and CHK1 inhibition as a strategy for HGSOC patients who would otherwise have minimal benefit to PARP inhibitor monotherapy.
Citation Format: Monica E. Wielgos, Jay Patibandla, Michelle Firlit, Elke Van Oudenhove, Paulina Cybulska, Petar Jelinic, Douglas A. Levine. Variable off-target effects of clinically advanced PARP inhibitors [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 335.
Abstract 3351: Myc inhibition by Omomyc impairs melanoma growth and progression through genome-wide gene expression reprogramming
Authors: Zacarias-Fluck Mariano F. , Martín Génesis , Massó-Vallés Daniel , Foradada Laia , Whitfield Jonathan R. , Beaulieu Marie-Eve , Soucek Laura 
Published: August 2018

Abstract
Myc encodes for a transcription factor deregulated in the vast majority of human cancers, mainly by amplification or constant upstream oncogenic signaling. Previous work from our laboratory showed that targeting Myc by transgenic expression of the Myc inhibitor Omomyc is an effective strategy to inhibit tumor progression and cause tumor regression in a wide array of mouse cancer models, without any evidence of toxicity in normal tissues. Our goal now is to assess whether Myc inhibition can be an effective approach to treat melanoma, the most dangerous form of skin cancer. For this purpose, we transfected human melanoma cell lines with a doxycycline-dependent vector expressing Omomyc-RFP and characterized the effect of Myc inhibition on proliferation and colony formation, as well as the expression of different cell cycle related proteins. We observed that Omomyc significantly reduced proliferation of a wide variety of cell lines, regardless of their driving mutations. In p53 wild type cells, Omomyc expression was accompanied by p53 stabilization and concomitant p21 upregulation, and in BRaf or NF1 mutated melanoma cells, by downregulation of cyclin D1. In order to elucidate the mechanism of action underlying this anti-tumorigenic effect, we performed a microarray analysis of A375 melanoma cells in the presence or absence of Omomyc-RFP expression. This analysis showed that Omomyc affected genome-wide gene expression. More in detail, Gene Set Enrichment Analysis showed that Omomyc significantly blunts the expression of both Myc and E2F targets, as well as RNA biogenesis, DNA replication and different cell cycle checkpoints, among many others relevant gene sets. Importantly, Omomyc significantly reduced the expression of genes related to melanoma metastases. Finally, in order to validate Omomyc therapeutic impact in vivo, A375 and SkMel147 cells were s.c. implanted into nude mice and the effect of Omomyc expression on tumor progression was evaluated. Our results show that Omomyc expression significantly impairs the growth of both cell lines, increasing the survival of tumor-bearing mice. These results combined clearly show that Omomyc-mediated Myc inhibition is an effective means to impair melanoma progression, by directly targeting Myc, inhibiting cell cycle and decreasing melanoma aggressiveness.
Citation Format: Mariano F. Zacarias-Fluck, Génesis Martín, Daniel Massó-Vallés, Laia Foradada, Jonathan R. Whitfield, Marie-Eve Beaulieu, Laura Soucek. Myc inhibition by Omomyc impairs melanoma growth and progression through genome-wide gene expression reprogramming [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 3351.
Abstract 3358: FOXF1 defines the core-regulatory circuitry in gastrointestinal stromal tumor (GIST)
Authors: Ran Leili , Chen Yuedan , Wong Wai Pung E. , Li Dan , Cao Zhen , Shukla Shipra , Xie Yuanyuan , Zheng Deyou , Koche Richard P. , Antonescu Cristina R. , Chen Yu , Chi Ping 
Published: August 2018

Abstract
The cellular context that integrates upstream signaling and downstream nuclear response dictates the oncogenic behaviour and shapes treatment responses in distinct cancer types. Here, we uncover that in GIST, the forkhead family member, FOXF1, directly controls the transcription of two master regulators, KIT and ETV1, both required for GIST precursor-interstitial cells of Cajal (ICC) lineage-specification and GIST tumorigenesis. Further, FOXF1 co-localizes with ETV1 at enhancers and functions as a pioneer factor that regulates the ETV1-dependent GIST-lineage specific transcriptome through modulation of the local chromatin context, including chromatin accessibility, enhancer maintenance and ETV1 binding. Functionally, FOXF1 is required for human GIST cell growth in vitro and murine GIST tumor growth and maintenance in vivo. The simultaneous control of the upstream signaling and nuclear response sets up a unique regulatory paradigm and highlights the critical role of FOXF1 in enforcing the GIST cellular context for highly lineage-restricted clinical behaviour and treatment response.
Citation Format: Leili Ran, Yuedan Chen, Wai Pung E. Wong, Dan Li, Zhen Cao, Shipra Shukla, Yuanyuan Xie, Deyou Zheng, Richard P. Koche, Cristina R. Antonescu, Yu Chen, Ping Chi. FOXF1 defines the core-regulatory circuitry in gastrointestinal stromal tumor (GIST) [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 3358.
Abstract 3360: Origins of mutations in colorectal cancer
Authors: Gold Barry 
Published: August 2018

Abstract
The origins of most human cancers remain unclear. In selected cases, exposure to potent environmental mutagens or familial germ line mutations, which affect tumor suppressor genes or oncogenes, have been identified with specific cancers. Wnt signaling due to mutations in APC is compromised as an early event in 75% of human colorectal cancer (CRC), with truncating nonsense mutations (65%) dominating the mutation spectrum. Because 43% of the nonsense mutations occur at Arg CGA codons, the C→T mutation is attributed to hydrolytic deamination of 5-methylC. The enhanced incidence of colorectal cancer (CRC) associated with the Western diet has been epidemiologically linked to heterocyclic aromatic amines (HAA) produced by high temperature cooking of meat. Analysis of the mutation spectra in CRC indicated that the G→T transversions, which are produced by this class of mutagens were not enriched but were actually lower than what would be statistically anticipated based on random mutations. Moreover, the APC mutation patterns in the U.S.A. vs. China are indistinguishable despite differences in diet. However, dissection of the APC mutation pattern in tumors that arise in the different anatomical regions of the large intestine shows that the nonsense mutation pattern in APC differ in the different regions: there is a statistically significant increase in G→T transversions in the rectum vs. the other regions, albeit, the percent of G→T mutations still remains lower than predicted based on random mutagenesis. Therefore, it appears that HAA's may contribute to the incidence of rectal cancer.
Citation Format: Barry Gold. Origins of mutations in colorectal cancer [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 3360.
Abstract 3362: Mice with a “deletor” phenotype allow high resolution detection of lymphoid leukemia tumor suppressor genes
Authors: Yin Mianmian , Baslan Timour , Freeland Amy , Pruitt Steven C. , Aplan Peter D. 
Published: August 2018

Abstract
Mice that are homozygous for a deficiency allele of the DNA replication factor minichromosome maintenance protein 2 (designated Mcm2def) are born viable and are healthy for the first 2 months of life. Beginning at three months, these mice develop precursor T-cell lymphoblastic leukemia/lymphoma (pre-T LBL). Copy number aberration (CNA) analysis showed that these pre-T LBL samples had 8-14 small (100-1000 kb) interstitial deletions per sample. Remarkably, all mice had two or more deletions that encompassed genes known to be relevant for human pre-T LBL, including Pten, Cdkn1a, Tcf3, and Tcf12.
Mice that express a NUP98-HOXD13 (NHD13) transgene develop a wide array of leukemias, most commonly myeloid, less commonly T-cell, and, rarely, B-lineage. To identify myeloid tumor suppressor genes, we crossed the NHD13 transgene onto the Mcm2def background. All Mcm2def:NHD13+ mice developed pre-T LBL by 3 months of age, reflecting the highly penetrant nature of the Mcm2def phenotype. None of the Mcm2def:NHD13+ mice developed myeloid leukemia. Surprisingly, approximately 30% of the Mcm2def:NHD13+ mice developed concurrent B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and pre-T LBL. The thymus was typically infiltrated with pre-T LBL cells, whereas the bone marrow and spleen were infiltrated with BCP-ALL cells, characterized by clonal VDJ rearrangement and CD19 staining. Parenchymal organs (lung, kidney, liver) were variably infiltrated with pre-T LBL, BCP-ALL, or both. CNA analysis showed that the pre-T LBL were characterized by Pten, CDkn1a, Tcf3, and Tcf12 deletions, similar to the Mcm2def pre-T LBL, whereas the BCP-ALL were characterized by homozygous or heterozygous deletions of Pax5 and a 400 kb region encompassing Cebpb and Ptpn1. There were no shared deletions present in both BCP-ALL and pre-T LBL from the same mouse, indicating that the BCP-ALL and pre-T LBL arose independently, and not from a common precursor. The high frequency (5/7 samples) of acquired Pax5 deletions in the BCP-ALL samples serves to validate the model; whereas the finding of Cebpb/Ptpn1 deletions (5/7 samples) suggests an unanticipated role of either Cebpb or Ptpn1 in BCP-ALL.
Citation Format: Mianmian Yin, Timour Baslan, Amy Freeland, Steven C. Pruitt, Peter D. Aplan. Mice with a “deletor” phenotype allow high resolution detection of lymphoid leukemia tumor suppressor genes [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 3362.
Abstract 3370: Mad2l2 inhibits colorectal cancer growth by promoting ncoa3 ubiquitination and degradation
Authors: li yixin , qin ge , long qian , zhang changlin , shi dingbo , chen miao , deng wuguo 
Published: August 2018

Abstract
Nuclear receptor coactivator 3 (NCOA3) is a transcriptional coactivator that has elevated expression in multiple tumor types, including colorectal cancer (CRC). However, the molecular mechanisms that regulate the tumorigenic functions of NCOA3 in CRC remain largely unknown. In this study, we aimed to discover and identify the novel regulatory proteins of NCOA3 and explore their mechanisms of action. Immunoprecipitation coupled with mass spectrometry analysis was used to detect, identify and verify the proteins that interacted with NCOA3 in CRC cells. The biological functions of the candidate proteins and the underlying molecular mechanism were investigated in CRC cell lines and a mouse model in vitro and in vivo. The clinical significance of NCOA3 and its interaction partner protein in CRC patients was also studied. We discovered and identified mitotic arrest deficient 2-like protein 2 (MAD2L2, also known as MAD2B or REV7) as an interaction partner of NCOA3 by immunoprecipitation coupled with mass spectrometry analysis. Overexpression of MAD2L2 suppressed the cell proliferation, migration and clonogenecity in CRC cell lines and a mouse model by inducing the degradation of NCOA3. We also found that increased MAD2L2 expression in CRC cells activated p38, which was required for the phosphorylation of NCOA3 that led to its ubiquitination and degradation by the proteasome. Moreover, we demonstrated that MAD2L2 predicted favorable prognosis in CRC patients. These results indicate that MAD2L2 inhibits colorectal cancer growth by promoting NCOA3 ubiquitination and degradation. Our study have discovered a novel role of MAD2L2 in the regulation of NCOA3 degradation, and proposed that MAD2L2 serves as a potential tumor suppressor in CRC.
Citation Format: yixin li, ge qin, qian long, changlin zhang, dingbo shi, miao chen, wuguo deng. Mad2l2 inhibits colorectal cancer growth by promoting ncoa3 ubiquitination and degradation [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 3370.
Abstract 3372: Mutations of mismatch repair genes in Her2 overexpressed breast cancer
Authors: Baghdadi Mohammed A. , Sobahy Turki M. , Alardati Hosam A. , Zekri Jamal E. 
Published: August 2018

Abstract
The importance of Mismatch Repair (MMR) in therapeutic selection is an area of recent research. Minority of unselected breast tumors exhibit mutations indicative of deficient MMR. Here, we present our preliminary data investigating 7 MMR genes exclusively in Her2-overexpressed (Her2OE) breast cancer (BC). Twenty-five archival formalin-fixed paraffin-embedded samples from 25 Her2OE BC patients underwent targeted next generation sequencing for 7 MMR genes (MLH1, MLH3, MSH2, MSH6, PMS2, POLD1 and EPCAM). The analysis was performed through the Saudi Human Genome Project bioinformatics pipeline. Data filtration was performed to rank genetic variants based on their predicted pathogenicity. Methods of filtration included mutation effect, ClinVar findings, ExAC loss of function index (pLI) and collective proteomics index. Twenty-four out of 25 (96%) tumors contained significant mutations in one or more MMR genes. Three cases (12%) contained mutations in 3-4 MMR genes while 21 (84%) had 1-2 alteration(s) in these gene(s). Only one case showed no significant mutations in any of the studied MMR genes. MLH1, MLH3, MSH2, MSH6, PMS2, POLD1 and EPCAM were mutated in 6(24%), 1(4%), 5(20%), 18(72%), 2(8%), 6(24%) and 3(12%) respectively. In this preliminary report, mutations in MMR genes affect up to 96% of Her2OE BC tumors. Such result may impact on therapeutic choices. This result is to be confirmed in larger cohort.
Citation Format: Mohammed A. Baghdadi, Turki M. Sobahy, Hosam A. Alardati, Jamal E. Zekri. Mutations of mismatch repair genes in Her2 overexpressed breast cancer [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 3372.
Abstract 3397: Clinical significance of 3q amplification in squamous cell carcinoma of lung
Authors: Lee Eunjung , Kim Chungyeul , Kim Han-Kyeom , Kim Baek-hui 
Published: August 2018

Abstract
Squamous cell carcinoma (SqCC) is major subtype of non-small cell lung cancer (NSCLC). One of the molecular characteristic of SqCC is amplification of distal portion of 3q. The aim of this study is to find out the clinical significance of the 3q amplification in SqCC of lung. Method : We extracted DNA from 90 cases of FFPE blocks of lung SqCC tissue. Ten genes (PIK3CA, SOX2, KLHL6, MCF2L2, LAMP3, MCCC1, ABCC5, ATP11B, TP63, YEATS2) included in 3q were selected and the amplification of each gene was analyzed by using NanoString nCounter analysis system (PhileKorea). The hierarchical clustering was performed with the resulting values. Results : We identified two groups in all 90 cases of SqCC by hierarchical clustering. One group with 3q amplification was 50 cases, and the other group without 3q amplification was 40 cases. There was no significant difference in sex, age, stage, smoking history, histologic grade and the results of immunohistochemical staining (p63, p40 and p53) between the two groups. It showed the tendency that the group with 3q amplification presented poor disease free survival (P=0.193) and overall survival (P=0.34) than the group without 3q amplification. Among the ten genes, PIK3CA and YEATS2 were significantly associated with survival. Each genes with amplification showed poor disease free survival (PIK3CA; P=0.036, YEATS2; P=0.025). Conclusion : The amplification of 3q can help sorting out two subsets of SqCC of lung whose clinical outcomes are likely to diverge. Among the genes included in 3q, PIK3CA and YEATS2 were associated with prognosis. These finding demonstrate the role of these genes in biologic behavior of tumor and suggest opportunities for targeted therapies.
Citation Format: Eunjung Lee, Chungyeul Kim, Han-Kyeom Kim, Baek-hui Kim. Clinical significance of 3q amplification in squamous cell carcinoma of lung [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 3397.