bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3896: Recurrent TERT promoter mutations in primary central nervous system lymphoma
Authors: Bruno Aurélie , Daniau Mailys , Mokhtari Karima , Rahimian Amithys , Polivka Marc , Jouvet Anne , Adam Clovis , Figarella-Branger Dominique , Miquel Catherine , Eimer Sandrine , Houillier Caroline , Soussain Carole , Alentorn Agusti , Hoang-Xuan Khê 
Published: August 2015

Abstract
Primary central nervous system lymphoma (PCNSL) is a rare extranodal diffuse large B-cell lymphoma (DLBCL) restricted to the CNS and associated with a poor prognosis. Despite a notable effort contributing to better characterize the genomic basis of these tumors, few molecular abnormalities were proposed as predictive or prognostic biomarkers. Recently, two hotspot mutations, C228T and C250T, and the polymorphism rs2853669, located within TERT core promoter region have known a growing interest due to their prognostic value in a wide range of tumors, including melanoma, hepatocellular carcinoma or glioblastoma.
Forty-one PCNSL tumor samples of newly diagnosed PCNSL were sequenced for C228T and C250T TERT somatic mutations. TERT promoter mutations status was correlated with clinical outcome and rs2853669 genotype.
We identified C228T and C250T mutations and rs2853669 genotype in 20%, 9.4% and 50%, respectively. No case with co-occurrence of C228T and C250T mutations was identified. C228T mutations, but not C250T, were significantly associated with shorter overall survival (OS) (median OS = 4.5 months vs 33 months for non-mutated, p = 0.0048) and progression free survival (PFS) (median PFS = 3 months vs 11.5 months for non-mutated, p = 0.0260). We found no association between TERT promoter mutations and the rs2853669 genotype.
To our knowledge, we showed the presence of TERT promoter mutations in PCNSL for the first time. In addition, C228T promoter mutation was associated with a poor outcome. Considering that these mutations are known to confer enhanced TERT promoter activity, we speculate that an increased telomerase activity could play a role in PCNSL aggressiveness.
This work was granted by the LOC study group network (réseau national de centres experts des lymphomes primitifs du SNC, INCa), the Ligue contre le Cancer (Comité du Val d’Oise), the Fondation pour la Recherche Médicale (FDT20140930968), the APHP-CRIC 2013 (assistance publique - hôpitaux de Paris), and the Association pour la Recherche sur les Tumeurs Cérébrales.
Citation Format: Aurélie Bruno, Mailys Daniau, Karima Mokhtari, Amithys Rahimian, Marc Polivka, Anne Jouvet, Clovis Adam, Dominique Figarella-Branger, Catherine Miquel, Sandrine Eimer, Caroline Houillier, Carole Soussain, Agusti Alentorn, Khê Hoang-Xuan. Recurrent TERT promoter mutations in primary central nervous system lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3896. doi:10.1158/1538-7445.AM2015-3896
Abstract 3897: High-throughput profiling of actionable mutations in salivary duct carcinoma
Authors: Ku Bo Mi , Bae Yeon-Hee , Jung Hyun Ae , Sun Jong-Mu , Ko Young Hyeh , Jeong Han-Sin , Son Young-Ik , Baek Chung-Hwan , Park Keunchil , Ahn Myung-Ju 
Published: August 2015

Abstract
Salivary duct carcinoma (SDC) is a highly aggressive subtype of salivary gland cancers and there is no established standard therapy for this disease. Thus, development of molecular markers for SDC will be important to guide the diagnosis and therapy of this aggressive tumor. We performed next-generation sequencing using the Ion Torrent AmpliSeq cancer panel, which explores the mutational status of hotspot regions in 50 cancer-associated genes, and we analyzed copy number variations (CNVs) of 21 genes by NanoString nCounter for 37 patients with SDC. Fluorescent in situ hybridization was also conducted to confirm ERBB2 gene amplification. Clinical records and tumor histopathology of the patients were retrospectively reviewed. Genetic alterations were detected in 29 of 37 (78.3%) tumors, including mutations in PIK3CA (N = 9, 24.3%), ERBB2 (N = 4, 10.8%), and EGFR (N = 4, 10.8%). To our knowledge, this is the first time that ERBB2 mutations have been reported in this tumor type. Both PIK3CA and ERBB2 mutation status were associated with poor overall survival, but without statistical significance. ERBB2 amplification was strong and common in SDC and almost all cases also exhibited EGFR and ERBB3 amplifications. This study reports the largest and most comprehensive analysis of DNA aberrations in SDC. Our results show that PIK3CA and/or ERBB2 alterations in the development of SDC might be a useful diagnostic tool and could serve as a potential therapeutic target.
Key words: Salivary duct carcinoma, next-generation sequencing, molecular markers, PIK3CA, ERBB2, EGFR
Citation Format: Bo Mi Ku, Yeon-Hee Bae, Hyun Ae Jung, Jong-Mu Sun, Young Hyeh Ko, Han-Sin Jeong, Young-Ik Son, Chung-Hwan Baek, Keunchil Park, Myung-Ju Ahn. High-throughput profiling of actionable mutations in salivary duct carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3897. doi:10.1158/1538-7445.AM2015-3897
Abstract 39: Fibroblast growth factor induces neoplastic cell transformation through a non-canonical signaling pathway
Authors: Yoo Sun-Mi , Lee Cheol-Jung , Lee Mee-Hyun , Cho Yong-Yeon 
Published: August 2015

Abstract
Induction of cell proliferation is closely related with the cellular signaling pathway activation by stimulation of diverse growth factors such as epidermal growth factor (EGF) and fibroblast growth factor. The stimulation of growth factors induces activation of extracellular signal-regulated kinases (ERKs)/p90 ribosomal S6 kinases (p90RSK), resulting in induction of cell proliferation and cell transformation. Although fibroblast growth factor (FGF) is a well-known growth factor and acts as a ligand of FGF receptor (FGFR), a receptor tyrosine kinase, in cytoplasmic membrane, the tumor promoter potential has not been clearly understood. Here, we provided the evidences that FGF acted as a tumor promoter. We found that FGF-induced cell proliferation and anchorage-independent cell transformation were correlated with the induction of G1/S cell cycle transition. Importantly, we found that kaempferol targeted and inhibited FGFR phosphorylation by in vitro and ex vivo. Interestingly, FGF stimulation utilized a non-canonical signaling pathway to activate RSK2 and ATF-1, which was not transduced by EGF stimulation. We confirmed that kaempferol inhibited tyrosine phosphorylation of FGFR, resulted in nuclear accumulation of phospho-ATF-1 at Ser63. Importantly, kaempferol, PKC412, PD98059 and U0126 inhibited EGF-induced anchorage-independent cell transformation in JB6 Cl41 cells. In contrast, FGF-induced cell transformation in soft agar was not inhibited by PD98059 and U0126. Taken together, these results demonstrate that FGF acts as a tumor promoter and dual inhibition of kaempferol on the kinase activities of FGFR and RSK2 suppresses the FGF-induced neoplastic cell transformation through a non-canonical signaling pathway which is not utilized by EGF stimulation.
Citation Format: Sun-Mi Yoo, Cheol-Jung Lee, Mee-Hyun Lee, Yong-Yeon Cho. Fibroblast growth factor induces neoplastic cell transformation through a non-canonical signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 39. doi:10.1158/1538-7445.AM2015-39
Abstract 3902: MSS HNPCC frequently contain CNVs in chromatin regulators
Authors: Chen WeiXiang , sheng Xia , Ding Jun 
Published: August 2015

Abstract
BACKGROUND & AIMS: Approximately half of hereditary non-polyposis colorectal cancers (HNPCCs) don't display evidence of mismatch repair defects. The pathogenesis of microsatellite-stable (MSS) HNPCCs, and their effects on patients’ prognoses and responses to treatment, differ from those of other colorectal cancers (CRCs). We sought to identify genetic somatic alterations associated with MSS HNPCCs. METHODS: We examined genomic DNA samples from 95 primary HNPCCs and adjacent normal appearing mucosae from patients undergoing surgery. We performed the copy number variation (CNV) of the entire genome using the Cytoscan HD Array in 20 MSS and 4 MSI HNPCC tumors and their adjacent normal tissues. Extensive comparison with somatic alterations in MSI HNPCCs allowed segregation of MSS HNPCC-exclusive alterations. RESULTS: We found that copy number of genes that regulate chromatin was altered in MSS HNPCCs; the most frequent CNV were observed in CHD6, CHD7 and CHD8, which encode members of the chromodomain helicase/adenosine triphosphate dependent chromatin remodeling family. Somatic genetic alterations in these 3 genes were detected in 13/10/5 of 20 MSS HNPCCs. Genes altered in patients with CHARGE syndrome (congenital malformations involving the central nervous system, eye, ear, nose, and mediastinal organs) who had CHD7 mutations were also altered in CRCs with copy number amplification in CHD7. CONCLUSIONS: Genetic aberrations in chromatin remodeling could contribute to the development of MSS HNPCCs.
Note: This abstract was not presented at the meeting.
Citation Format: WeiXiang Chen, Xia sheng, Jun Ding. MSS HNPCC frequently contain CNVs in chromatin regulators. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3902. doi:10.1158/1538-7445.AM2015-3902
Abstract 3904: Rspondin-1 contributes to tumor cell proliferation via Wnt signaling pathway
Authors: Park So Hyun , Kim Sol , Choi Min Yeong , Park Jiwoon , Kang Shinae , Kim Hak-Zoo 
Published: August 2015

Abstract
Diabetes mellitus and pancreatic cancer have long been considered to be clinically related to each other. Despite the ample epidemiological evidences indicating relevance between two major human diseases, the precise mechanism to link both of these diseases are still unclear. We demonstrated altered beta-catenin and Wnt3a protein expression in pancreas of diabetic mouse in age-dependent manner, which indicates the chronic diabetic condition may contribute to the pancreatic cancer progression of peri-islet region through elevated Wnt signaling. We also identified the altered expression level of Rspondin-1, secreted agonist of Wnt signaling pathway, in in vivo diabetic mouse model, which showed a similar expression pattern of Wnt3a and beta-catenin. Finally we demonstrated the effect of in vitro diabetic condition on Rspondin expression level of mouse pancreatic beta cell(Min6) and pancreatic cancer cell lines(Panc-1, AsPc-1). The expression level of Rspondin-1 was down-regulated in Min6 cells cultured in high glucose condition, whereas up-regulated in pancreatic cancer cells cultured in in vitro diabetic condition, which correlates with in vivo Rspondin-1 expression study. These results provide new insights about the Wnt signaling and related proteins as molecular linkers of chronic diabetes and pancreatic cancer.
Citation Format: So Hyun Park, Sol Kim, Min Yeong Choi, Jiwoon Park, Shinae Kang, Hak-Zoo Kim. Rspondin-1 contributes to tumor cell proliferation via Wnt signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3904. doi:10.1158/1538-7445.AM2015-3904
Abstract 3907: Differential effects of 1α, 25-dihydroxyvitamin D3 dose on keratinocyte proliferation and ΔNp63α stabilization
Authors: Hill Natasha T. , Zhang Jin , Leonard Mary K. , Lee Miryoung , Kadakia Madhavi 
Published: August 2015

Abstract
1α, 25-dihydroxyvitamin D3 (VD3) is a secosteriod that has been explored as an anti-cancer agent, but has also been shown to promote cell survival. Its receptor, Vitamin D Receptor (VDR), is a direct target of the oncogene ΔNp63α, which is overexpressed in non-melanoma skin cancers. The interconnection between VDR/VD3 signaling and ΔNp63α, led us to examine whether VDR/VD3 signaling promotes keratinocyte proliferation by regulating ΔNp63α levels. We show that VDR regulates ΔNp63α expression at both the transcript and protein level. Interestingly, while low doses of VD3 led to an increase in ΔNp63α protein levels and keratinocyte proliferation, high doses of VD3 failed to increase ΔNp63α protein levels and resulted in reduced proliferation. Increased levels of ΔNp63α by low dose VD3 was shown to be VDR dependent and critical for the pro-proliferative effects of VD3. Furthermore, VD3 mediated increases in ΔNp63α protein levels occur via p38 activation. Analysis of squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and precursors to invasive SCC demonstrated a significant correlation between p63 and VDR levels when compared to normal skin samples. In this study we demonstrated a differential dose effect of VD3 on ΔNp63α stability, which directly resulted in differential effects on cell growth. Delineation of the mechanisms by which VD3 exerts its effect on ΔNp63α will be critical for determining the future of VD3 in cancer therapies.
Citation Format: Natasha T. Hill, Jin Zhang, Mary K. Leonard, Miryoung Lee, Madhavi Kadakia. Differential effects of 1α, 25-dihydroxyvitamin D3 dose on keratinocyte proliferation and ΔNp63α stabilization. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3907. doi:10.1158/1538-7445.AM2015-3907
Abstract 3912: GDF2 promotes anoikis susceptibility in ovarian and breast epithelia
Authors: Varadaraj Archana , Patel Pratik , Serrao Anne , Bandyopadhyay Tirthankar , Lee Nam Y. , Jazaeri Amir , Murphy Susan , Mythreye Karthikeyan 
Published: August 2015

Abstract
Resistance to anchorage independent cell death (anoikis) is one of the features of metastasis and can be regulated by a diverse array of growth factors. The protein encoded by GDF2 is BMP9 and is a member of the Bone Morphogenetic protein family and the TGFβ superfamily with defined roles in angiogenesis and emerging yet controversial roles in carcinogenesis. We used normal and oncogenic epithelial systems to examine the role of GDF2 in ovarian and breast epithelia. We find that both normal and transformed epithelial cells are competent to activate the Smad1/5 signaling cascade in response to GDF2. This activation occurs via specific complex formation between the Type I receptor Serine threonine kinases Alk3 and Alk6 and the Type II receptor serine threonine kinase BMPRII. We find that in breast and ovarian epithelial cells GDF2 specifically regulates anchorage independent growth by increasing anoikis sensitivity that is dependent on GDF2's ability to sustain SMAD1/5 activation via Alk3 and Alk6. Analysis of cell lines and patient data indicates epigenetic regulation of GDF2 expression in ovarian and breast cancers. These findings reveal an antimetastatic role for GDF2 in ovarian and breast cancer models of disease with significant implications for the use of epigenetic drugs currently in clinical trials.
Citation Format: Archana Varadaraj, Pratik Patel, Anne Serrao, Tirthankar Bandyopadhyay, Nam Y. Lee, Amir Jazaeri, Susan Murphy, Karthikeyan Mythreye. GDF2 promotes anoikis susceptibility in ovarian and breast epithelia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3912. doi:10.1158/1538-7445.AM2015-3912
Abstract 3924: A homogenous bioluminescent system for measuring GTPase, GAP and GEF activities
Authors: Mondal Subhanjan , Hsiao Kevin , Goueli Said A. 
Published: August 2015

Abstract
GTPases play a major role in various cellular functions such as cell signaling, cell proliferation, cell differentiation, cytoskeleton modulation and cell motility. Deregulation or mutation of these proteins has considerable consequences resulting in multiple pathological conditions. Targeting GTPases and its regulators have been challenging due to lack of convenient assays. To overcome the challenges in analyzing activities of GTPases and their regulatory proteins GTPase Activating Proteins (GAP) and Guanine Nucleotide Exchange Factors (GEF) we have developed a homogenous bioluminescent assay (GTPase/GAP/GEF-Glo) system to analyze these proteins in a simple, convenient “add-mix-read” format. Mg2+ plays a critical role in influencing affinity of GTPases with GTP/GDP and the process of nucleotide exchange. Manipulating Mg2+ concentrations in the GTPase reaction buffer allows continuous progression of the GTPase cycle and faster hydrolysis of GTP. The assay relies on enzymatic conversion of GTP remaining after the GTPase reaction to ATP and detection of the ATP using luciferin/luciferase combination. We show that the assay is sensitive, and robust when analyzing for analyzing intrinsic GTPase- activity, GAP-stimulated GTPase- activity, GAP-activity and GEF- activity. The system can also be used to analyze these proteins expressed in cells as a fusion protein performing the assay in a pulldown -format. Furthermore, there was minimal false hits when tested for compound interference using the library of pharmacologically active compounds (LOPAC) and its robustness as indicated by high Z’-factor of 0.93 and CV of 2.2%.
Citation Format: Subhanjan Mondal, Kevin Hsiao, Said A. Goueli. A homogenous bioluminescent system for measuring GTPase, GAP and GEF activities. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3924. doi:10.1158/1538-7445.AM2015-3924
Abstract 3925: Production and biochemical characterization of farnesylated and methylated KRAS4b using engineered baculovirus
Authors: Stephen Andrew G. , Gillette William K. , Grose Carissa , Esposito Dominic 
Published: August 2015

Abstract
KRAS4b, which is frequently mutated in pancreatic, colon and lung cancers, is processed in several steps including farnesylation by farnesyl-transferase (FNT); proteolytic cleavage at the C-terminus by ras converting enzyme 1 (RCE1) and carboxymethylation by isoprenylcysteine carboxymethyl transferase (ICMT). Plasma membrane localization of KRAS4b requires this processing as does KRAS4b-dependent RAF kinase activation. Previous attempts to produce modified KRAS have relied on protein engineering approaches or in vitro farnesylation of bacterially expressed KRAS protein. The proteins produced by these methods do not completely replicate the final KRAS protein found in mammalian cells and the yield and quality of the protein are typically low. Using an engineered baculovirus containing the two subunits of farnesyl-transferase (FNTA/B) and a maltose-binding protein (MBP)-KRAS4b fusion we are able to produce highly purified, farnesylated, and methylated KRAS4b (FMe-KRAS4b) in insect cells at yields of approximately 10mg/L. This protein has been extensively characterized by electrospray-ionization mass spectrometry, analytical ultracentrifugation, and circular dichroism. In addition, we demonstrate that FMe-KRAS4b is fully active in hydrolyzing GTP, binding to RAF-RBD, and interacting with lipid nanodiscs.
Citation Format: Andrew G. Stephen, William K. Gillette, Carissa Grose, Dominic Esposito. Production and biochemical characterization of farnesylated and methylated KRAS4b using engineered baculovirus. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3925. doi:10.1158/1538-7445.AM2015-3925
Abstract 3927: Structural and mechanistic insights into the roles of RIAM in integrin signaling
Authors: Wu Jinhua 
Published: August 2015

Abstract
Changes in integrin signaling promotes tumor cell proliferation, metastasis and survival. The Rap1-interacting adaptor molecule (RIAM) mediates integrin activation by responding to Rap1 activation and recruiting talin, the integrin activator, to the plasma membrane (PM). The structural details of how RIAM is recognized by Rap1 and in turn recruits talin are lacking. We have elucidated the specificities for RIAM interacting with Rap1 and talin via X-ray crystallography and functional analyses. Crystal structure of Rap1 in complex with the central structural module of RIAM reveals essential specificity determinants, especially a Lys31 residue that is oppositely charged in other Ras GTPases. Furthermore, our study on the RIAM:talin interaction suggests that the talin-binding site 1 (TBS1) of RIAM is required for recruiting cytoplasmic talin to the PM, primarily via an interaction with the R8 domain of talin. Interestingly, an unexpected kink in the helical TBS1 fragment is required for inducing integrin activation. These characteristics are not seen in other related molecules including the highly homologous Lpd, providing the molecular basis for the specific signaling function of RIAM that mediates the integrin activation.
Citation Format: Jinhua Wu. Structural and mechanistic insights into the roles of RIAM in integrin signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3927. doi:10.1158/1538-7445.AM2015-3927
Abstract 3940: Inactivation of the PARD3 gene is a recurrent event in lung squamous cell carcinomas and affects STAT3 activity and tumor invasiveness
Authors: Bonastre Ester , Verdura Sara , Zondervan Ilse , Facchinetti Federica , Lantuejoul Sylvie , Chiara Maria Dolores , Rodrigo Juan Pablo , Carretero Julian , Sidransky David , Villanueva Alberto , Condom Enric , Vidal Agustin , Roz Luca , Brambilla Elisabeth , Savola Suvi , Sanchez-Cespedes Montse 
Published: August 2015

Abstract
Correct apicobasal polarization and intercellular adhesions are essential for the appropriate development of normal epithelia. Here, we investigated the contribution of the partitioning defective 3 gene, PARD3, to the carcinogenesis of lung squamous cell carcinomas (LSCCs). Tumor-specific PARD3 alterations were found in eight per cent of the tumors, placing PARD3 among the most common tumor suppressor genes in LSCC. Some PAR3 mutant proteins prevented the formation of contacts between neighboring cells, i.e. had reduced ability to form tight junctions and actin-based protrusions. This affected subsequent downstream signaling, i.e. binding to aPKC and activation of RAC1. Further, we discovered that PAR3 wild type triggered the expression of cell adhesion and polarity-related transcripts and the activation of STAT3, by cell confluence. Finally, restitution of PAR3 in vivo significantly reduced the formation of metastasis. In conclusion, PARD3 is recurrently inactivated in LSCC and its deficiency contributes to the tumor aggressiveness.
Citation Format: Ester Bonastre, Sara Verdura, Ilse Zondervan, Federica Facchinetti, Sylvie Lantuejoul, Maria Dolores Chiara, Juan Pablo Rodrigo, Julian Carretero, David Sidransky, Alberto Villanueva, Enric Condom, Agustin Vidal, Luca Roz, Elisabeth Brambilla, Suvi Savola, Montse Sanchez-Cespedes. Inactivation of the PARD3 gene is a recurrent event in lung squamous cell carcinomas and affects STAT3 activity and tumor invasiveness. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3940. doi:10.1158/1538-7445.AM2015-3940