bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4723: Mesenchymal status promotes metastatic colonization via a cancer cell-stroma crosstalk which uncouples EMT and stemness
Authors: Del Pozo Martin Yaiza , Park Danielle , Sahai Erik , Malanchi Ilaria 
Published: August 2015

Abstract
During metastatic colonisation tumour cells must establish a favourable microenvironment, or niche, that will sustain their growth. However, both the temporal and molecular details of this process are poorly understood.
Here, using breast cancer models, we find that metastatic initiating cells (MICs) in a mesenchymal phenotype exhibit high niche activation ability as a result of Thrombospondin 2 (THBS2) secretion, which prompts lung fibroblasts activation. Importantly, inhibiting the mesenchymal phenotype of MICs, by blocking the epithelial to mesenchymal transition (EMT)-associated kinase AXL during the early stages of cancer cell infiltration, reduces THBS2 secretion, niche activation ability, and consequently metastatic establishment. Subsequently, cancer cells start expanding at the target site and revert to a more epithelial phenotype. Interestingly, the activated fibroblasts of the newly formed metastatic niche trigger the reversion of cancer cell mesenchymal phenotype without compromising self-renewal. Preventing this phenotypic reversion by enhancing AXL expression during colonization block metastasis.
In summary, we demonstrate that during metastatic colonization the two events of niche activation and EMT are functionally linked at the target site. However, in this context, EMT becomes uncoupled from the ‘stemness’ required for metastatic growth. Further, once fibroblasts within the niche are activated they promote the mesenchymal to epithelial transition (MET) of tumour cells, leading to the outgrowth of metastases with similar epithelial characteristics and stromal cell networks to their original primary tumours.
Citation Format: Yaiza Del Pozo Martin, Danielle Park, Erik Sahai, Ilaria Malanchi. Mesenchymal status promotes metastatic colonization via a cancer cell-stroma crosstalk which uncouples EMT and stemness. [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 4723. doi:10.1158/1538-7445.AM2015-4723
Abstract 4766: DNA methylation changes in Lynch syndrome associated colorectal adenomas and carcinomas
Authors: Valo Satu , Kaur Sippy , Ristimäki Ari , Renkonen-Sinisalo Laura , Järvinen Heikki , Mecklin Jukka-Pekka , Nyström Minna , Peltomäki Päivi 
Published: August 2015

Abstract
Colorectal cancer (CRC) develops via multiple steps which involve genetic changes, such as mutations in growth-regulatory genes, and epigenetic alterations, such as CpG island hypermethylation. Lynch syndrome (LS) is one of the most common inherited cancer susceptibility syndromes and is associated with inherited defects of the DNA mismatch repair (MMR) genes, which together with other genetic and epigenetic changes are known to accelerate tumorigenesis. In this investigation we explored the timing of CpG island methylation changes in the course of transformation of normal colonic mucosa to pre-cancerous and cancerous lesions in genetically predisposed individuals.
Colorectal neoplastic lesions including low-grade adenomas, high-grade adenomas and carcinomas together with matching normal tissue were gathered from 43 LS mutation carriers enrolled in colonoscopy surveillance. Frequency of CpG island methylator phenotype (CIMP) in different tumor types was analyzed with the methylation-specific multiplex ligation-dependent probe amplification test (MS-MLPA) which detects simultaneously the methylation status of eight CIMP marker genes. Additionally, we analyzed the methylation status of seven selected tumor suppressor genes previously associated with early colon oncogenesis. Immunohistochemistry was used to detect MMR protein expression in neoplastic lesions.
We show that the expression of the MMR protein corresponding to the germline mutation decreases along with increasing dysplasia in tumors. Similarly, methylation increases in LS adenomas and carcinomas together with dysplasia grade in comparison to normal colonic mucosa. A proportion of low-grade adenomas could already be classified CIMP positive, and the frequency of CIMP further increased in high-grade adenomas and carcinomas. Our results offer new insights into the molecular mechanisms through which DNA methylation can affect colorectal carcinogenesis in LS mutation carriers.
Citation Format: Satu Valo, Sippy Kaur, Ari Ristimäki, Laura Renkonen-Sinisalo, Heikki Järvinen, Jukka-Pekka Mecklin, Minna Nyström, Päivi Peltomäki. DNA methylation changes in Lynch syndrome associated colorectal adenomas and carcinomas. [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 4766. doi:10.1158/1538-7445.AM2015-4766
Abstract 4778: HP1-mediated spatiotemporal control of estrogen-responsive transcription in breast cancer cells
Authors: Hsu Pei-Yin , Hsu Hang-Kai , Jin Victor X. , Sharp Zelton D. , Huang Tim H.-M. 
Published: August 2015

Abstract
Recruitment of transcriptional machinery to target promoters for aberrant gene expression has been well studied, but underlying control directed by distant-acting enhancers remains unclear in cancer development. Our previous study demonstrated that distant estrogen response elements (DEREs) located on chromosome 20q13 were frequently amplified (50∼60 copies) and translocated to other chromosomes in ERα-positive breast cancer cells. In this study, we used three-dimensional interphase fluorescence in situ hybridization to decipher spatiotemporal gathering of multiple DEREs in the nucleus. Upon estrogen stimulation, the majority of 20q13 DEREs were mobilized to form regulatory depots for synchronized regulation of target loci. A chromosome conformation capture assay coupled with chromatin immunoprecipitation further uncovered that ERα-bound regulatory depots are tethered to heterochromatin protein 1 (HP1) for coordinated chromatin movement and subsequent facilitation of histone modifications of target loci, resulting in transcription repression. Neutralizing HP1 function dissembled these regulatory depots and reversed this transcription inactivation of candidate tumor-suppressor genes. Deletion of amplified DEREs using the CRISPR/Cas9 genomic-editing system profoundly altered transcriptional profiles of JAK/STAT signaling networks, leading to proliferation inhibition of cancer cells with beneficial outcome of breast cancers. These findings reveal a formerly uncharacterized feature of oncogenic amplicons that multiple copies of the amplicon congregate as transcriptional unions in the nucleus for synchronous regulation of function-related loci in tumorigenesis. Disruption of their assembly can be a new strategy for treating breast cancers and other malignancies.
Citation Format: Pei-Yin Hsu, Hang-Kai Hsu, Victor X. Jin, Zelton D. Sharp, Tim H.-M. Huang. HP1-mediated spatiotemporal control of estrogen-responsive transcription in breast cancer cells. [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 4778. doi:10.1158/1538-7445.AM2015-4778
Abstract 4811: Pro-oncogenic role of NOTCH1 in early tongue squamous cell carcinoma
Authors: Upadhyay Pawan , Aich Jyotirmoi , Sethunath Vidyalakshmi , Dani Prachi , Kannan Sadhana , Chandrani Pratik , Sonawane Kavitha , Agarwal Beamon , Kane Shubhada , Nair Sudhir , Dutt Amit 
Published: August 2015

Abstract
Notch pathway play a context-dependent tumor-suppressive or pro-oncogenic role in solid tumors and hematological malignancies. In head and neck cancer, inactivating mutations in NOTCH1 are associated with poor prognosis. Here we perform meta-analysis of DNA copy number and gene expression profiling of NOTCH signaling pathway genes in 35 paired primary T1 and T2 stage tongue tumors, comprising of Notch ligands, receptors and target genes. We find 32% of primary tongue squamous cell carcinoma (TSCC) tumors amplify NOTCH signaling pathway components; and over express activated NOTCH1based on immuno-histochemical staining in an additional series of 50 surgically resected paired TSCC tumors. Interestingly, these alterations: amplification at Notch ligand DLL3 (χ2 = 7.575, P = 0.023); over expression of Notch pathway target gene HEY2 transcript (χ2 = 9.885, P = 0.007); and expression of activated NOTCH1 (χ2 = 7.575, P = 0.023) positively correlate with N+ve and non- smoking status of patients. In a parallel effort, we characterized four HNSCC cell lines– NT8E, OT9, AW13516, and AW8507– established from Indian patients using whole exome, whole transcriptome sequencing and SNP array assays. Significant amplification and over expression of NOTCH signaling pathway components were observed in AW13516 and NT8E cells. Inhibition of NOTCH activation by gamma secretase inhibitor or shRNA mediated knockdown of NOTCH1 could inhibit transformation, survival, migration and invasion of NT8E cells. Taken together, we present that activation of Notch signaling pathway in a subset of TSCC patients is associated with nodal positivity and non-smoking status among early tongue cancer patients.
Citation Format: Pawan Upadhyay, Jyotirmoi Aich, Vidyalakshmi Sethunath, Prachi Dani, Sadhana Kannan, Pratik Chandrani, Kavitha Sonawane, Beamon Agarwal, Shubhada Kane, Sudhir Nair, Amit Dutt. Pro-oncogenic role of NOTCH1 in early tongue squamous cell 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 4811. doi:10.1158/1538-7445.AM2015-4811
Abstract 4813: High-depth sequencing of 800 cancer-associated genes in 48 matched tumor-normal tissues to identify somatic alterations including low-frequency variants in colorectal cancer
Authors: Chua Clarinda , Ho Dan Liang , Suzuki Yuka , Malik Simeen , McPherson John , Gan Anna , Koh Dennis , Tang Choon Leong , Ng Sarah Boon Hsi , Tan Patrick , Rozen Steve , Tan Iain Beehuat 
Published: August 2015

Abstract
Purpose: Colorectal cancer is the 3rd most common cancer globally accounting for 10% of the global cancer burden. Catalogues of somatic mutations in cancer (e.g. The Cancer Genome Atlas (TCGA)) are based upon exome sequencing, typically performed at depths of ∼ 80x, which will miss sub-clonal low-frequency somatic variants. We performed high depth sequencing of 800 cancer-associated genes across 48 tumor/normal pairs of CRC to catalogue somatic variants including those present at low variant allele frequencies.
Method: We used the Agilent SureSelect Target Enrichment system to design a customized enrichment panel comprising all coding exons of ∼800 cancer-associated genes. From genomic DNA extracted from frozen tissue specimens (matched primary tumor and adjacent normal), we performed library construction, target enrichment and illumina next generation sequencing. We used 3 variant-calling algorithms - a Genome Analyzer Toolkit (GATK) based pipeline, LoFreq and MuTect to identify somatic variants including sub-clonal variants present at low variant allele frequencies.
Results: Sequencing was performed to a median of 302-fold and 310-fold coverage across target regions in the tumor tissues and normal tissues respectively. The use of 3 bioinformatics variant-calling algorithm allowed sensitive and comprehensive identification of variants down to a variant allele frequency of 2.5%; selected variants were validated by an orthogonal sequencing platform (Ion Torrent). The validation rate was &gt; 97%. Each patient had a variant in a median of 19 genes (range 8-100) with a different complement of clonal and sub-clonal variants. Recurrent alterations (e.g. APC, KRAS, TP53) tended to be clonal. Broad regions of allelic imbalance (based on heterozygous SNPs identified in each patient's normal tissue) could also be mapped in each patient.
Conclusion: High Depth sequencing of 800 cancer-associated genes in 48 matched tumor normal tissues permits identification of somatic alterations including low-frequency variants and sub-clonal alterations in patients with colorectal cancer.
Citation Format: Clarinda Chua, Dan Liang Ho, Yuka Suzuki, Simeen Malik, John McPherson, Anna Gan, Dennis Koh, Choon Leong Tang, Sarah Boon Hsi Ng, Patrick Tan, Steve Rozen, Iain Beehuat Tan. High-depth sequencing of 800 cancer-associated genes in 48 matched tumor-normal tissues to identify somatic alterations including low-frequency variants in colorectal cancer. [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 4813. doi:10.1158/1538-7445.AM2015-4813
Abstract 4815: Tumor heterogeneity of advanced primary lung cancer evaluated by multiregion sequencing
Authors: Um Sang-Won , Joung Je-Gun , Lee Su Yeon , Bae Joon Seol , Park Jinha , Park Woong-Yang 
Published: August 2015

Abstract
Background: Cancers are composed of cells with distinct genetic and phenotypic characteristics. Tumor heterogeneity in each patient may influence on personalized medicine strategies that depend on results from single tumor-biopsy samples. However, tumor heterogeneity in advanced primary lung cancer has not been well studied. The purpose of this study was to investigate the tumor heterogeneity in advanced primary lung cancer.
Methods: We sequenced fourteen regions from four patients who were suspicious for primary lung cancer with multiple lymph node metastasis. Tumor samples were obtained from primary tumor and metastatic lymph node(s) or distant metastasis using bronchoscopic forcep biopsy, endobronchial ultrasound-guided transbronchial needle aspiration, and percutaneous needle biopsy. The profiles of somatic mutations, copy number alterations and gene expression were compared among primary tumor and metastatic sites in each patient. Clonal evolution was evaluated using the concept of cancer cell fraction by SciClone analysis.
Results: We performed multiregion whole exome sequencing and RNA sequencing on three non-small cell lung cancers (2 adenocarcinomas [TH1 and TH4] and 1 squamous cell carcinoma [TH2]) and one small cell lung cancer (TH3). EML4-ALK fusion was noticed in TH1 and TH4. There was profound tumor heterogeneity in terms of somatic mutation, copy number alteration, or gene expression in each patient. The frequency of private somatic mutation from spatially distinct regions were 59% in TH1, 44% in TH2, 13% in TH3, and 30% in TH4. Known driver mutation was also heterogeneous in TH1 and TH2. Analysis of the clonal architecture confirmed the presence of clonal heterogeneity in each patient. Phylogenetic reconstruction revealed the evidence of branched clonal evolution.
Conclusions: Tumor heterogeneity was noticed from spatially distinct regions from advanced primary lung cancers. The single biopsy specimens may not represent the whole landscape of genetic alteration in advanced primary lung cancers.
Citation Format: Sang-Won Um, Je-Gun Joung, Su Yeon Lee, Joon Seol Bae, Jinha Park, Woong-Yang Park. Tumor heterogeneity of advanced primary lung cancer evaluated by multiregion sequencing. [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 4815. doi:10.1158/1538-7445.AM2015-4815
Abstract 4819: Differential evolution of tumor heterogeneity in leiomyosarcomas and liposarcomas suggested by genomic profiling
Authors: Amin-Mansour Ali , Sioletic Stefano , Carter Scott L. , Garraway Levi A. , Demetri George D. , George Suzanne , Van Allen Eliezer M. , Wagner Andrew J. 
Published: August 2015

Abstract
Sarcomas represent a heterogeneous set of malignant tumors originating from mesenchymal cells. Liposarcomas (LPS) and Leiomyosarcomas (LMS) are two of the most common histotypes, accounting for approximately 25% and 30% of all soft tissue sarcomas, respectively. The most frequent form of LPS is represented by a spectrum of disease including well-differentiated LPS (WDLPS), a non-metastasizing but locally recurrent disease with adipocytic differentiation, and de-differentiated LPS (DDLPS), an aggressive, frequently metastasizing high grade sarcoma which can arise in conjunction with elements of WDLPS. Besides the known oncogenic KIT or PDGFRA driver mutations in GIST, somatic alterations in RB1, deletions in PTEN, MDM2 amplifications in LPS, and TP53 mutations in LMS are the most commonly reported genomic aberrancies identified in sarcomas. Both WDLPS and DDLPS share amplification of 12q13-15, a genomic region containing the MDM2 and CDK4 loci, yet little is understood about the other genetic processes that yield such different phenotypes. In LMS, recurrent mutations in TP53 have been identified, but a detailed analysis of primary and metastatic tumors has not previously been described.
To evaluate genetic events in these transitions, we performed whole exome sequencing (WES) on trios comprising normal tissue, WDLPS, and DDLPS obtained from individual patients (n = 19), as well as on trios of normal tissue, primary and metastatic LMS tumors obtained from separate individual patients (n = 8). Consistent with prior reports of the molecular characterization of LPS, we observed arm-level amplifications in Chr 12 in all LPS samples, and Chr 17 amplification in many LMS cases. There were no shared somatic alterations across paired WDLPS and DLPS pairs from individual patients aside from the common Chr 12 amplification (MDM2 & CDK4). A higher mutation rate was observed in LMS, and there were many clonal somatic alterations shared between the primary and metastatic lesions of individuals.
This study demonstrates the heterogeneity of evolution between different subtypes of sarcomas using whole exome sequencing of clinical specimens. This finding has implications for better understanding of the molecular drivers of these tumors and opportunities to identify subtype-specific therapeutic targets.
Citation Format: Ali Amin-Mansour, Stefano Sioletic, Scott L. Carter, Levi A. Garraway, George D. Demetri, Suzanne George, Eliezer M. Van Allen, Andrew J. Wagner. Differential evolution of tumor heterogeneity in leiomyosarcomas and liposarcomas suggested by genomic profiling. [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 4819. doi:10.1158/1538-7445.AM2015-4819
Abstract 4828: Differential gene expression profile of tissue factor pathway inhibitor-2 (TFPI-2) in malignant pleural mesothelioma
Authors: Wali Anil , Wang Ying , Tarca Adi , Lonardo Fulvio , Liu Zhandong , Rishi Arun K. , Pass Harvey I. 
Published: August 2015

Abstract
Malignant pleural mesothelioma (MPM) is an asbestos-related malignancy characterized by rapid progressive local growth, late metastases, and poor prognosis despite aggressive strategies involving surgery, chemotherapy, and radiation. The tissue factor pathway inhibitor-2 (TFPI-2) has been shown to play an important role in the regulation of extracellular matrix digestion and remodeling, and its reduced synthesis is implicated in various pathophysiological processes such as inflammation and tumor growth/metastasis. In this study we have elucidated the gene expression profile of TFPI-2 among 22 MPM tumor samples using Affymetrix U133AB chip platform. We noticed 13/22 tumors had more than 3-fold reduction in their TFPI-2 gene expression patterns compared to three normal peritoneums. Decreased TFPI-2 expression was observed in majority of epithelial histotypes that exhibited short-term recurrence (STR &lt;12 months) compared to longer time to relapse (LTR after surgery), group of MPM tumor samples. TFPI-2 expression was profoundly decreased (&gt;4-fold) among 5 out of 7 autologous normal pleura-MPM tumor samples. We also found &gt; 3-fold decreased TFPI-2 gene expression pattern in three out of six MPM patient derived cell lines. A robust 2-fold induction in TFPI-2 gene expression was found as a consequence of 5′-aza-2′-deoxycytidine (5-AzaC) and trichostatin-A combination treatment of two MPM patient derived cell lines. Studies are underway to assess whether TFPI-2 promoter hypermethylation is involved in the down-regulation of its expression pattern seen among fifty percent of MPM tumor samples. Further studies are needed to understand the regulation and interaction of TFPI-2 in mesothelioma carcinogenesis that could be utilized for future early detection and therapeutic strategies to combat this insidious disease.
Note: This abstract was not presented at the meeting.
Citation Format: Anil Wali, Ying Wang, Adi Tarca, Fulvio Lonardo, Zhandong Liu, Arun K. Rishi, Harvey I. Pass. Differential gene expression profile of tissue factor pathway inhibitor-2 (TFPI-2) in malignant pleural mesothelioma. [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 4828. doi:10.1158/1538-7445.AM2015-4828
Abstract 4854: A computational framework for prioritizing noncoding regulatory variants in cancer
Authors: Fu Yao , Liu Zhu , Lou Shaoke , Colonna Vincenza , Bedford Jason , Mu Xinmeng , Yip Kevin Y. , Kang Hyun Min , Lappalainen Tuuli , Sboner Andrea , Yu Haiyuan ,   1000 Genomes Project Consortium, Rubin Mark , Tyler-Smith Chris , Khurana Ekta , Gerstein Mark 
Published: August 2015

Abstract
Mutations in key regulatory sequences have been suggested to cause oncogenesis. However, identification of noncoding cancer “drivers” from thousands of somatic alterations is a difficult and unsolved problem. We report a computational framework, FunSeq, to annotate and prioritize these mutations. The framework combines an adjustable data context integrating large-scale genomics (e.g. ENCODE) and cancer resources with a streamlined variant-prioritization pipeline. The pipeline has a weighted scoring system combining: inter- and intra-species (we used patterns of natural polymorphisms to identify human-specific conserved elements) conservation; loss- and gain-of function events for transcription-factor binding; enhancer-gene linkages and network centrality; and per-element recurrence across samples. We further highlight putative drivers with information specific to a particular sample, such as differential gene expression. When applied to an individual tumor genome, our method is able to prioritize the TERT promoter mutation. We then evaluated our framework on a larger-scale first by doing various comparisons with other existing noncoding variant-prioritization tools. Next, we used the recurrence of somatic mutations to validate some of our prioritized mutations. Finally, we developed the recurrence analysis into a database combining all whole-genome sequenced cancer samples and used this to provide higher confidence in mutation prioritization. FunSeq is available from funseq.gersteinlab.org.
Note: This abstract was not presented at the meeting.
Citation Format: Yao Fu, Zhu Liu, Shaoke Lou, Vincenza Colonna, Jason Bedford, Xinmeng Mu, Kevin Y. Yip, Hyun Min Kang, Tuuli Lappalainen, Andrea Sboner, Haiyuan Yu, 1000 Genomes Project Consortium, Mark Rubin, Chris Tyler-Smith, Ekta Khurana, Mark Gerstein. A computational framework for prioritizing noncoding regulatory variants in cancer. [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 4854. doi:10.1158/1538-7445.AM2015-4854