bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3360: Targeted catalytic inhibition of EZH2 synergizes with low-dose HDACi in malignant rhabdoid tumors
Authors: Popovski Dean , Algar Elizabeth M. , Cochrane Catherine R. , Szczepny Anette , Jayasekara W. Samantha , Ashley David M. , Downie Peter , Watkins D. Neil , Cain Jason E. 
Published: July 2017

Abstract
Malignant Rhabdoid Tumor (MRT) is a rare pediatric cancer of the kidney and CNS that is resistant to current treatment protocols. MRT is genetically characterized by homozygous inactivation of SMARCB1, a critical subunit of the SWI/SNF chromatin-remodeling complex. Next-generation sequencing data suggests that inactivation of SMARCB1 is the primary driver mutation, implicating epigenetic deregulation in the pathogenesis of MRT. Recently, we showed that sustained treatment of MRT cell lines with low-dose Panobinostat (LBH589), inhibited tumor growth by driving multi-lineage differentiation in vitro and in vivo. Furthermore, re-expression of physiological levels of SMARCB1 in G401 MRT cells phenocopied the low-dose LBH589 treatment and led to growth inhibition, senescence and terminal differentiation in vitro and in vivo. Enhancer of Zeste homolog 2 (EZH2), a core subunit of the Polycomb Repressive Complex 2 (PRC2), confers transcriptional silencing via the addition of methyl groups to Lysine 27 of Histone 3 (H3K27me3), and is a transcriptional target of SMARCB1. EZH2 expression and H3K27me3 were drastically reduced following sustained low-dose LBH589 treatment and re-expression of SMARCB1 in G401 MRT cells. Sustained siRNA knockdown of EZH2 in G401 cells resulted in reduced cell growth and changes in mRNA expression similar to those observed following low-dose LBH589 treatment and SMARCB1 re-expression. Treatment of MRT cells with the EZH2-catalytic domain inhibitor, GSK-126, had no effect on EZH2 expression and only partially reduced H3K27me3 and cell growth at doses 1nM-10μM suggesting important non-catalytic EZH2 function. However, MRT cells treated in combination with low-dose LBH589 and GSK-126, lost EZH2 and H3K27me3 expression and exhibited significantly reduced cell growth in vitro compared to single agent controls, revealing a synergistic relationship. Similar effects were observed in an in vivo xenograft model, with low-dose LBH589 and GSK-126 treatment leading to a marked reduction in tumor growth, not observed with single agent treatment. This data suggests EZH2 is an important mediator of MRT proliferation and differentiation and provides evidence for dual therapeutic targeting of EZH2 with low-dose HDACi in MRT.
Citation Format: Dean Popovski, Elizabeth M. Algar, Catherine R. Cochrane, Anette Szczepny, W. Samantha Jayasekara, David M. Ashley, Peter Downie, D. Neil Watkins, Jason E. Cain. Targeted catalytic inhibition of EZH2 synergizes with low-dose HDACi in malignant rhabdoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3360. doi:10.1158/1538-7445.AM2017-3360
Abstract 3378: Whole exome sequencing identifies recurrent alterations of genes in malignant phyllodes tumors in nine Korean individuals
Authors: Yun Jihui , Moon Hyeong-Gon , Yoo Tae-Kyung , Lee Eunshin , Chae Jeesoo , Hur Sam , Lee Jiwoo , Kim Jong-Il , Noh Dong-Young 
Published: July 2017

Abstract
Phyllodes tumors of the breast are rare fibroepithelial neoplasms with variable clinical behavior accounting for about 1% of all breast neoplasms. Phyllodes tumors are classified into benign, borderline, and malignant grades on the basis of histological features. Among those categories, Malignant phyllodes tumor has a higher propensity for local recurrence and distant metastasis, however the malignant potential of phyllodes tumors is difficult to assess on initial pathologic examination. In previous studies, an important role of mediator complex subunit 12 (MED12) in phyllodes tumors has been frequently revealed. However, except that, genetic abnormalities that drive tumor initiation and progress in malignant phyllodes tumor remain still unclear. Here, by performing whole exome sequencing of 9 malignant phyllodes tumors with matching normal cases, we frequently observed mutations in MED12 (3/9, 33.34%). Additionally, non-silent mutations in p53(TP53) and epidermal growth factor receptor (EGFR) were recurrently identified. Whole-gene amplifications of EGFR were also found in six cases (6/9, 66.67%). We suggest that EGFR has an underlying role in malignant phyllodes tumors. This study identifies potential therapeutic targets in malignant phyllodes tumors, including EGFR.
Citation Format: Jihui Yun, Hyeong-Gon Moon, Tae-Kyung Yoo, Eunshin Lee, Jeesoo Chae, Sam Hur, Jiwoo Lee, Jong-Il Kim, Dong-Young Noh. Whole exome sequencing identifies recurrent alterations of genes in malignant phyllodes tumors in nine Korean individuals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3378. doi:10.1158/1538-7445.AM2017-3378
Abstract 3383: Exome sequencing in dedifferentiated ovarian mucinous carcinoma
Authors: Sanuki Kaori , Nakayama Kentaro , Nakamura Kohei , Ishikawa Masako , Ishibashi Tomoka , Yamashita Hitomi , Ono Ruriko , Minamoto Toshiko , Yoshihara Kosuke , Kyo Satoru 
Published: July 2017

Abstract
Mucinous ovarian tumor represent a distinct histotype of epithelial ovarian cancer and is thought to begin as a mucinous adenoma that progresses in a slow stepwise fashion. Dedifferentiated mucinous ovarian carcinoma is a rare type of carcinoma with a few reports and a progressive and poor prognosis. While the molecular genetic features of ovarian mucinous carcinoma is now well known, the pathogenesis of dedifferentiated mucinous carcinoma is largely unknown. In order to comprehensively analyse somatic mutations in dedifferentiated mucinous carcinoma, we applied exome sequencing to the DNA of a sample of affinity-purified, dedifferentiated mucinous carcinoma. Through comparative analyses of normal cells from the same patient, we identified several genes that were mutated in this tumor. P53, which encodes a well-known tumor suppressor protein, and KRAS, which encodes a well-known oncoprotein, had previously been implicated in ovarian mucinous carcinoma. The other mutated genes were previously unknown to be involved in mucinous carcinoma. CEP170 encodes a microtubule-binding protein that controls the targeting of the kinesin-13 depolymerase protein to the mitotic spindle, and kinesin-13 family influence the dynamics of microtubule growth and shrinkage. CEP170 gene mutation may be related to inability of a cell division properly. CEP170 mutations were identified with a prevalence of 33.3% in dedifferentiated mucinous ovarian carcinoma. Currently, CEP170 gene knock down assay and engineered expression of CEP170 assay in ovarian mucinous carcinoma is being performed whether morphologic change is observed. In summary, CEP170 may be one of the responsible gene in carcinogenesis of differentiated mucinous carcinoma.
Citation Format: Kaori Sanuki, Kentaro Nakayama, Kohei Nakamura, Masako Ishikawa, Tomoka Ishibashi, Hitomi Yamashita, Ruriko Ono, Toshiko Minamoto, Kosuke Yoshihara, Satoru Kyo. Exome sequencing in dedifferentiated ovarian mucinous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3383. doi:10.1158/1538-7445.AM2017-3383
Abstract 339: Identification of a novel isoform of WNT/planar cell polarity VANGL2 in breast cancer
Authors: Borg Jean-Paul , Walton Alexandra , Bailly Eric , Marchetto Sylvie , Audebert Stéphane 
Published: July 2017

Abstract
The WNT/PCP pathway is an evolutionarily conserved developmental process which is essential in embryogenesis and development of polarized structures in metazoans. Its importance in human diseases is best demonstrated in neural tube closure defects and cancer. WNT/PCP signaling involves a set of evolutionarily conserved WNT/PCP genes encoding WNT ligands, transmembrane (vangl2, frizzled, fat, dachsous) and cytoplasmic (scribble, prickle, dishevelled, diego) molecules triggering a genetically well-defined non-canonical WNT-JNK pathway. Recent work has linked defects of this pathway to breast cancer aggressiveness. We have shown that the non-canonical WNT/PCP transmembrane receptor VANGL2 is overexpressed in poor prognosis basal breast cancers and implicated in tumor growth. We also found that VANGL2 binds through its C-terminal sequence to Scribble and p62/SQSTM1 which are involved in cancer cell migration and growth. A recent in silico study has suggested the existence of an N-terminally extended VANGL2 isoform (VANGL2-Long), owing to the occurrence of an alternative non-AUG translation initiation site, upstream of the conventional start site. Translation initiation from this alternative site is expected to add an N-terminal extension of 48 amino acids. Accordingly, by analyzing VANGL2 immunoprecipitates by mass spectrometry, we identified a peptide mapping upstream of the first methionine supporting the existence of a longer isoform of VANGL2. While missing in Drosophila, this N-terminal extension is found in all vertebrate VANGL2 sequences that have been examined, suggesting a function for VANGL2-Long. We provide further experimental evidence in favor of the VANGL2-Long isoform, using polyclonal antibodies that have been raised against the predicted VANGL2 N-terminal extension. Using these tools, we characterized VANGL2-Long and showed that it dimerizes with VANGL2 and VANGL1, a close homologue, at the endogenous level in living cells. Our data depict a complex organization of VANGL1/VANGL2 molecules at the plasma membrane and improve the mechanistic understanding of VANGL2 in normal and cancer cells.
Citation Format: Jean-Paul Borg, Alexandra Walton, Eric Bailly, Sylvie Marchetto, Stéphane Audebert. Identification of a novel isoform of WNT/planar cell polarity VANGL2 in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 339. doi:10.1158/1538-7445.AM2017-339
Abstract 3392: Genomic analysis of prostate cancer in Korean men
Authors: Jang Se Song , Kim Min Jung , Hong Dong Wan , Joung Jae Young , Kim Sung Han , Lee Kang Hyun , Park Weon Seo , Kim Jong-Il 
Published: July 2017

Abstract
Prostate cancer currently has the fifth highest incidence rate in Korean males, and is the most common cancer in western males. Prostate cancer is the second most common malignancy in men worldwide, and is responsible for approximately 250,000 cancer-related deaths annually. The search for accurate biomarkers and characterization of prostate cancer is critical for evolution of accurate management of prostate cancer. Previous studies have identified that several genomic alterations in prostate cancer including TMPRSS2-ERG fusion, PTEN deletion and SPOP single nucleotide variants (SNVs), the majority of which are from western population. In order to investigate the somatic mutations of Korean prostate cancers, we performed whole exome sequencing on 51 prostate cancer patient’s tumor tissues, and matched normal tissue. For the accurate detections of structural variations, we additionally performed whole genome sequencing on 9 matched pairs (tumor, normal). A total of 738 somatic non-silent variants affecting 692 distinct genes were identified. In addition to already known genes such as SPOP, FOXA1, TP53 and PTEN, we also found previously uncharacterized genes such as GRIN2A, LRP1, FNDC1 and LRP1B. Of the 40 mutated genes across multiple cases, missense SNVs of SPOP (10/60 cases, 16.7%) were the most frequent, followed by missense and splice-site SNVs of GRIN2A (5/60 cases, 8.3%). Mutations in low-density lipoprotein-related protein encoded by LRP1 and LRP1B affected considerable portion of all cases (7/60, 11.7%), describe the probable relation between lipid metabolism and prostate cancer. We found TMPRSS2-ERG fusion in 4 of 9 whole genome samples. Moreover, 5 samples had 8p whole arm deletion, which is found frequent in western prostate cancers. As a result, we describe the genomic patterns of genetic variations and structural variations involved in prostate cancer of Korean population.
Citation Format: Se Song Jang, Min Jung Kim, Dong Wan Hong, Jae Young Joung, Sung Han Kim, Kang Hyun Lee, Weon Seo Park, Jong-Il Kim. Genomic analysis of prostate cancer in Korean men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3392. doi:10.1158/1538-7445.AM2017-3392
Abstract 3398: The genomic and transcriptomic analysis of nine widely invasive follicular thyroid carcinomas (wiFTC) in Korean patients
Authors: Cho Angela Byuri , Yoo Seong-Keun , Sohn Min-Hwan , Shin Jong-Yeon , Kim Su-jin , Lee Eun Kyung , Park Young Joo , Seo Jeong-Sun 
Published: July 2017

Abstract
Widely invasive follicular thyroid carcinoma (wiFTC) can be characterized from minimally invasive follicular thyroid carcinoma (miFTC) as it exhibits poor prognosis with frequent distant metastasis. We have reported that miFTC shows similar mutational and transcriptional spectrum when compared to follicular adenoma (FA). Here, we performed whole-exome and transcriptome sequencing on wiFTC samples to define their aggressive biological features by comparing with 30 miFTCs and 26 FAs. Well-known miFTC and FA driver genes, NRAS (66.67%), HRAS (11.11%), and EIF1AX (11.11%), were identified in wiFTC. TERT mutation was found in all samples which can explain its aggressive feature. Chromosome 17p/q amplification was found in most wiFTC samples as well as 22q deletion that is frequently aberrant in H/K/NRAS mutated thyroid cancers. Most of wiFTCs were classified as RAS-like (66.67%) and a few were BRAF-like (22.22%) and NBNR (11.11%) molecular subtypes. From differentially expressed gene analysis, we found 1,832 and 1,384 up-regulated and down-regulated genes when wiFTC was compared to miFTC and FA together. wiFTC had many overlapped down-regulated genes as poorly differentiated and anaplastic thyroid carcinoma which also supports its aggressiveness. Through weighted correlation network analysis we have established gene expression networks, highly associated with wiFTC, that have SIRT6 and TGFBR2 as the central nodes. In this study, we demonstrated the distinctive mutational and transcriptional characteristics of wiFTC hence found the underlying molecular mechanism for its aggressiveness.
Citation Format: Angela Byuri Cho, Seong-Keun Yoo, Min-Hwan Sohn, Jong-Yeon Shin, Su-jin Kim, Eun Kyung Lee, Young Joo Park, Jeong-Sun Seo. The genomic and transcriptomic analysis of nine widely invasive follicular thyroid carcinomas (wiFTC) in Korean patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3398. doi:10.1158/1538-7445.AM2017-3398
Abstract 3399: Genomic analysis of melanoma evolution following a 30 year disease-free interval
Authors: Miller Jerry J. , Lofgren Kristopher A. , Hughes Sarah R. , Cash Steven E. , Meier David R. , Kenny Paraic A. 
Published: July 2017

Abstract
The rate of ultra-late recurrence (beyond 10-15 years) of cutaneous melanoma has been estimated to be between 2.0-6.9% from large case series. Two major factors complicate the interpretation of these data. Firstly, the risk of second primary melanoma is approximately 5% creating uncertainty about whether at least some of these late onset tumors might be independent of the original lesion. Secondly, in the majority of cases, the original pathology specimen is no longer available for comparative analysis. Accordingly, putative late recurrences are difficult to unambiguously distinguish from a new primary melanoma. We identified a patient with a second melanoma diagnosed after a 30 year disease-free interval, and sought to determine if this new lesion was a recurrence of the original melanoma. We report the genomic sequence analysis of the exomes of two melanoma lesions isolated from the same individual in 1985 and 2015, and their comparison to each other and to the germline DNA of the patient. Identification of many shared somatic mutations between these lesions prove a lineal relationship spanning 30 years. Unlike prior reports of ultra-late melanoma recurrence, the availability of the original tumor and the use of comprehensive genomic analysis allowed us to confirm that the second lesion is truly a recurrence. We demonstrate the acquisition of numerous additional mutations during the three decade asymptomatic period. This is, to our knowledge, the longest disease-free interval that has been rigorously confirmed in melanoma or any other solid tumor type. These data highlight the low but very long-lasting risk of recurrence in this patient population.
Citation Format: Jerry J. Miller, Kristopher A. Lofgren, Sarah R. Hughes, Steven E. Cash, David R. Meier, Paraic A. Kenny. Genomic analysis of melanoma evolution following a 30 year disease-free interval [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3399. doi:10.1158/1538-7445.AM2017-3399
Abstract 3401: Role of membrane-associated guanylate kinase inverted 2 in advanced and castration-resistant prostate cancers
Authors: Le Bao , Hammer Kimberly , Frantskevich Katya , Ong Irene , Huang Wei , Marker Paul 
Published: July 2017

Abstract
Background: Prostate cancer is the most common non-cutaneous malignancy for men in the U.S. Patients with advanced and/or metastatic prostate cancer are commonly treated with androgen deprivation therapy. Unfortunately, incurable castration resistant prostate cancer commonly develops 2-3 years after initial treatment.
Methods: To identify candidate cancer genes involved in the development of castration resistance, the Sleeping Beauty (SB) transposon system and androgen-sensitive LNCaP cell line were used in a forward mutagenesis screen designed to model the transition from androgen sensitive to androgen insensitive prostate cancer. MAGI-2 was identified in the screen as a common insertion site gene, potentially involved in the transition to androgen independence. Clinical significance of MAGI-2 in prostate cancer was further supported by human TCGA data. Functional assays were used to confirm the involvement of MAGI-2 in prostate cancer progression.
Results: MAGI-2 expression was prognostic for patient survival outcome. Ectopic expression of MAGI-2 in 22Rv1 cells resulted in a decrease in cell proliferation and colony formation in in vitro studies. At the molecular level, overexpression of MAGI2 induced a suppression of known androgen responsive genes. MAGI-2 overexpression also limited the growth of grafts compared to empty vector grafts in in vivo xenograft models.
Conclusion: MAGI-2 was identified in a forward mutagenesis screen modeling the development of castration resistant prostate cancer. Human protein expression data from patient tissues supported a possible role for MAGI-2 in prostate cancer. Functional studies confirmed the potential involvement of MAGI-2 in prostate cancer progression. Future studies are seeking to elucidate the functional role and mechanism-of-action for MAGI-2 in prostate cancer. Ultimately, this may identify MAGI-2-regulated signaling pathways as therapeutic targets for prostate cancer.
Citation Format: Bao Le, Kimberly Hammer, Katya Frantskevich, Irene Ong, Wei Huang, Paul Marker. Role of membrane-associated guanylate kinase inverted 2 in advanced and castration-resistant prostate cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3401. doi:10.1158/1538-7445.AM2017-3401
Abstract 3403: Telomere shortening in pancreatic cancer is correlated to KRAS mutation
Authors: Matsuda Yoko , Izumiyama Naotaka , Fujiwara Mutsunori , Ishikawa Naoshi , Aida Junko , Takubo Kaiyo , Ishiwata Toshiyuki , Arai Tomio 
Published: July 2017

Abstract
Background: Pancreatic cancer is characterized by genomic complexity and chromosomal instability, and atypical mitotic figures are morphological features of this phenotype. Previously we have reported that approximately 30% of total mitosis in pancreatic cancer was atypical including multipolar, lag-type, ring and asymmetrical mitosis, and anaphase bridges, and the number of total mitosis and atypical mitosis in pancreatic cancers was correlated with aggressive phenotype and prognosis (Pancreatology, 2016). In the present study, we clarified the relation between atypical mitotic figures, telomere length, and genetic abnormality in the pancreatic cancer.
Methods: We surveyed the mitotic figures of the normal epithelium, pancreatic intraepithelial neoplasias (PanINs), and pancreatic cancers using surgically resected pancreatic cancer specimens (n=40). Telomere length was analyzed using quantitative fluorescent in situ hybridization technique. We also analyzed mutations of Kras codon 12 and 13 by PCR and microsatellite instability by immunohistochemical staining of MLH1, MSH2, MSH6 and PMS2.
Results: Pancreatic cancer and duodenal epithelium showed significantly higher mitotic indices as compared with the duct, acinar cells, and PanINs. Normal mitosis was also higher in pancreatic cancers and the duodenal epithelium, while atypical mitosis was significantly elevated only in pancreatic cancers. Number of total mitosis and atypical mitosis were negatively correlated with telomere length, suggesting that telomere shortening plays important roles in cancer proliferation and chromosomal instability. In comparison with normal ducts, telomere length was decreased in PanIN-1, -2 and -3 and cancer. Furthermore, telomere length was gradually shorter among PanIN grades. Most of pancreatic cancers harbored mutations in Kras codon 12, and pancreatic cancer cases with Kras mutation showed shorter telomere length as compared with cases without Kras mutation. All pancreatic cancer cases in the present study were microsatellite stable.
Conclusion: Our data strongly suggest that telomere shortening occurs in the early stages of pancreatic carcinogenesis and progresses with precancerous development. Telomere shortening and chromosomal instability in the duct epithelium plays key roles on carcinogenesis of the pancreas.
Citation Format: Yoko Matsuda, Naotaka Izumiyama, Mutsunori Fujiwara, Naoshi Ishikawa, Junko Aida, Kaiyo Takubo, Toshiyuki Ishiwata, Tomio Arai. Telomere shortening in pancreatic cancer is correlated to KRAS mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3403. doi:10.1158/1538-7445.AM2017-3403