bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4352: Identification of ZFP42/REX1 as a regulator of cancer stemness in CD133+ liver cancer stem cells by genome-wide DNA methylation analysis
Authors: Luk Steve Tin-Chi , Tong Man , Ng Kai Yu , Yip Kevin Yuk-Lap , Guan Xin Yuan , Ma Stephanie 
Published: July 2017

Abstract
The existence of a cancer stem cell (CSCs) subset is well established in hepatocellular carcinoma (HCC). This subset can be characterized by its CD133 expression. Since the discovery of this marker, studies have revealed deregulated pathways and epigenetic alterations associated with this subset, but few have focused on changes in DNA methylation. This study aims to fill this research gap by discovering aberrant DNA methylation patterns governing CD133+ CSC-driven HCC. Results from Infinium HumanMethylation450 BeadChip (HuMet450 BeadChip) have led to the discovery of differential methylation patterns between CD133+ liver CSCs and matched CD133- differentiated samples. ZFP42/REX1 is one of the top-ranking differentially methylated candidates. Probes corresponding to its promoter are extensively hypermethylated in the CD133+ samples. To explore the hypothesis that promoter DNA hypermethylation modulates REX1 expression, REX1 mRNA levels were first validated to be down regulated in sorted CD133+ HCC cell lines (n=2) and HCC samples (n=46, p&lt;0.05) by RT-qPCR. Upon 5-AZA treatment, only low-REX1-expressing cells re-expressed REX1. By in silico prediction, a CpG island of interest located in the REX1 promoter region was selected for further investigation. Results of pyrosequencing of this CpG island show that REX1 expression appears to be negatively correlated with the degree of DNA methylation in HCC cell lines (n=3); and that HCC samples (n=13) exhibit a predominantly hypermethylated state compared to the matched non-tumor samples. To add onto the clinical relevance of REX1, two HuMet450 BeadChip datasets of HCC sample cohorts (GSE54503 and GSE60753) were obtained from Gene Expression Omnibus (GEO). In these cohorts, the CpG probes corresponding to the REX1 promoter region are significantly hypermethylated (p&lt;0.01) in HCC samples compared to the adjacent non-tumor tissues. Lentiviral-based approaches were adopted to establish stable REX1 overexpressing and knockdown cells in HCC cell lines. REX1 expression appears to be negatively correlated with the cells’ abilities to migrate, invade, and form foci in vitro; and tumorigenicity in vivo. ChIP-seq has been adopted to study the DNA-binding property of REX1 in HCC cells. These findings suggest that REX1 may play a part in mediating various cancer properties in HCC.
Citation Format: Steve Tin-Chi Luk, Man Tong, Kai Yu Ng, Kevin Yuk-Lap Yip, Xin Yuan Guan, Stephanie Ma. Identification of ZFP42/REX1 as a regulator of cancer stemness in CD133+ liver cancer stem cells by genome-wide DNA methylation analysis [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 4352. doi:10.1158/1538-7445.AM2017-4352
Abstract 4363: Bisulfite DNA sequencing analyses to detect methylation patterns in the p73 gene promoter in prostate cancer cell lines
Authors: Braganca Nicholas E. , Carastro L. Michael , Schabort Johannes J. , Park Jong Y. 
Published: July 2017

Abstract
Transcription is regulated through a variety of different mechanisms. One facet of transcriptional regulation is epigenetics, which is the regulation of gene expression without altering the nucleotide sequence of the genome, but rather reversible modifications, e.g. CpG methylation. The CpG islands in tumor suppressor gene promoters are often hypermethylated, thus down regulating their expression. The p73 gene is a member of the p53 tumor suppressor family of proteins, and like p53, has a bifurcated promoter. The p73 P1 promoter transcribes a full-length mRNA, which then translates into the transcriptionally active p73. The p73 P2 promoter transcribes a truncated mRNA, which translated into transcriptionally inactive ΔNp73. The ΔNp73 product lacks the N-terminal trans-activation domain that TAp73 possesses. This study sought to analyze the extent of DNA methylation in the CpG islands in the p73 P1 promoter of three prostate cancer (PCa) cell lines (LNCaP, PC-3, and DU145), and primary prostate cells. We hypothesized that the p73 P1 promoter would be hypermethylated in prostate cancer cell lines and hypomethylated in primary prostate cells. The methylation status of the p73 P1 promoter in all four prostate cell lines was analyzed by using bisulfite sequencing PCR (BSP). Our analyses revealed that a CpG island in the p73 P1 was hypermethylated in LNCaP, PC-3, and DU145 cells compared to primary prostate cells. Furthermore, among the three PCa cell lines evaluated, the p73 P1 promoter was the most methylated in DU145 cells, and the least methylated in LNCaP cells. The P1 region sequenced contained 28 CpG islands, and among them, only five were methylated in the primary prostate cells (18% methylated), 23 were methylated in LNCaP cells (82% methylated), 26 in PC-3 cells (93% methylated), and 28 in DU145 cells (100% methylated). Furthermore, of the 28 CpG sites, 14 of them were differentially methylated in the primary prostate cell line versus the three PCa cell lines evaluated in this study. These data are consistent with the PCa tumor-derived cell lines (LNCaP, PC-3, and DU145) having hypermethylated CpG sites in the p73 P1 promoter compared to the primary prostate cell line.
Citation Format: Nicholas E. Braganca, L. Michael Carastro, Johannes J. Schabort, Jong Y. Park. Bisulfite DNA sequencing analyses to detect methylation patterns in the p73 gene promoter in prostate cancer cell lines [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 4363. doi:10.1158/1538-7445.AM2017-4363
Abstract 437: Stromal support of pancreatic tumor metabolism
Authors: Lyssiotis Costas A. 
Published: July 2017

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive disease characterized by a prominent desmoplastic stromal reaction and deregulated metabolism. The role of stroma in PDAC biology is complex and has been shown to play critical roles that may differ depending on the biological context. The intense stromal reaction also impacts the vasculature, leading to a highly hypoxic and nutrient poor environment. As such, these tumors must adapt how nutrients are captured and utilized to support their metabolic needs. In this talk, I will describe how stromal-associated pancreatic stellate cells (PSCs) are critical for PDAC metabolism through the secretion of non-essential amino acids (NEAA). Specifically, we uncovered an undescribed role for alanine, which outcompetes glucose and glutamine-derived carbon in PDAC to fuel the tricarboxylic acid (TCA) cycle, and thus NEAA and lipid biosynthesis. This shift in fuel sources decreases the dependence on glucose and serum-derived nutrients, which are limiting in the pancreatic tumor microenvironment. Moreover, we demonstrated that PSC alanine secretion is dependent on PSC autophagy, a process stimulated by the cancer cells. Thus, our results demonstrate a novel metabolic crosstalk between PSCs and cancer cells, with PSC-derived alanine as an alternative carbon source, and highlight a previously unappreciated metabolic network within pancreatic tumors where diverse fuel sources are utilized to promote growth in an austere tumor microenvironment.
Citation Format: Costas A. Lyssiotis. Stromal support of pancreatic tumor metabolism [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 437. doi:10.1158/1538-7445.AM2017-437
Abstract 4370: ASNS and other significant mutations in head and neck squamous cell carcinomas: mutational landscape in a South Asian population
Authors: Rehmani Sadiq , Razzak Safina Abdul , Madhani Sarosh , Azim M Kamran , Ahmed Rashdia , Khan Mumtaz , Ghias Kulsoom 
Published: July 2017

Abstract
Head and neck cancers are the sixth most common cancer type globally and contribute significantly to the burden of disease in South Asia. Specifically in Pakistan, they are the most commonly diagnosed cancer in males and the second most common in females. The increasing burden of head and neck squamous cell carcinoma (HNSCC) in the region along with a unique set of risk factors merited a deeper investigation of the disease at the genomic level. Whole exome sequencing of HPV-negative HNSCC samples and matched normal genomic DNA (n = 7) was performed. Smoking, oral tobacco use and alcohol were identified risk factors in the study cohort. Significant somatic single nucleotide variants (SNVs) were identified and pathway analysis performed to determine most frequently affected signaling pathways. Significant, novel recurrent mutation in ASNS (asparagine synthetase) and driver mutations in previously reported genes, including TP53, PIK3CA, FGFR2, ARID2, MLL3, MYC and ALK, were identified. Using the IntOGen platform, we identified MAP kinase, cell cycle, actin cytoskeleton regulation, PI3K-Akt signaling and other pathways in cancer as among the most commonly affected pathways in all the samples. This data is the first of its kind from the Pakistani population. The results of this study can guide a better mechanistic understanding of HNSCC in the population, ultimately contributing new, rational therapeutic targets for the treatment of the disease.
Citation Format: Sadiq Rehmani, Safina Abdul Razzak, Sarosh Madhani, M Kamran Azim, Rashdia Ahmed, Mumtaz Khan, Kulsoom Ghias. ASNS and other significant mutations in head and neck squamous cell carcinomas: mutational landscape in a South Asian population [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 4370. doi:10.1158/1538-7445.AM2017-4370
Abstract 4382: Genomic events associated with metastasis of colorectal cancer by whole-genome sequencing
Authors: Pan Yi , Tong Joanna , Kwan Johnny , Lo Kwok Wai , Chan Anthony , To Ka Fai 
Published: July 2017

Abstract
Background: The diversity of the genomic landscape in colorectal cancer (CRC) is under active investigation. Concordance in molecular events between primary CRC and metastatic tumors is a subject of debate. Understanding the genetic background of metastatic CRC facilitates personalized therapies that target specific molecular events associated with the tumor.
Methods: We performed whole genome sequencing in matched primary, metastasis and normal tissues from 3 patients with RAS/NRAS/BRAF wild types and microsatellite stable CRC. We implemented an analysis pipeline that integrated the genetic lesions to characterize somatic single nucleotide variations (SNVs), short insertions and deletions (indels), structural variations including fusions and copy number alterations.
Results: Both primary and metastatic tumors showed a predominant mutational signature of C: G →T: A transition. A total of 282 non-silent mutations were identified in 3 pairs of CRC (median 63 per tumor, range 42 to 98). There were 148 (52.5%) variants shared in matched primary and metastatic tumors, 63 (22.3%) were found unique to primary and 71 (25.2%) were unique to the metastases. Only common well known genes (APC and TP53) and TTN mutations were found to be recurrent in the 3 patients. A total of 609 (range 33-171 per tumor) structural variants were discovered with 44.1% concordance between primary and metastasis pairs. We also identified 6 novel candidate fusions shared in primary and metastases and 2 private to the primary tumors. Consistent with the result of previous studies, copy loss at chromosome 17p and 18, and gain at chromosome 5, 8 and 13 were the common events both in the primary and metastatic tumor.
Discussion and conclusions: Our data demonstrated a considerable difference in mutational landscape between primary CRCs and their matching metastatic tumors. The result suggested that the metastasis might originate from a distinct subclone from a heterogeneous primary tumor, or additional gain or loss of function via mutation to permit tumor invasion and spreading is necessary to facilitate metastasis. Each of the two models is complicated by the possibility of tumor heterogeneity within the primary tumor. In conclusion, comprehensive analysis and assessment for the genomic events is a powerful approach to delve deeper into the internal relations and contradictions between primary and paired metastases, helping to identify novel genomic events associated with metastasis of CRC.
Citation Format: Yi Pan, Joanna Tong, Johnny Kwan, Kwok Wai Lo, Anthony Chan, Ka Fai To. Genomic events associated with metastasis of colorectal cancer by whole-genome sequencing [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 4382. doi:10.1158/1538-7445.AM2017-4382
Abstract 4386: Identification of clinically relevant colon cancer genes predictve of improved relapse free survival
Authors: Parsons Marie J. 
Published: July 2017

Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide, affecting over 15,000 individuals in Australia each year. While CRC is often detected at a stage where resection of the primary tumour is possible, approximately 50% will relapse and die from metastatic disease. Prognostication is mainly determined by tumour depth (T), lymph node stage (N) and the extent of cancer spread (M). However, clinical outcomes of patients with the same TNM stage can be heterogeneous. Therefore, there is a need to identify markers to better predict prognosis and stratify patients for treatment regimes.
A panel of 113 candidate CRC genes were identified as significantly mutated in whole genome and whole exome sequencing studies from 361 MSS colon cancers and 63 CRC cell lines. Custom amplicon panels for target enrichment were designed for use with the HaloPlexTM target enrichment system. Sample libraries were prepared for 274 patients with stage II/III CRC using the automated Bravo liquid handling platform followed by next-generation sequencing (NGS) on the Illumina Next-Seq 500.
Analysis of the 113 candidate genes identified 31 genes recurrently mutated above 10 percent in our discovery cohort. We identified 4 genes previously reported as colon cancer genes (APC 68%, TP53 60%, KRAS 30% and PIK3CA 20%), confirming APC, TP53 and KRAS as the most frequently mutated genes in CRC. To identify novel and clinically relevant genes, the 31 genes in our discovery cohort were tested for association with clinical features of CRC. In the discovery cohort, 24/31 genes were significantly associated with right sided CRC, 10/31 with mucinous CRC, 9/31 with stage II CRC and 7/31 with improved relapse free survival (RFS). Of these significantly associated genes, 10/24 genes were validated as significantly associated with right sided colon cancer, 3/9 with stage II and 3/10 with mucinous CRC in the validation cohort. Five of these genes were selected for further investigation as they were significantly associated with improved RFS, together with one or more clinical feature of CRC.
Identification of novel recurrently mutated genes is key to a better understanding of the molecular mechanisms of CRC and development of novel therapeutics.
Citation Format: Marie J. Parsons. Identification of clinically relevant colon cancer genes predictve of improved relapse free survival [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 4386. doi:10.1158/1538-7445.AM2017-4386
Abstract 4389: TSC1/2 mutations define a molecular subset of HCC with aggressive behavior and treatment implication
Authors: Ho Daniel Wai , Chan Lo Kong , Chiu Yung Tuen , Xu Iris Ming , Poon Ronnie , Cheung Tan To , Tang Chung Ngai , Tang Victor , Lo Irene , Lam Polly , Yau Derek , Li Miao Xin , Wong Chun Ming , Ng Irene O. L. 
Published: July 2017

Abstract
We investigated the mutational landscape of mTOR signaling cascade in hepatocellular carcinomas (HCCs) with chronic hepatitis B (HBV) background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyper-activation in hepatocarcinogenesis. We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of TSC1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony formation assay in HCC cell lines and the treatment was further tested using our patient derived tumor xenograft (PDTX) models. Results: We identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n = 18/111) mutations of TSC1 and TSC2 genes in the HCC samples. The spectrum of TSC1/2 mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leading to more aggressive tumor behavior. Mutational disruption of TSC1 and TSC2 was also observed in HCC cell lines and our PDTX models. TSC-mutant cells exhibited reduced colony forming ability upon Rapamycin treatment. With the use of the biologically relevant TSC2-mutant PDTXs, we demonstrated the therapeutic benefits of the hyper-sensitivity towards Rapamycin treatment. Taken together, our findings suggest the significance of previously undocumented mutation-dependent mTOR hyper-activation and frequent TSC1/2 mutations in HBV-associated HCCs. They define a molecular subset of HCC having genetic aberrations in mTOR signaling, with potential significance of effective specific drug therapy.
Citation Format: Daniel Wai Ho, Lo Kong Chan, Yung Tuen Chiu, Iris Ming Xu, Ronnie Poon, Tan To Cheung, Chung Ngai Tang, Victor Tang, Irene Lo, Polly Lam, Derek Yau, Miao Xin Li, Chun Ming Wong, Irene O. L. Ng. TSC1/2 mutations define a molecular subset of HCC with aggressive behavior and treatment implication [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 4389. doi:10.1158/1538-7445.AM2017-4389
Abstract 4401: Role of estrogen signaling in colon microenvironment during obesity
Authors: Archer Amena , Pettersson Linnea , González-Granillo Marcela , Savva Christina , Korach-André Marion , Williams Cecilia 
Published: July 2017

Abstract
Recent epidemiological studies highlight the strong association between high body mass index (BMI) and enhanced risk of colon cancer. This association appears stronger in men than in women, indicating a possible protective role of estrogens in this context. The biological action of the estrogens is mediated by specific transcription factors, the estrogen receptors (ERs). ERβ is the main ER in the intestine; and it is expressed in both epithelial cells and immune cells. Anti-inflammatory and anti-tumorigenic effects of ERβ in colitis-associated neoplasia have been demonstrated. Several rodent models for obesity show an impaired intestinal epithelial barrier function and an increase of pro-inflammatory markers in the colon. Moreover, in murine colitis models, high fat diet (HFD) exacerbates colonic inflammation. However, the specific molecular mechanisms linking obesity to increased colon cancer development, where estrogen signaling may be involved, is not clear.
We hypothesize that ERβ-selective agonists can oppose the HFD-mediated inflammatory pro-tumorigenic colonic signalling in a gender-specific manner during obesity, and thereby protect against colorectal cancer. Our study is focused on the initiation of colon inflammation during obesity and aims to investigate the impact of ERβ activation in this context. To address this question, male and female mice were fed a HFD for 26 weeks and treated with a ERβ-selective agonist for 3 weeks prior sacrifice. Stool pellets were regularly collected. Animals were sacrificed; colon samples and caecal contents were collected for further analysis. We show that the expression pattern of inflammatory genes in colon is modified by the ERβ-selective agonist in HFD fed mice. Moreover the ERβ-selective agonist appears to induce gender-specific changes of the microbiota of HFD-fed mice. Our results show that an ERβ-selective agonist can modulate the colon microenvironment during obesity in mice and will provide a better comprehension of the molecular mechanisms leading to obesity-associated colonic inflammation.
Citation Format: Amena Archer, Linnea Pettersson, Marcela González-Granillo, Christina Savva, Marion Korach-André, Cecilia Williams. Role of estrogen signaling in colon microenvironment during obesity [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 4401. doi:10.1158/1538-7445.AM2017-4401
Abstract 4402: CHTM1, a novel protein linked to cellular metabolism and human malignancy
Authors: Babbar Mansi , Huang Ying , Sheikh M Saeed 
Published: July 2017

Abstract
Several lines of emerging evidence indicate that alterations in metabolism are linked to pathogenesis of human malignancies. However, more studies are needed to completely understand the link between tumorigenesis and metabolism. In this context, we have characterized a novel protein named CHTM1 (Coiled-coil Helix Tumor and Metabolism 1) that appears to be associated with cancer and cellular metabolism. Per our findings, CHTM1 was present in cytosol as well as mitochondria. CHTM1 knockdown in human cancer cell lines caused oxidative stress, and decrease in cellular oxygen consumption and mitochondrial ATP levels, suggesting mitochondrial dysfunction. In view of the importance of mitochondria to nutrient stress, the effect of CHTM1 deficiency on human cancer cells in glucose-deprived conditions was also analyzed. The results indicated that CHTM1-deficient cells became more sensitive to glucose deprivation and exhibited altered cellular metabolism involving down regulation of PKC-CREB-PGC1 alpha signaling events. CHTM1 expression was also found to be increased in patient samples representing breast, colon and lung cancers when compared to their respective matching normal tissues. Based on our findings, we propose CHTM1 to be a valuable tumor marker that can also be developed as a target for novel therapeutics particularly those that exploit cellular metabolism to mediate their effects.
Citation Format: Mansi Babbar, Ying Huang, M Saeed Sheikh. CHTM1, a novel protein linked to cellular metabolism and human malignancy [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 4402. doi:10.1158/1538-7445.AM2017-4402