bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3823: Dysregulation of bone morphogenetic protein 2 serves as a candidate molecular marker in human renal cell carcinoma
Authors: Mitsui Yozo , Hirata Hiroshi , Arichi Naoko , Hiraki Miho , Yasumono Hiroaki , Chang Inik , Fukuhara Shinichiro , Yamamura Soichiro , Shahryari Varahram , Deng Guoren , Saini Sharanjot , Majid Shahana , Tanaka Yuichiro , Dahiya Rajvir , Shiina Hiroaki 
Published: August 2015

Abstract
Introduction and Objective
Bone morphogenetic protein-2 (BMP-2) has been shown to function as a tumor suppressor with several different cancers, while its expression level is down-regulated by CpG hypermethylation. We hypothesized that impaired regulation of BMP-2 through epigenetic pathways is associated with the pathogenesis of renal cell carcinoma (RCC).
Methods
To test our hypothesis, CpG methylation of the BMP-2 gene was analyzed using 2 RCC cell lines, and 96 matched RCC and normal renal tissues. We also performed functional analysis using BMP-2 restored RCC cells.
Results
BMP-2 mRNA expression was significantly enhanced in the RCC cells by 5-aza-2′-deoxycitidie treatment. The prevalence of BMP-2 promoter methylation was significantly higher, while BMP-2 mRNA expression was significantly lower in RCC samples as compared to normal kidney samples. Furthermore, a significant correlation was found between BMP-2 promoter methylation and mRNA transcription in the tumors. There was also a significant association of BMP-2 mRNA expression with tumor stage and lymph node involvement, while lower BMP-2 mRNA expression was significantly associated with poor overall survival after a radical nephrectomy. In RCC cells, BMP-2 restoration significantly inhibited cell proliferation, migration, invasion, and colony formation. In addition, BMP-2 overexpression effectively induced p21WAF1/CIP1 and p27KIP1 expression, and cellular apoptosis in RCC cells.
Conclusion
This is the first study to show inactivation of the BMP-2 gene via epigenetic pathways in RCC. Aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be useful as a molecular marker for designing improved diagnostic and therapeutic strategies for RCC.
Citation Format: Yozo Mitsui, Hiroshi Hirata, Naoko Arichi, Miho Hiraki, Hiroaki Yasumono, Inik Chang, Shinichiro Fukuhara, Soichiro Yamamura, Varahram Shahryari, Guoren Deng, Sharanjot Saini, Shahana Majid, Yuichiro Tanaka, Rajvir Dahiya, Hiroaki Shiina. Dysregulation of bone morphogenetic protein 2 serves as a candidate molecular marker in human renal 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 3823. doi:10.1158/1538-7445.AM2015-3823
Abstract 3834: Validation of potential methylation biomarkers in HPV-associated HNSCC
Authors: Chen Kang Mei , Stephen Josena K. , Divine George , Chitale Dhananjay , Ghanem Tamer , Chang Steven , Worsham Maria J. 
Published: August 2015

Abstract
Epidemiological and laboratory evidence indicate the human papilloma virus (HPV) as a causative agent for some squamous head and neck cancer (HNSCC). The biologic significance of HPV as independent risk factor is also underscored by the improved prognosis for patients with HPV positive HNSCC relative to HPV negative HNSCC, due in part to a better therapeutic response to chemoradiotherapy. The mechanism for this improved prognosis remains underexplored.
To assess the potential of HPV specific methylation biomarkers, we evaluated the status of 10 genes (CDH8, CRMP1, HTRE1, ELMO1, MEI1, MSX2, PCDH10, PCDHB11, C14orf162, and PITX2) in a cohort of 18 HPV positive and 14 HPV negative HNSCC using targeted sequencing (Illumina MiSeq). The genes were previously reported as significantly differentially methylated between HPV positive and HPV negative HNSCC using the Infinium HumanMethylation450 BeadChip (Lechner et al., 2013).
In our sample, of the 10 genes, targeted sequencing confirmed significant differential methylation between HPV positive and negative for C14orf162 (p = 0.007), MEI1(p = 0.004), MSX2 (p = 0.002), and PCDHB11(p = 0.002). PCDHB11 and MSX2 were hypermethylated; MEI1 and C14orf162 were hypomethylated, concordant with the Lechner et al., study.
In this independent sample set, confirmation of 4 of the 10 genes as differentially methylated in HPV positive vs HPV negative HNSCC with concordance of methylation direction (hypo- vs hypermethylated), validates their potential for differentiating HPV positive and HPV negative HNSCC. Cadherins are implicated in tumor progression and metastasis and are targets of the Polycomb group (PcG) proteins, which form chromatin-modifying complexes that are essential for embryonic development and stem cell renewal and are commonly deregulated in cancer. Our study further supports cadherin PCDHB11, together with C14orf162, MEI1, and MSX2 as likely biomarkers in HPV-associated HNSCC.
Support: Komen KG110218
Citation Format: Kang Mei Chen, Josena K. Stephen, George Divine, Dhananjay Chitale, Tamer Ghanem, Steven Chang, Maria J. Worsham. Validation of potential methylation biomarkers in HPV-associated HNSCC. [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 3834. doi:10.1158/1538-7445.AM2015-3834
Abstract 3835: DNA methylation levels in mononuclear DNA in breast cancer from the New York site of the BCFR
Authors: Wu Hui-Chen , Wang Qiao , Santella Regina M. , Terry Mary B. 
Published: August 2015

Abstract
Alterations in DNA methylation both at specific loci and overall, have been associated with breast cancer. These alterations have primarily been observed at the tissue level, although emerging studies are evaluating white blood cell (WBC) DNA methylation.
To examine whether DNA methylation change measured prospectively in a family-based cohort are associated with breast cancer risk, we measured methylation levels of two repetitive elements (LINE-1, and Sat2) and three genes in mononuclear cell DNA (BLNK, CUEDC1, and IBSP) previously identified as differentially methylated in breast cancer in a genome-wide association study. After an average of 8 years of followup, we observed 81 invasive incident breast cancers and compared their methylation levels measured with baseline bloods with the remaining 1,508 women not affected with breast cancer in the New York site of the Breast Cancer Family Registry (BCFR). We found that the overall percent methylation in CUEDC1 was statistically significantly higher in breast cancer cases than in controls (78.0% versus 76.8%, respectively, p = 0.02). In a multivariable Cox Proportional Hazards model adjusting for age at blood draw, with each 1 unit increase in CUEDC1 methylation level, the OR for breast cancer increased by 1.07 (95% Confidence Interval (CI) = 1.00-1.14). We did not find the other methylation markers to be related to risk. The area under the curve was 67.6% (95% CI = 61.4% to 73.8%) for the 5 methylation markers and Gail risk score, compared with 63.3% for the Gail score only.
Our finding for CUEDC1 replicates the finding from the Sisters Study supporting that selected markers selected markers of epigenetic changes measured in WBC may be potential biomarkers of breast cancer risk.
Citation Format: Hui-Chen Wu, Qiao Wang, Regina M. Santella, Mary B. Terry. DNA methylation levels in mononuclear DNA in breast cancer from the New York site of the BCFR. [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 3835. doi:10.1158/1538-7445.AM2015-3835
Abstract 3837: Super-enhancers define breast cancer subclasses and identify novel tumor cell vulnerabilities
Authors: Collins Cindy , Chen Mei Wei , Eaton Matthew , Orlando David , McKeown Michael , Fritz Christian , Olson Eric , Guenther Matthew 
Published: August 2015

Abstract
Breast cancer cell state is driven by genomic mutational events, aberrant signaling cascades and transcriptional misregulation. The profound clinical impact of ER-modulatory drugs underscores the importance of understanding and targeting the transcriptional dependencies of breast cancer cells in an effort to create new therapeutics. Recently, large clusters of cis-acting enhancers, termed Super-enhancers, have emerged as dominant transcriptional regulators of oncogenes and other key tumor drivers in cancer cells, indicating that these elements control and maintain breast tumor cell state. Mapping these elements and the genes they control in patient tumors can provide insight into breast cancer classification and identify therapeutic targets.
We have discovered Super-enhancers in breast cancer patient tissue and have characterized their roles in enforcing tumor cell state. We find that Super-enhancers define known clinical subgroups in invasive ductal carcinoma and pinpoint the putative transcriptional drivers of each subgroup. Super-enhancer-associated genes encode both known and novel therapeutic targets including kinases, phosphatases, chromatin regulators and transmembrane proteins, including key drivers such as ERRB2 in HER2+ patient samples, ESR1 in estrogen receptor positive samples, and CCND1 in samples of luminal subtype. shRNA knockdown confirms that Super-enhancer regulated genes are indeed essential for tumor cell survival and that Super-enhancer analysis in primary patient samples can be used to define new subtype specific cancer vulnerabilities.
In sum, we describe the biological and disease relevance of Super-enhancer-associated genes in the context of tumor cell state, genome mutational landscape and drug target discovery.
Citation Format: Cindy Collins, Mei Wei Chen, Matthew Eaton, David Orlando, Michael McKeown, Christian Fritz, Eric Olson, Matthew Guenther. Super-enhancers define breast cancer subclasses and identify novel tumor cell vulnerabilities. [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 3837. doi:10.1158/1538-7445.AM2015-3837
Abstract 3842: Expression analysis of SMYD5 in breast cancer and normal tissues
Authors: Matos Neto João Nunes de , Araujo Maíra de Azevedo Feitosa , Rabello Doralina do Amaral , Motoyama Andrea Barretto , Oliveira Diego Madureira de , Pittella Silva Fabio 
Published: August 2015

Abstract
Lysine methyltransferases are a group of enzymes that carry a SET domain, which catalyzes the addition of methyl groups to specific lysine residues. Several lysine methyltransferases have been described to be involved in human carcinogenesis. The SMYD family of methyltransferases constitutes a group of five genes that encodes proteins bearing a SET and a MYND domain, whose activity have not yet been completely characterized. Although deregulation of SMYD family members has been reported to contribute to cancer progression through several different mechanisms, to date a clear relationship of SMYD5 with breast cancer, the second most frequent cancer worldwide and the most common among women, was not determined. In the present study we investigated the expression profile of SMYD5 in breast tumors and adjacent non-tumor samples, in breast cancer cell lines and in several normal tissues. qPCR revealed SMYD5 mRNA expression level was downregulated in 7 breast cancer cell lines when compared to normal breast tissues. Relative expression of SMYD5 in breast tumors and normal breast samples revealed a significant (p&lt;0.001) reduction of SMYD5 expression in tumors comparing to the non-cancerous breast samples. These findings led us to investigate the role of SMYD5 in cell proliferation. We observed that reduction of SMYD5 expression by shRNA in HEK293 cells induced acceleration in culture growth. Moreover, the generation of MDA-MB-231 tumor sublines expressing varying levels of SMYD5 revealed different proliferative profiles. SMYD5 expression inversely correlated with growth rate in highly proliferative cultures. However, slow proliferating cells (i.e. long doubling time) do not seem to be affected by SMYD5 levels. This observation indicates that specific subgroup of highly proliferative cells may depend on SMYD5 downregulation to exhibit this phenotype. In addition, we found that SMYD5 has a sub-cellular distribution similar to other SMYD family proteins suggesting it may exert enzymatic activity in both cytosolic and nuclear substrates. Taken together, our data indicates a possible role for SMYD5 in modulating breast carcinogenesis through epigenetic alterations, probably acting as tumor suppressor.
Note: This abstract was not presented at the meeting.
Citation Format: João Nunes de Matos Neto, Maíra de Azevedo Feitosa Araujo, Doralina do Amaral Rabello, Andrea Barretto Motoyama, Diego Madureira de Oliveira, Fabio Pittella Silva. Expression analysis of SMYD5 in breast cancer and normal tissues. [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 3842. doi:10.1158/1538-7445.AM2015-3842
Abstract 3843: Nrf2-keap1 axis: uncovers molecular profile in lung carcinoids
Authors: Sparaneo Angelo , la Torre Annamaria , Trombetta Domenico , Di Candia Leonarda , Copetti Massimiliano , Balsamo Teresa , Maiello Evaristo , Graziano Paolo , Fazio Vito M. , Muscarella Lucia A. , Sanchez-Cespedes Montse 
Published: August 2015

Abstract
Introduction. The Keap1/Nrf2 pathway is a master regulator of antioxidants and cellular stress re-sponses implicated in resistance of tumour cells against chemotherapeutic drugs. Recent data suggest that genetic and epigenetic mechanisms may play a pivotal role in the regulation of KEAP1 expression in Non Small Cell Lung Cancer. At present, the data concerning the mechanism of alteration of Nrf2-Keap1 pathway in the Carcinoids of the lung remain almost incomplete.
Materials and methods. Here we report a comprehensive molecular characterization of Keap1/Nrf2 axis in cell lines and 48 tissues from Lung Carcinoid affected patients by integrating data from altera-tions at DNA, transcript and protein levels.
Results. An hypermethylation of the CpGs island located into the P1 promoter region of the KEAP1 was detected in 16 out of the 32 Typical Carcinoids (50%) and 8 out of the 16 Atypical Carcinoids (50%). No somatic mutations were detected both in the kelch-repeats region of the KEAP1 gene and in the Nhe2 domain of NFE2L2 gene, whereas LOH at the KEAP1 locus (19p13.2) was found in more than 50% of cases, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event in lung carcinoids. Decreased of the KEAP1 expression in methylated cancer cells induced greater nuclear accumulation of Nrf2, causing enhanced transcriptional xenobiotic metabolism enzymes.
Conclusions. This is the first study to our knowledge that provides new insights into the mechanism of deregulation of Nrf2/Keap1 detoxification pathway in lung carcinoids. Loss of KEAP1 function leading to constitutive activation of Nrf2-mediated gene expression in cancer suggests that deregulation of the Keap1/Nrf2 system could play a pivotal role in the pathogenesis of carcinoids.
Citation Format: Angelo Sparaneo, Annamaria la Torre, Domenico Trombetta, Leonarda Di Candia, Massimiliano Copetti, Teresa Balsamo, Evaristo Maiello, Paolo Graziano, Vito M. Fazio, Lucia A. Muscarella, Montse Sanchez-Cespedes. Nrf2-keap1 axis: uncovers molecular profile in lung carcinoids. [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 3843. doi:10.1158/1538-7445.AM2015-3843
Abstract 3847: MSI status frequency, MSI-target genes mutation profile and ancestry proportions in Brazilian colorectal carcinoma patients
Authors: Berardinelli Gustavo N. , Scapulatempo-Neto Cristovam , Duraes Ronilson , Peixoto-Guimaraes Denise , Melani Armando , Pereira Rui , Reis Rui 
Published: August 2015

Abstract
Introduction: Colorectal cancer (CRC) is the fourth in incidence and in mortality worldwide for both sexes. There are three pathways in the pathogenesis of CRC: chromosome instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). These pathways are closely related and some tumors may harbor alterations in multiple pathways. The MSI is the less common and is more frequently related with HNPCC Syndrome. In Brazil, CRC incidence is increasing and the frequency of MSI and its biological and clinical impact are largely unexplored. Furthermore, the literature has reported the influence of ancestry factors on the incidence and prognosis in this tumor type. Goals: to assess the frequency of MSI status in Brazil CRC tumors; to analyze the mutation profile of MSI target genes in MSI-positive tumors and to determine the patients ancestry by molecular markers. Materials and Methods: 1013 CRC patients were enrolled in the study. The MSI evaluation was performed using a multiplex PCR comprising 5 markers (NR27, NR21, NR24, BAT25, and BAT26). The MSI-H tumors were also assessed for mutations in a panel of 25 MSI-target genes, and their genetic ancestry will be evaluated using a panel of 46 AIMs (Ancestry-Informative Markers). Results: MSS status was observed in 86.0%, MSI-L in 4.0% and MSI-H in 10.0% of cases. The analysis of 25 MSI-target genes in 101 MSI-H cases showed distinct mutations frequencies, with the highest mutated genes been ATM (83.0%), EGFR (80.0%) and MRE11 (78.0%) and the lowest mutated genes been BLM (3.0%), WISP3 (2.0%) and TRBP2 (1.0%). No alterations were observed in BRCA1, BRCA2, XRCC2, PTEN and XPO5. We showed that the average ancestry proportions for MSS+MSI-L group were 74.1% of European, 12.3% of African, 6.6% of Native Americans, and 7.0% of East Asian, while for MSI-H group were 73.7% of European, 14.3% of African, 6.8% of Native Americans, and 5.2% of East Asian. So, no statistical difference was observed between distinct MSI status groups. Conclusion: The MSI frequencies identified in Brazilian CRC patients are in agreement with the international literature. We identify altered MSI-target genes in MSI-H tumors samples with potential clinical impact. For while, the ancestry proportions not showed an important factor for MSI status in Brazilian CRC patients.
Citation Format: Gustavo N. Berardinelli, Cristovam Scapulatempo-Neto, Ronilson Duraes, Denise Peixoto-Guimaraes, Armando Melani, Rui Pereira, Rui Reis. MSI status frequency, MSI-target genes mutation profile and ancestry proportions in Brazilian colorectal carcinoma patients. [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 3847. doi:10.1158/1538-7445.AM2015-3847
Abstract 3848: Subtype-specific DNA damage dependent and independent functions of damage repair proteins confer chemo-resistance to leukemia
Authors: Salunkhe Sameer , Kaur Ekjot , Ramaswamy Ashwin , Patkar Ketaki , Dutt Shilpee 
Published: August 2015

Abstract
Resistance to chemotherapy is a major challenge in the field of leukemia. Since, cancer cells can acquire resistance to DNA damage based therapy by modulating DNA Damage Repair (DDR) pathways, an in-depth understanding of DDR is important for novel drug discoveries. Hence, to understand relation between DDR and resistance we used doxorubicin resistant sub-line (K562-R) of K562 and Mitoxantrone resistant sub-line (HL60/MX) of HL60 as a model system.
We show that lethal doses of Mitoxantrone to HL60 and HL60/MX do not induce DNA DSBs (double strand breaks) and accordingly there is no activation of Chk2, although there is equal uptake of drug in both, sensitive and resistant cell types. Since Mitoxantrone produce DSBs by targeting TOP2B, we checked the expression of TOPB2 and found significant decrease in the levels of topoisomerase 2 B (TOP2B). Moreover, negative regulator of TOPB2, mir 21-5P is upregulation in untreated HL60/MX explaining the absence of DSBs in HL-60/MX with Mitoxantrone treatment. Surprisingly, although there are no DSBs induced, we find high levels of DNA-PKcs, MRE11 and Rad50 in HL-60/MX. Furthermore, inhibition of DNA-PKcs re-sensitizes HL-60/MX cells to Mitoxantrone, suggesting a DNA damage independent role for DNA-PK in HL-60/MX cells. Recently DNA-PKcs is shown to play key role in fat metabolism. Indeed we find significant differences in the metabolism of HL60 and HL-60/MX where HL-60 cells use glucose but HL-60/MX cells show reduced glucose and glutamine metabolism and an over expression of fatty acid synthase. However link between DNA-PKcs over expression and differential metabolism in these cells still need to be explored. Interestingly, in contrast to HL60 model, Doxorubicin does induce equal DSBs in K562 and K562-R cells. However K562-R cells hyperactivate ATM and Chk2 to repair their DNA and survive. Importantly, we show that K562 start to show elevated activation of ATM and Chk-2 as early as two rounds of drug treatment. Accordingly, ATM inhibition leads to induction of apoptosis in resistant K562 cells.
In conclusion, we show that K562 and HL60 cells use the DNA double strand break repair proteins in DNA damage dependent and independent pathways to acquire resistance to DSB inducing chemo therapeutics. Our data also highlight the importance of considering subtype specific therapeutics in leukemia.
Note: This abstract was not presented at the meeting.
Citation Format: Sameer Salunkhe, Ekjot Kaur, Ashwin Ramaswamy, Ketaki Patkar, Shilpee Dutt. Subtype-specific DNA damage dependent and independent functions of damage repair proteins confer chemo-resistance to leukemia. [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 3848. doi:10.1158/1538-7445.AM2015-3848