bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-151: Methylation-mediated silencing of TIMP-3 facilitates oral cancer metastasis by modulating binding of SP1 transcription factor
Authors: Yang Shun-Fa , Su Chun-Wen , Lin Chiao-Wen 
Published: August 2015

Abstract
Tissue inhibitor of metalloproteinase (TIMP)-3, a member of the TIMP family, is the only substance that can bind with the ECM and its main role is regulating the cell cycle and cancer cell progression. However, little is known about whether abnormal expression and promoter methylation of TIMP-3 facilitates oral cancer metastasis. In this study, DNA methylation levels of the TIMP-3 CpG islands were assessed using bisulfite DNA sequencing and methylation-specific PCR. The results shown that expression of TIMP-3 is decreased in most oral cancer tissues compared with adjacent normal tissues (p&lt;0.001). DNA methylation analysis showed a hypermethylation of TIMP-3 gene in oral cancer cell lines and in oral cancer tumors. Furthermore, suppression of TIMP-3 transcription by DNA methylation involves inhibition of transcription factor SP1 binding to the TIMP-3 promoter. Functional analyses revealed that the stable overexpression of TIMP-3 reduced the migration ability in oral cancer cells (p&lt;0.001). Moreover, the expression levels of the epithelial markers E-cadherin were increased, while the expression levels of the mesenchymal markers vimentin and fibronectin were decreased in cells overexpressing TIMP-3. In conclusion, these results suggest that suppression of TIMP-3 by DNA methylation contributes to oral cancer metastasis.
Citation Format: Shun-Fa Yang, Chun-Wen Su, Chiao-Wen Lin. Methylation-mediated silencing of TIMP-3 facilitates oral cancer metastasis by modulating binding of SP1 transcription factor. [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 LB-151. doi:10.1158/1538-7445.AM2015-LB-151
Abstract LB-163: Pan-cancer analysis of the causes and consequences of Intra-tumor heterogeneity
Authors: Andor Noemi , Graham Trevor A. , Aktipis Athena C. , Petritsch Claudia , Ji Hanlee P. , Maley Carlo C. 
Published: August 2015

Abstract
Tumors are typically mosaics of mutant clones that have evolved from a common ancestral cell. This intra-tumor heterogeneity (ITH) is thought to drive both neoplastic progression and acquired therapeutic resistance. Availability of just one sample per tumor and moderate sequencing depth have limited systematic analysis of ITH during previous TCGA pan-cancer analyses, confining the study of ITH to a small numbers of tumor samples and cancer types. The molecular and histopathological causes of ITH and its prognostic significance have thus far remained uncertain.
To overcome these limitations, we used an analysis method called EXPANDS that estimates the proportion of cells harboring specific mutations from exome sequencing data, as well as other methods that quantify ITH. We extrapolate the number of genetically diverse clonal subpopulations in 1,165 primary tumors among 12 different cancer types from TCGA and investigate mechanisms underpinning ITH as well as the correlation of ITH and genomic instability with prognosis. Lastly we validate the prognostic significance of genomic instability in an independent, high-density SNP-array dataset consisting of 2010 tumor samples, across seven additional cancer types.
We found evidence of ITH in the vast majority of tumors. Mutations in driver genes tended to have a characteristic clone size, suggesting differential fitness effects of those mutations. The detection of a mutation in a driver gene that typically appears in a small clone was a predictor of poor survival. Driver gene mutations, tumor microenvironment composition and prevalence of copy number gains were significantly associated with increased ITH. In general, the prevalence of copy number alterations was a universal biomarker of prognosis: tumors with intermediate copy number burden (50 to 75% of the genome affected by copy number alterations) progressed faster than tumors with higher copy number burden, independent of cancer type. Chemo-radiation therapy administration was more efficient in decelerating tumor progression among patients with intermediate copy number burden than among patients with low or high copy number burden. These results were validated and confirmed in the independent SNP-array dataset.
This study suggests a tradeoff exists between the costs and benefits of genomic instability that impacts both the evolvability and fitness of the tumor cell population. In the future, this tradeoff might be exploited to improve survival.
Citation Format: Noemi Andor, Trevor A. Graham, Athena C. Aktipis, Claudia Petritsch, Hanlee P. Ji, Carlo C. Maley. Pan-cancer analysis of the causes and consequences of Intra-tumor heterogeneity. [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 LB-163. doi:10.1158/1538-7445.AM2015-LB-163
Abstract LB-170: Single cell sequencing identifies clonal stasis and punctuated copy number evolution in triple-negative breast cancer patients
Authors: Gao Ruli , Davis Alexander , Sei Emi , Shi Xiuqing , Unruh Anna , Waters Jill , Zhang Amy (Hong) , Meric-Bernstam Funda , Navin Nicholas 
Published: August 2015

Abstract
Intratumor heterogeneity is widely reported in many human tumors including breast cancer. However most studies to date have been limited to genomic analysis of bulk tumor tissues and cytogenetic analysis. Here, we applied single cell copy number profiling to delineate the clonal substructure of triple-negative (ER-, PR-, Her2-) breast cancer (TNBC). We applied Single Nucleus Sequencing (SNS) to profile genomic copy number in 1000 single cells from 11 TNBC patients. Our data show that copy number profiles within the tumor are highly stable, belonging to a few (N = 1-3) major clonal subpopulations that share similar amplifications and deletions,. In addition to the clonal cells, we also identified diverse copy number profiles that belong to two classifications: 1) replicating cells, or 2) apoptotic cells. We also find evidence of rare diploid cells that harbor non-clonal amplification and deletions and may play an important role in aneuploidy initiation. Our data suggests a model of punctuated genome evolution and clonal stasis, in which aneuploidy occurs early in tumor evolution, followed by one or more stable clonal expansion to form the tumor mass. These data challenge the paradigm of gradual copy number evolution and extensive copy number diversity in triple-negative breast cancer, and suggest that that amplifications and deletions are ideal markers for personalized cancer therapy.
Citation Format: Ruli Gao, Alexander Davis, Emi Sei, Xiuqing Shi, Anna Unruh, Jill Waters, Amy (Hong) Zhang, Funda Meric-Bernstam, Nicholas Navin. Single cell sequencing identifies clonal stasis and punctuated copy number evolution in triple-negative breast cancer 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 LB-170. doi:10.1158/1538-7445.AM2015-LB-170
Abstract LB-171: Collaborating mutations in gastrointestinal stromal tumor
Authors: Waterfall Joshua , Killian J. Keith , Zhu Yuelin Jack , Lau C. Christopher , Miettinen Markku , Helman Lee J. , Meltzer Paul S. 
Published: August 2015

Abstract
Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the gastrointestinal tract, is driven most commonly by activating mutations in the receptor tyrosine kinases KIT or PDGFRA. Alternatively, inactivating mutations of genes for the succinate dehydrogenase complex (SDH) constitute a distinct oncogenic mechanism in GIST. Using integrated genomic analyses we have recently reported that SDH deficiency in GIST may also arise from epigenomic inactivation of SDHC, reflected by coupled DNA methylation and expression silencing (1). SDHC epimutation is particularly frequent in, though not restricted to, patients with the cancer predisposition syndrome Carney Triad. It is well established that these primary driver mechanisms correlate with unique clinical, molecular, and epidemiological profiles. In order to identify collaborating oncogenic pathways associated with specific GIST subtypes we have extended our integrated genomic profiling of over 70 tumors enriched for SDH deficient cases. The primary focus is sequencing a panel of 200 cancer related genes for both somatic and inherited variants. We also include RNA expression arrays, DNA methylation arrays, and SNP arrays in this analysis. We have identified mutations in several known cancer associated genes including PTEN, KRAS, ARID1A, and TP53. In conclusion, collaborating mutations and deregulated pathways are identifiable in GIST and can increase our understanding of the underlying cancer biology as well as suggesting treatment possibilities for this malignancy. We acknowledge the contributions of the NIH Wild-Type GIST clinic investigators to this project.
References
1. Killian JK, Miettinen M, Walker RL, Wang Y, Zhu YJ, Waterfall JJ, et al. Recurrent epimutation of SDHC in gastrointestinal stromal tumors. Sci Transl Med. 2014;6:268ra177.
Citation Format: Joshua Waterfall, J. Keith Killian, Yuelin Jack Zhu, C. Christopher Lau, Markku Miettinen, Lee J. Helman, Paul S. Meltzer. Collaborating mutations in gastrointestinal stromal tumor. [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 LB-171. doi:10.1158/1538-7445.AM2015-LB-171
Abstract LB-172: Novel candidate oncogenic drivers in pineoblastoma
Authors: Snuderl Matija , Kannan Kasthuri , Aminova Olga , Dolgalev Igor , Heguy Adriana , Faustin Arline , Zagzag David , Gardner Sharon L. , Allen Jeffrey C. , Wisoff Jeffrey H. , Capper David , Hovestadt Volker , Ahsan Sama , Eberhart Charles , Pfister Stefan M. , Jones David T. w. , Karajannis Matthias A. 
Published: August 2015

Abstract
INTRODUCTION: Pineoblastoma (PB) is one of the rarest and most aggressive brain tumors of childhood. PB is considered a “primitive neuroectodermal tumor” (PNET) based on histology, and commonly treated using treatment protocols developed for medulloblastoma; however the survival remains poor. A subset of PBs may occur in the setting of germline mutations involving DICER1 or RB1, but no next-generation sequencing studies have been published on PB to date, and the genetic drivers of sporadic PB remain unknown. METHODS: 21 tumor samples with a histological diagnosis of PB (including recurrent/metastatic samples) from 15 patients were included in this study. Matching germline DNA was available from 2 patients. We performed genome-wide methylation array profiling (Illumina Infinium 450k) on all samples, as well as whole-genome (for samples with matching germline DNA) or whole-exome sequence analysis. Fluorescence in situ hybridization (FISH) and digital droplet PCR (ddPCR) was performed to confirm select focal somatic gains.
RESULTS: 14/18 samples from 9/13 patients analyzed by 450k profiling had a methylation signature similar to previously profiled PBs from a reference cohort. Samples from 4 patients were found to be more consistent with a diagnosis of embryonal tumor with multilayered rosettes (ETMR) - like tumor (non 19q amplified), papillary tumor of the pineal region, or pineal parenchymal tumor of intermediate differentiation, respectively. No mutations in DICER1 or RB1 were found. Homozygous deletions in DROSHA were found in tumors from 3 PB patients. In addition, we identified novel recurrent somatic gains involving chromosomal region 1q21 that were confirmed by FISH and ddPCR in 4/5 PB patients.
CONCLUSION: Our studies revealed multiple candidate drivers of oncogenesis in PB. We identified novel homozygous deletions in DROSHA, a nuclease involved in microRNA processing. We also identified novel, highly recurrent somatic focal gains involving chromosomal region 1q21, which has been linked to brain growth, autism and schizophrenia, but not previously associated with cancer.
Citation Format: Matija Snuderl, Kasthuri Kannan, Olga Aminova, Igor Dolgalev, Adriana Heguy, Arline Faustin, David Zagzag, Sharon L. Gardner, Jeffrey C. Allen, Jeffrey H. Wisoff, David Capper, Volker Hovestadt, Sama Ahsan, Charles Eberhart, Stefan M. Pfister, David T. w. Jones, Matthias A. Karajannis. Novel candidate oncogenic drivers in pineoblastoma. [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 LB-172. doi:10.1158/1538-7445.AM2015-LB-172
Abstract LB-191: Association of anti-estrogen therapy in breast cancer patients and subsequent risk of rheumatoid arthritis: An electronic health record study
Authors: Breitenstein Matthew K. , Ho Ming-Fen , Weinshilboum Richard M. , Cerhan James R. , Pathak Jyotishman , Bongartz Tim , Wang Liewei , Ingle James N. 
Published: August 2015

Abstract
Background: The use of anti-estrogen (AE) therapies (selective estrogen receptor modulators [SERMs], aromatase inhibitors [AIs]) in breast cancer (BC) patients was recently associated with risk of developing rheumatoid arthritis (RA) (J Rheum 2015;42:55-9). We attempted to replicate and extend these results using electronic health record (EHR) enhanced cancer registry data that assessed specific AE therapies and also accounted for potential confounding by age, smoking status, and chemotherapy use.
Methods: Using cancer registry and EHR data, we identified a cohort of BC patients who were newly diagnosed and treated at Mayo Clinic Rochester from 1998-2011 and had no previous diagnosis of RA. Smoking status at diagnosis, BC treatments and RA at diagnosis and during follow-up were identified using validated EHR-based algorithms. Hazard ratios (HRs) and 95% confidence intervals (CI) from a multivariate Cox model were used to estimate the association of AE use with risk of RA, controlling for age, smoking status at BC diagnosis, and BC chemotherapy use.
Results: The analytic cohort of 9,244 newly diagnosed BC patients treated and followed at Mayo Clinic had a median age at diagnosis of 59 years (range 18-97); 32% were smokers; and 29% were treated with chemotherapy. During a median follow-up of 49 months (range 1-191), 19 patients developed RA. Compared to BC patients not receiving any AE therapy, those receiving AI monotherapy, but not SERM monotherapy or both SERMs and AIs, were at significantly increased risk of developing RA (Table).
AE Therapy# of RA Cases / # patientsHR* (95% CI)P-valueNo AE therapy6/4,0711.00 (reference)SERMs only5/2,5371.20 (0.36 - 3.95)0.77AIs only5/7126.37 (1.77 - 22.92)0.005SERMs then AIs3/1,8750.90AI then SERMs0/490.91 (0.21 - 3.86)*Adjusted for age, smoking status and use of chemotherapy
Conclusions: Our findings indicate that the use of AIs for BC therapy, but not SERMs or SERMs followed by AIs, is associated with increased risk for development of RA, when controlling for smoking status and use of chemotherapy. While needing replication, these findings suggest a specific role for AIs in RA development and suggest pathways that could be targeted to prevent this potential treatment complication.
Citation Format: Matthew K. Breitenstein, Ming-Fen Ho, Richard M. Weinshilboum, James R. Cerhan, Jyotishman Pathak, Tim Bongartz, Liewei Wang, James N. Ingle. Association of anti-estrogen therapy in breast cancer patients and subsequent risk of rheumatoid arthritis: An electronic health record study. [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 LB-191. doi:10.1158/1538-7445.AM2015-LB-191
Abstract LB-204: Reprogramming inflammatory monocytes to mediate anti-tumor activity in pancreatic carcinoma
Authors: Long Kristen B. , Gladney Whitney L. , Tooker Graham M. , Beatty Gregory L. 
Published: August 2015

Abstract
In cancer, increased mobilization of inflammatory monocytes from the bone marrow into the peripheral blood correlates inversely with patient survival. Peripheral blood inflammatory monocytes, which express CCR2, are recruited to tumor tissue by the chemokine CCL2 where they then differentiate into macrophages and support tumor development, growth, and metastasis. While neutralization of CCL2 can block inflammatory monocyte recruitment and inhibit metastasis, this approach has recently been shown to be at risk for lethal outcomes if therapy is interrupted. An alternative approach to inhibiting inflammatory monocyte recruitment to tumors is to reprogram monocytes with anti-tumor activity. Using the KrasG12D/+; Trp53R172H/+; Pdx-1 Cre (KPC) genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC), we report that systemic immune activation induced with an agonist CD40 monoclonal antibody can redirect Gr-1+ inflammatory monocytes to infiltrate the tumor microenvironment and degrade tumor-associated fibrosis leading to tumor regression. Extra-tumoral macrophages were found to be necessary for mobilization of inflammatory monocytes from the bone marrow into the peripheral blood. In addition, systemic IFN-γ released in response to anti-CD40 therapy was necessary for reprogramming inflammatory monocytes with anti-tumor activity. Inflammatory monocytes responding to IFN-γ displayed a distinct matrix metalloproteinase gene expression profile necessary for selective degradation of extracellular matrix proteins, including type I collagen and fibronectin, which define fibrosis in PDAC. Therefore, although inflammatory monocytes are commonly associated with pro-tumor activity, our findings demonstrate that they can also be reprogrammed with potent anti-tumor properties.
Citation Format: Kristen B. Long, Whitney L. Gladney, Graham M. Tooker, Gregory L. Beatty. Reprogramming inflammatory monocytes to mediate anti-tumor activity in pancreatic 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 LB-204. doi:10.1158/1538-7445.AM2015-LB-204
Abstract LB-214: DNAJB1-PRKACA chimera increases Aurora kinase A expression in fibrolamellar hepatocellular carcinoma
Authors: Lim Irene Isabel P. , Greene-Colozzi Emily A. , Murphy Jennifer M. , Heaton Todd E. , Simon Sanford M. , LaQuaglia Michael P. 
Published: August 2015

Abstract
Purpose: Treatment of fibrolamellar hepatocellular carcinoma (FL-HCC), a rare liver cancer affecting the pediatric and adolescent population, is limited to surgical resection with no agents or therapeutic modalities available for unresectable disease. There has been recent interest in using Aurora kinase A (AURKA) inhibitors, with a clinical trial evaluating its efficacy in FL-HCC pending. Previously, we described a consistent single deletion of approximately 400 kB in chromosome 19 that results in a chimera between the heat shock protein DNAJB1 and the catalytic subunit of protein kinase A, PRKACA, in all FL-HCC tumor tissue studied. Furthermore, comparative ribonucleic acid sequence analysis has demonstrated that expression of AURKA, a regulator of cytokinesis and mitosis, is increased in FL-HCC tumor tissue compared with adjacent normal tissue. We hypothesize that the DNAJB1-PRKACA chimera is responsible for changes in AURKA expression in FL-HCC.
Methods: The DNAJB1-PRKACA chimera was cloned into a lentiviral vector with a fluorescent reporter. Two stable cell lines (HeLa and a hepatocyte cell line, Huh-7) were transduced with a lentivirus containing either an empty multicloning site (control) or the DNAJB1-PRKACA chimera. Transduction was confirmed by the presence of a positive epifluorescent signal and immunoblots showing expression of the chimeric protein. Microarray data were evaluated for changes in AURKA expression while immunoblots were analyzed for the presence of AURKA in all transduced cells.
Results: Microarray analysis showed an increase in AURKA transcripts in cells stably expressing the DNAJB1-PRKACA chimera. Compared to cells transduced with the control lentivirus, HeLa and Huh-7 cells transduced with the DNAJB1-PRKACA chimera demonstrated an increase in AURKA on immunoblots. Levels of a loading control, actin, were equivalent, indicating equal levels of protein examined between samples.
Conclusion: Expression of the DNAJB1-PRKACA chimera results in an increase in AURKA. Upregulation of AURKA, in turn, may be responsible for subsequent tumor formation in FL-HCC. This finding further supports the DNAJB1-PRKACA chimera's role in the pathogenesis of FL-HCC and provides a potential therapeutic target for a disease that has no effective treatment besides surgery.
Citation Format: Irene Isabel P. Lim, Emily A. Greene-Colozzi, Jennifer M. Murphy, Todd E. Heaton, Sanford M. Simon, Michael P. LaQuaglia. DNAJB1-PRKACA chimera increases Aurora kinase A expression in fibrolamellar hepatocellular 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 LB-214. doi:10.1158/1538-7445.AM2015-LB-214
Abstract LB-217: PD-1 suppresses antibody responses to Tn+ tumors
Authors: Leyva Marcela A. , Haas Karen M. 
Published: August 2015

Abstract
Cancer cells often have aberrant glycosylation of surface molecules leading to glycan antigens that are not typically found on normal cells. These antigens are referred to as tumor associated carbohydrate antigens (TACAs) and are a promising target for anti-cancer vaccines. One such TACA is the Thomsen-nouvelle (Tn) antigen, which is expressed by up to 90% of adenocarcinomas. The mechanisms regulating the B cell response to Tn and other TACAs are not well understood. This knowledge is essential for the development of vaccines to elicit protective immune responses to tumors bearing TACAs.
PD-1 (programmed cell death 1) is a member of the B7:CD28 superfamily of receptors found on antigen-activated B and T cells. It negatively regulates antigen receptor signaling and thereby limits adaptive immune responses, including the anti-tumor T cell response. However, virtually nothing is known about the role of PD-1 in regulating B cell responses to tumors. In this study, we tested the hypothesis that PD-1 suppresses B cell production of Tn-specific antibodies and thereby suppresses protective humoral immunity against Tn+ tumors. Our results show that PD-1−/− mice immunized with a Tn-bearing mucin (desialyated bovine submaxillary mucin) have increased Tn+ tumor-reactive IgM and IgG antibodies, relative to wild type mice. PD-1−/− mice immunized with the Tn+ mucin had significantly increased survival relative to wild type mice following challenge with a Tn+ bearing mammary tumor (TA3-Ha). Survival in PD-1−/− mice was dependent on the presence of B cells. Therefore, our results show that PD-1 plays a critical role in suppressing the protective anti-tumor B cell response elicited by Tn-bearing antigen immunization.
This work was supported by NIH/NCI F31 CA183567-01 fellowship to M.A.L. and an American Cancer Society Research Scholar Grant (RSG-12-170-01-LIB) to K.M.H.
Citation Format: Marcela A. Leyva, Karen M. Haas. PD-1 suppresses antibody responses to Tn+ tumors. [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 LB-217. doi:10.1158/1538-7445.AM2015-LB-217