bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2567: Characterizing histologic subtypes in lung cancer using principal component analysis
Authors: Byun Jinyoung , Han Younghun , Amos Christopher I. 
Published: July 2016

Abstract
Lung cancer is the leading cause of cancer death in the United States and worldwide. The two major forms of lung cancer are small-cell lung carcinoma (SCLC) and non-SCLC (NSCLC). NSCLC is divided into three major histologic subtypes: Squamous-cell carcinoma, adenocarcinoma, and large-cell. Histological subtypes of cancers vary with respect to the genes that shows altered regulation, compared to normal bronchioepithelial cells. Lung cancer histologic diagnosis is clinically relevant because there are histology-specific treatment indications and contradictions.
Principal component analysis (PCA) is one of the useful statistical tools for analyzing multivariate data and recently high-dimensional data in genetics and genomics. We demonstrated the classification between two major subtypes of lung cancer: 488 squamous cell carcinoma and 788 adenocarcinoma cases. We selected the top 20k significant SNPs using logistic regression and then conducted PCA as the unsupervised approach.
We observed a distinct pattern between two major subtypes of NSCLC in genome-wide association study (GWAS). There were several publications to classify the subtypes of histology in lung cancer using gene expression data. This enables to understand the patterns for other subtypes of lung cancer in GWAS.
Citation Format: Jinyoung Byun, Younghun Han, Christopher I. Amos. Characterizing histologic subtypes in lung cancer using principal component analysis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2567.
Abstract 2574: Outcomes of contralateral prophylactic mastectomy in relation to familial history: a decision analysis
Authors: Davies Kalatu R. , Brewster Abenaa , Bedrosian Isabelle , Parker Patricia , Crosby Melissa A. , Peterson Susan K. , Shen Yu , Volk Robert , Cantor Scott B. 
Published: July 2016

Abstract
Purpose
Family history of breast cancer is associated with an increased risk of contralateral breast cancer (CBC) even in the absence of mutations in the breast cancer susceptibility genes BRCA1/2. We compared quality-adjusted survival outcomes after contralateral prophylactic mastectomy (CPM) with surveillance only (no CPM) among women with breast cancer in relation to degree of family history.
Methods
We created a microsimulation model for women with a first-degree, second-degree and no family history treated for a stage I, II, or III estrogen receptor (ER)-positive or -negative breast cancer at the ages of 40, 50, 60, and 70 years. The model incorporated a 10-year post-treatment period for risk of developing CBC and/or dying of the primary cancer or CBC. For each patient profile, we used 100,000 microsimulation trials to estimate the quality-adjusted life expectancy for two clinical strategies: CPM and no CPM.
Results
CPM had a minimal improvement on quality-adjusted life expectancy among women age 50 to 60 with no or a unilateral first or second-degree family history (range -.06 to 0.31) and was unfavorable for the majority of women age 70 with stage III breast cancer regardless of degree of family history (range -.08 to -.02). Sensitivity analysis showed the highest predicted benefit of CPM with 95% risk reduction was 0.57 QALY for a 40-year-old woman with stage I breast cancer who had a first-degree relative with bilateral breast cancer.
Conclusion
Women age 40 years with stage I breast cancer and a first-degree relative with bilateral breast cancer have a QALY benefit from CPM similar to that reported for BRCA1/2 mutation carriers. For the majority of women, having a family history does not improve the minimal effect of CPM on quality-adjusted life expectancy.
Citation Format: Kalatu R. Davies, Abenaa Brewster, Isabelle Bedrosian, Patricia Parker, Melissa A. Crosby, Susan K. Peterson, Yu Shen, Robert Volk, Scott B. Cantor. Outcomes of contralateral prophylactic mastectomy in relation to familial history: a decision analysis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2574.
Abstract 2618: Oncogenic mutant KRAS modulates CREB activation through MEK-ERK and AKT signaling in pancreatic cancer
Authors: Castellanos Jason , Srinivasan Supriya , Honnenahally Kumar , Shi Chanjuan , VanSaun Michael , Robbins David , Merchant Nipun , Nagathihalli Nagaraj 
Published: July 2016

Abstract
Introduction: Cyclic AMP (cAMP) response element binding (CREB) overexpression in pancreatic ductal adenocarcinoma (PDAC) is associated with poor outcome, however, the mechanism(s) driving CREB overexpression in PDAC are not fully understood. We investigated the association of CREB activation with oncogenic KRAS, MEK-ERK and AKT signaling pathways.
Experimental procedure: Mouse lines derived from the Ptf1aCre/+; LSL-KrasG12D/+ (K518), Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT), LSL-KrasG12D/+;Pdx1Cre/+ (PanIN) and LSL-KrasG12D/+; Trp53R172H/+;Pdx1Cre/+ (PDA) mouse models of PDAC, human immortalized pancreatic ductal epithelial lines (HPDE6-E6E7 or H6c7, HPNE E6/E7 and HPNE E6/E7/KRAS) were immunoblotted for phospho-CREB (pCREB) and total CREB expression. KRAS mutant PDAC cell lines and CREB shRNA flank xenografts (PKT GEMM and nude mice) were treated with CREB (ICG-001), MEK (AZD6244) and AKT (MK-2206) inhibitors. The effects on downstream signaling targets were interrogated with cell cycle, apoptosis, survival and anchorage-independent growth analysis. Human CREB shRNA cells were treated with AZD6244 and MK-2206 to confirm the molecular mechanism of the CREB inhibition together with MEK and AKT.
Results: The expression of pCREB was higher in cells with KRAS mutation. MEK inhibition resulted in activation of AKT, while combined inhibition of CREB and MEK prevented AKT reactivation. Treatment with the combination of MEK and CREB inhibitors significantly decreased tumorigenic potential and increased cell apoptosis. Combined MEK, AKT and CREB inhibition synergistically enhanced these effects further, more so in KRAS mutant cell lines. To explore the relationship of CREB, MEK and AKT signaling in vivo, PKT mice were treated with their respective inhibitors individually and in combination. Either CREB/MEK or CREB/AKT two drug combinations significantly extended the median survival compared with individual agents. Lysates from MEK and AKT inhibited tumors showed decreased phosphorylation of CREB, confirming that CREB is activated through both, MEK and AKT signaling in vivo.
Conclusions: Our study demonstrates that oncogenic KRAS activation enhances the expression of CREB through MEK and AKT signaling. CREB inhibition results in increased sensitivity to MEK and AKT targeted therapy in KRAS mutant PDACs.
Citation Format: Jason Castellanos, Supriya Srinivasan, Kumar Honnenahally, Chanjuan Shi, Michael VanSaun, David Robbins, Nipun Merchant, Nagaraj Nagathihalli. Oncogenic mutant KRAS modulates CREB activation through MEK-ERK and AKT signaling in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2618.
Abstract 2626A: A lignan compound arctigenin inhibits prostate tumor growth in vitro and in vivo
Authors: Wang Piwen , Henning Susanne M. , Vadgama Jaydutt V. 
Published: July 2016

Abstract
Arctigenin is a novel anti-inflammatory lignan derived mainly from the seeds of Arctium lappa, an herb widely used in traditional Chinese medicine to treat inflammation related diseases such as cough, cold and swelling of throat. The present study was designed to investigate whether arctigenin is a potent inhibitor of prostate cancer using both in vitro and xenograft mouse models. The treatments with arctigenin at lower doses (&lt; 2μM) for 48h dose-dependently inhibited the proliferation of two androgen-sensitive prostate cancer cell lines, LNCaP and LAPC-4, by 40-50% compared to control. There was no cytotoxicity observed in normal prostate epithelial PrEC cells with arctigenin doses up to 10μM. An intervention study was then conducted in severe combined immunodeficiency (SCID) mice to confirm the tumor-inhibitory effect of arctigenin in vivo. Male SCID mice (n = 10 per group) were inoculated with 5×10⁁5 LAPC-4 cells subcutaneously. One week later when tumors were palpable the intervention started. Mice were administered with arctigenin at 50mg/kg (LD) or 100mg/kg (HD) or vehicle control daily for 6 weeks by oral gavage. After 4 weeks of intervention the tumor growth was significantly inhibited by both of the arctigenin doses. After 6 weeks of intervention, the tumor volumes were reduced by 48% (LD arctigenin) and 67% (HD arctigenin) compared to control. There was no significant difference in food or water consumption or body weight among groups. An ELISA assay of growth factors demonstrates that arctigenin treatments significantly decreased the concentrations of VEGF, EGF, NGF-β, TNF-α, and FGF-β in tumor tissues compared to control. Western blot analysis revealed a significantly reduced expression of galectin-4 in tumor tissues by arctigenin treatment. Previous studies have shown that strong expression of galectin-4 can be induced in different types of cancer, associated with tumor growth and progression. A microRNA PCR array assay was performed to measure the tumor concentrations of 84 microRNAs involved in prostate cancer development and progression. A panel of microRNAs including miR-126 and miR-135 were identified to be responsive to arctigenin treatment. Further mechanistic investigation using tissue microarray assay is ongoing to measure the protein markers of proliferation and apoptosis in tumor tissues. This study provides a promising non-toxic agent to enhance chemoprevention of prostate cancer. These results warrant future clinical trial studies to confirm the anti-carcinogenic effect of arctigenin in humans.
Citation Format: Piwen Wang, Susanne M. Henning, Jaydutt V. Vadgama. A lignan compound arctigenin inhibits prostate tumor growth in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2626A.
Abstract 2635: Methylation in benign prostate and risk of disease progression in men subsequently diagnosed with prostate cancer
Authors: Rybicki Benjamin A. , Rundle Andrew , Kryvenko Oleksandr , Chitale Dhananjay , Belinsky Steven , Tang Deliang 
Published: July 2016

Abstract
In DNA from prostate cancer tumors, methylation patterns in gene promoter regions can be a biomarker for disease progression. It remains unclear whether methylation patterns in benign prostate tissue—prior to malignant transformation—may provide similar prognostic information. To determine whether early methylation events predict prostate cancer outcomes, we evaluated histologically benign prostate specimens from 353 men who eventually developed prostate cancer and received “definitive” treatment (radical prostatectomy [58%] or radiation therapy [42%]). Cases were drawn from a large hospital-based cohort of men with benign prostate biopsy specimens collected between 1990 and 2002. Risk of disease progression associated with methylation was estimated using time-to-event analyses. Average follow-up was over 5 years; biochemical recurrence (BCR) occurred in 91 cases (26%). In White men, methylation of the APC gene was associated with increased risk of BCR, even after adjusting for standard clinical risk factors for prostate cancer progression (adjusted hazard ratio (aHR) = 2.26; 95%CI 1.23-4.16). APC methylation was most strongly associated with a significant increased risk of BCR in White men with low prostate specific antigen at cohort entry (HR = 3.66; 95%CI 1.51-8.85). In additional stratified analyses, we found that methylation of the RARB gene significantly increased risk of BCR in African American cases who demonstrated methylation of at least one of the other four genes under study (HR = 3.80; 95%CI 1.07-13.53). These findings may have implications in the early identification of aggressive prostate cancer as well as reducing unnecessary medical procedures and emotional distress for men who present with markers of indolent disease.
Citation Format: Benjamin A. Rybicki, Andrew Rundle, Oleksandr Kryvenko, Dhananjay Chitale, Steven Belinsky, Deliang Tang. Methylation in benign prostate and risk of disease progression in men subsequently diagnosed with prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2635.
Abstract 2657: Target specificity of epigenetic therapy in cancer
Authors: Sato Takahiro , Cesaroni Matteo , Panjarian Shoghag , Tran Anthony , Madzo Jozef , Okamoto Yasuyuki , Zhang Hanghang , Chen Xiaowei , Jelinek Jaroslav , Issa Jean-Pierre J. 
Published: July 2016

Abstract
A major question facing the use of epigenetic therapies in cancer is specificity in modulating gene expression. In addition, combined targeting of DNA and histone methylation remains largely unexplored despite the promising synergistic effects observed from combining DNA methyltransferase inhibitors with HDAC inhibitors. To address these questions, we performed RNA-seq, DNA methylation analysis and ChIP-seq (H3K4me2, H3K9me2, and H3K27me3) to study the effects of inhibitors of DNA methyltransferases (DAC), histone deacetylases (Depsi), histone demethylases (KDM1A inhibitor S2101), and histone methylases (EHMT2 inhibitor UNC0638 and EZH2 inhibitor GSK343) in three different cancer models (colon cancer, breast cancer, and leukemia). In colon cancer cells (YB5), DAC affected 3% of the transcriptome and 93% of the effect was gene upregulation. DAC had a greater effect on genes expressed in normal tissues and silenced in cancer (443 genes) compared to genes that do not change in cancer (194 genes). 90% of DAC targets genes showed no promoter DNA methylation in normal colon but gained methylation in cancer. Depsi changed the expression of 35% of the transcriptome and showed little specificity for gene upregulation or silenced genes. S2101, UNC0638, and GSK343 had limited effects on their own (&lt;1.5% of the transcriptome), but UNC0638 and GSK343 preferentially targeted genes with H3K9me2 or H3K27me3, respectively. DAC combined with histone methylation inhibitors led to synergistic gene upregulation while still maintaining specificity for DNA methylated and silenced genes. These synergistic genes had limited overlap, indicating the possibility to target distinct sets of genes based on different epigenetic therapy combinations. IPA analysis demonstrated that these genes are enriched in cancer pathways, and consistent with this analysis, the combination therapies were able to decrease cancer cell proliferation more effectively than monotherapy. Broadly similar results were seen with genome wide studies in both breast cancer (MCF7) and leukemia (HL-60) cells. These results demonstrate that DNA methyltransferase inhibitors preferentially target cancer relevant genes, and can be combined with inhibitors targeting histone methylation for synergistic effects while still maintaining specificity.
Citation Format: Takahiro Sato, Matteo Cesaroni, Shoghag Panjarian, Anthony Tran, Jozef Madzo, Yasuyuki Okamoto, Hanghang Zhang, Xiaowei Chen, Jaroslav Jelinek, Jean-Pierre J. Issa. Target specificity of epigenetic therapy in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2657.
Abstract 2661: The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers
Authors: Liang Han 
Published: July 2016

Abstract
Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We characterized the global A-to-I RNA editing profiles of &gt;6000 patient samples of 20 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions. We experimentally demonstrated the functional effects of several RNA editing events and provide the evidence that RNA editing could selectively affect drug sensitivity. These results highlight RNA editing as an exciting theme for investigating cancer mechanisms, biomarkers and treatments.
Citation Format: Han Liang. The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2661.
Abstract 2672: Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures
Authors: Graham Nicholas A. , Minasyan Aspram , Christofk Heather R. , Mellinghoff Ingo K. , Graeber Thomas G. 
Published: July 2016

Abstract
Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including FDG-avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes. A cross-species comparison of CNA identified 21 conserved altered DNA regions containing 13 enzymes in the glycolysis and pentose phosphate pathways in addition to known cancer driving genes. Furthermore, exogenous expression of hexokinase and enolase enzymes in an experimental immortalization system altered the copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Taken together, these results demonstrate that metabolic stress acts as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution.
Citation Format: Nicholas A. Graham, Aspram Minasyan, Heather R. Christofk, Ingo K. Mellinghoff, Thomas G. Graeber. Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2672.
Abstract 2676: Epithelial-mesenchymal transition does not require transcriptional repression of the epithelial program in vivo
Authors: Aiello Nicole M. , Balli David , Norgard Robert , Li Jinyang , Sahmoud Amine , Stanger Ben Z. 
Published: July 2016

Abstract
Epithelial-mesenchymal transition (EMT), the process by which an epithelial cell loses its adhesion to neighboring cells and acquires a motile, fibroblast-like phenotype, is critical for many aspects of embryogenesis and has been strongly implicated in tumor cell invasion and metastasis. EMT is thought to be primarily regulated at the transcriptional level through repression of epithelial genes by transcription factors such as Snail, Zeb and Twist. To date, the mechanisms driving EMT have been parsed out almost exclusively in vitro under pre-defined conditions (ie, using TGFβ as an EMT inducer), but it remains to be seen whether the machinery that regulates in vitro EMT is physiologically relevant. Using a lineage labeled mouse model of pancreatic ductal adenocarcinoma (PDAC), we isolated tumor cells that have spontaneously undergone EMT to interrogate the molecular mechanisms driving this process in vivo. By comparing the transcriptomes of epithelial (E-cadherin+) and mesenchymal (E-cadherin-) tumor cells, we found that for a majority of PDAC tumors, EMT does not require transcriptional repression of the epithelial program. These cells were fully capable of upregulating a mesenchymal program, as evidenced by the increased expression of collagens, SPARC, MMP2, PDPN, and PRRX1; however, despite the loss of E-cadherin protein, we detected no change in transcript levels of E-cadherin or other epithelial genes after EMT. Our results suggest that in vivo, cells that undergo EMT retain epithelial gene transcription, which may confer the ability to rapidly oscillate between epithelial and mesenchymal states.
Citation Format: Nicole M. Aiello, David Balli, Robert Norgard, Jinyang Li, Amine Sahmoud, Ben Z. Stanger. Epithelial-mesenchymal transition does not require transcriptional repression of the epithelial program in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2676.