bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 774: Proteogenomic characterization of high-grade serous ovarian cancer
Authors: McDermott Jason E. , Payne Samuel , Ray Debjit , Petyuk Vladislav , Moore Ronald , Gritsenko Marina , Smith Richard , Rodland Karin 
Published: July 2016

Abstract
High grade serous ovarian carcinoma (HGSOC) is a highly lethal gynecological malignancy, in large part because most patients develop resistance to the standard of care chemotherapy with platinum and taxanes. We performed deep proteomic and phosphoproteomic characterization on ovarian high-grade serous carcinomas (HGSC) previously characterized genomically by the The Cancer Genome Atlas (TCGA) as part of the Clinical Proteomic Tumor Analysis Consortium (CPTAC; http://proteomics.cancer.gov/programs/cptacnetwork). We constructed an integrated proteogenomic landscape of HGSC and identified functional modules statistically associated with outcomes including platinum resistance and overall survival.
Integration of genomic data such as copy number alterations (CNA) with global protein abundance data revealed several chromosomal regions that have significant trans effects on protein expression. These genetically affected proteins were used to construct statistical models capable of predicting survival outcomes. Trans-affected proteins were enriched in proliferation, cell motility and invasion, and immune regulation, hallmarks of cancer.
We used statistical methods to identify functional pathways able to discriminate between short surviving and long surviving patients. We found that protein abundance and phosphorylation indicated pathway activity that was able to clearly discriminate between these two groups, but that transcriptional expression and CNAs were not. We integrated proteomic abundance and phosphorylation state to elucidate specific signaling interactions and pathways differentially active in tumors from patients with short overall survival as well as to predict novel kinase substrate relationships important in HGSC. Finally, we identified druggable pathways that are differentially active across proteomic subtypes.
A key point arising from our multimodal analysis is that combining different types of molecular data from these tumors greatly increases the ability to identify biologically relevant differences between groups. Using a Lasso-based regression approach to integrate data we show that the most robustly predictive survival models can be obtained using integrated CNA, transcriptome, proteome, and phosphoproteome data than with any of the individual sources of data.
Citation Format: Jason E. McDermott, Samuel Payne, Debjit Ray, Vladislav Petyuk, Ronald Moore, Marina Gritsenko, Richard Smith, Karin Rodland. Proteogenomic characterization of high-grade serous ovarian 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 774.
Abstract 777: The CoGAPS matrix factorization algorithm infers feedback mechanisms from therapeutic inhibition of EGFR that increases expression of growth factor receptors
Authors: Fertig Elana J. , Ozawa Hiroyuki , Thakar Manjusha , Howard Jason , Krigsfeld Gabriel , Favorov Alexander V. , Gaykalova Daria A. , Ochs Michael F. , Chung Christine H. 
Published: July 2016

Abstract
Next generation sequencing technologies enable precise personalized medicine. Thus, patients with oncogene driven tumors are currently treated with targeted therapeutics such as EGFR inhibitors. However, drug interactions with other activated signaling pathways in treated tumors often alter predicted therapeutic response. Therefore, bioinformatics algorithms are needed to infer unanticipated molecular interactions from anticipated molecular response to targeted therapeutics in diverse genetic backgrounds. To model heterogeneous genetic backgrounds in HNSCC, we use HaCaT cells with forced overexpression of EGFR, HRAS, and PIK3CA. Previously, the CoGAPS matrix factorization algorithm was shown to infer the specific signaling pathways that were activated in these HaCaT knock-in constructs from gene expression data. In this study, we evaluated whether CoGAPS could also delineate unanticipated signaling changes from anticipated cellular signaling response caused by targeted therapeutic in diverse genetic backgrounds. To delineate these signaling responses, we measured gene expression after treating the modified HaCaT cells with three EGFR targeted agents (gefitinib, cetuximab and afatinib) for 24 hours. The CoGAPS matrix factorization algorithm distinguished a gene expression signature associated with the anticipated silencing of the EGFR network and a signature associated with unanticipated transcriptional feedback in HaCaT constructs that were sensitive to EGFR inhibitors. Notably, the feedback signature showed that EGFR gene expression itself increased in cells that were responsive to EGFR inhibitors. The CoGAPS algorithm further associated such feedback with increased expression of several growth factor receptors by the AP-2 family of transcription factors. Once transcribed, these growth factor receptors may ultimately compensate for EGFR inhibition in these sensitive cells. Our data suggest, that CoGAPS gene expression signatures delineate on target and feedback effects of drugs related to therapeutic sensitivity in diverse genetic backgrounds.
Citation Format: Elana J. Fertig, Hiroyuki Ozawa, Manjusha Thakar, Jason Howard, Gabriel Krigsfeld, Alexander V. Favorov, Daria A. Gaykalova, Michael F. Ochs, Christine H. Chung. The CoGAPS matrix factorization algorithm infers feedback mechanisms from therapeutic inhibition of EGFR that increases expression of growth factor receptors. [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 777.
Abstract 79: Andrographolide alters genes associated with DNA repair in prostate cancer
Authors: Forestier-Román Ingrid , Sánchez-Vázquez María , Rohena-Rivera Krizia , Cadilla Carmen , Martínez-Ferrer Magaly 
Published: July 2016

Abstract
Prostate cancer is the most frequently diagnosed non-cutaneous cancer and the second cause of cancer-related deaths in American men. Andrographolide, a labdane diterpenoid that is a component of the medicinal plant Andrographis paniculata, has been reported to have a wide range of biological activities including anticarcinogenic properties. In previous studies, we found that Andrographolide inhibits cell growth, tumor growth and angiogenesis in prostate cancer. Therefore, the objective of this study is to determine the mechanism of action of Andrographolide in prostate cancer. In order to determine the mechanism of action, we did gene expression profile to compare genes differentially expressed in tumors treated with Andrographolide (10 mg/kg and 25 mg/kg) and their vehicle. Tumors were developed using a xenograft model in which the prostates of SCID mice were injected with 22RV1, and mice were treated bi-weekly with Andrographolide (10 mg/kg and 25 mg/kg). Tumor tissues were collected and snap frozen. Gene expression was analyzed using the Affymetrix GeneChip® Human Gene 2.0 array. Microarray studies showed a total of 674 genes differentially expressed in tumors treated with Andrographolide (10 mg/kg) when compared to their vehicle. In addition, 218 genes were differentially expressed in tumors treated with Andrographolide (25 mg/kg) when compared to their vehicle. Genes involved in cellular processes such as cell cycle, DNA damage response, MAPK signaling, TCA cycle, glycolysis and metabolism of amino acids were differentially expressed. Ingenuity Pathway Analysis (IPA) revealed networks associated to DNA replication, recombination and repair, and post-translational modification in tumors treated with Andrographolide (10 mg/kg). Moreover, IPA revealed networks associated to cell death and survival, cellular function and maintenance, and carbohydrate metabolism in tumors treated with Andrographolide (25 mg/kg). The microarray results were confirmed by quantitative real-time PCR. Our results demonstrated that Andrographolide altered the expression of genes associated with DNA repair which could be a possible mechanism of action of its anticarcinogenic effect.
Citation Format: Ingrid Forestier-Román, María Sánchez-Vázquez, Krizia Rohena-Rivera, Carmen Cadilla, Magaly Martínez-Ferrer. Andrographolide alters genes associated with DNA repair in 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 79.
Abstract 800: ALDH2 rs671 polymorphism and alcohol consumption in the risk of gastric cancer: A Mendelian randomization study
Authors: Kim Jeongseon , Yang Sarah , Lee Jeonghee , Choi Il Ju , Kim Young Woo , Ryu Keun Won , Sung Joohon 
Published: July 2016

Abstract
Background: The effect of increased alcohol consumption on the risk for gastric cancer (GC) has not been fully elucidated, due to the presence of confounders and gender differences. In this study, aldehyde dehydrogenase 2 (ALDH2) rs671, the genetic polymorphism related to the elimination of acetaldehyde, was used as an instrumental variable (IV) for Mendelian randomization analysis to dissect the role of alcohol in GC risk.
Methods: The study included Korean 450 GC cases and 1,050 controls recruited at the National Cancer Center. Data of 795 GC patients and 4,893 controls from the Korean Centers for Disease Control were used for further validation. The odds ratios (OR) for the ALDH2 genotype and its interaction with alcohol consumption were estimated using multivariate logistic regression. The two-stage control function method was performed using rs671 as the IV for alcohol consumption.
Results: All AG carriers had an OR of 1.26 (95% confidence interval, 1.11-1.42) compared with GG carriers. In a quantitative analysis of alcohol intake, the conventional OR was 1.21(1.09-1.36) and the IV-OR was 0.90(0.63-1.28). Females had low alcohol consumption and did not show a significant risk for GC while males had a high risk for GC.
Conclusions: Alcohol consumption is not associated with a risk for GC by itself, and ALDH2 polymorphism should be considered simultaneously when assessing the risk. Females did not display an evident risk for GC regarding alcohol, partly due to their lower level of alcohol consumption. However, further dissection of gender difference is necessary.
Citation Format: Jeongseon Kim, Sarah Yang, Jeonghee Lee, Il Ju Choi, Young Woo Kim, Keun Won Ryu, Joohon Sung. ALDH2 rs671 polymorphism and alcohol consumption in the risk of gastric cancer: A Mendelian randomization study. [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 800.
Abstract 803: Obesity and associated lifestyles modify the effect of glucose metabolism-related genetic variants on impaired glucose homeostasis among postmenopausal women
Authors: Jung Su Yon , Sobel Eric M. , Papp Jeanette C. , Crandall Carolyn J. , Fu Alan N. , Zhang Zuo-Feng 
Published: July 2016

Abstract
Background: Impaired glucose metabolism-related genetic variants likely interact with obesity-modifiable factors in response to glucose intolerance, yet their interconnected pathways have not been fully characterized. We assessed in postmenopausal women whether obesity, physical activity, and high dietary fat intake interact with the single-nucleotide polymorphisms (SNPs)-glucose variations.
Methods: We used data from 1,027 postmenopausal participants of the Genomics and Randomized Trials Network study and 15 SNPs associated with glucose homeostasis. We used regression analysis plus stratification and graphic approaches.
Results: Fasting levels of glucose, insulin, and homeostatic model assessment-insulin resistance (HOMA-IR) were higher in obese, inactive, and high fat-diet women than in their respective counterparts. Carriers within subgroups differently demonstrated the direction and/or magnitude of the variants’ effect on glucose-relevant traits. Variants in GCKR, GCK, DGKB/TMEM195 (P for interactions = 0.02, 0.02, and 0.01), especially, showed interactions with obesity: obese, inactive, and high fat-diet women had greater increases in fasting glucose, insulin, and HOMA-IR levels. Obese carriers at TCF7L2 variant had greater increases in fasting glucose levels than non-obese carriers (P for interaction = 0.04), whereas active women had greater decreases in insulin and HOMA-IR levels than inactive women (P for interaction = 0.02 in both levels).
Conclusions: Our data support the important role of obesity in modifying glucose homeostasis in response to glucose metabolism-relevant variants. These findings may inform research on the role of glucose homeostasis in the etiology of disease, particularly obesity-related cancer, and the development of intervention strategies to reduce risk in postmenopausal women.
Citation Format: Su Yon Jung, Eric M. Sobel, Jeanette C. Papp, Carolyn J. Crandall, Alan N. Fu, Zuo-Feng Zhang. Obesity and associated lifestyles modify the effect of glucose metabolism-related genetic variants on impaired glucose homeostasis among postmenopausal women. [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 803.
Abstract 804: Gene-environment interactions and the risk of Barrett's esophagus in three US cohorts
Authors: Crous-Bou Marta , Feskanich Diane , Stampfer Meir J. , Fuchs Charles S. , De Vivo Immaculata , Jacobson Brian C. 
Published: July 2016

Abstract
Background: Several single nucleotide polymorphisms (SNPs) have been associated with Barrett's esophagus (BE) risk. Additionally, environmental factors including smoking, alcohol consumption and heartburn have been shown to increase BE risk. However, no studies have evaluated whether interactions between these genetic and environmental factors influence BE risk. Understanding how genes and environmental risk factors interact may provide key insight into the pathophysiology of BE.
Objectives: To examine the main effects and the potential effect-modification between known genetic loci (SNPS) and established environmental risk factors for BE.
Patients and Methods: We performed a nested case-control study using data on 401 incident BE cases and 436 age-matched controls from the Nurses’ Health Study, Nurses’ Health Study II, and Health Professionals Follow-up Study cohorts, who gave blood and completed biennial questionnaires. We genotyped SNPs identified in previous BE GWAS as well as SNPs in candidate genes related to BE susceptibility (i.e., related to excess body fat, fat distribution, factors associated with insulin resistance, and inflammatory mediators). A genetic risk score (GRS) was constructed to evaluate the combined effect of the selected SNPs on BE risk. Interactions between SNPs and BE risk factors were also assessed.
Results and Conclusions: We found a borderline association between our GRS and BE risk: a one-allele increase in the unweighted GRS increased the risk of Barrett's esophagus by a factor of 1.20 (95%CI = 1.00-1.44; p = 0.057). We observed a significant interaction between smoking and BE genotypes (p-interaction = 0.016). However, while alcohol consumption and heartburn duration were strongly associated with BE, we did not observe any significant gene-environment interactions.
Citation Format: Marta Crous-Bou, Diane Feskanich, Meir J. Stampfer, Charles S. Fuchs, Immaculata De Vivo, Brian C. Jacobson. Gene-environment interactions and the risk of Barrett's esophagus in three US cohorts. [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 804.
Abstract 809: Dietary iron intake, genetic variants in microRNA related iron regulatory pathway genes, and the risk of non-small cell lung cancer
Authors: Zhang Liren , Ye Yuanquing , Tu Huakang , Hildebrandt Michelle A.t. , Heymach John V. , Roth Jack A. , Gu Jian , Wu Xifeng 
Published: July 2016

Abstract
As an essential nutrient that facilitates DNA synthesis, cell proliferation and metabolism, iron is involved in carcinogenesis. While epidemiological studies suggest a J-shaped model for the relationship of serum iron level and cancer risk with both too low and too high levels associated with increased cancer risks, the effect of genetic variants related to intracellular iron regulatory pathway and dietary iron intake on non-small cell lung cancer (NSCLC) risk is little known. In this study, we evaluated a panel of miRNA related genetic variants in iron regulatory pathway genes on the risk of NSCLC. In discovery phrase, 157 miRNA related single nucleotide polymorphisms (SNPs) from 81 genes of iron regulatory pathway were genotyped in 1656 NSCLC cases and 1486 healthy controls. Eight SNPs in 6 genes were significantly associated with risk of NSCLC. A SNP in 3’ UTR of Iron-Responsive Element Binding Protein 2 (IREB2) gene at 15q25 region was subsequently replicated in dbGaP lung cancer GWAS dataset. Combining all subjects (7,352 cases, 7,296 controls), the overall P-value was 4.9 × 10−9 (Odds ratio (OR) = 0.86). eQTL analysis showed that the SNP on IREB2 alters IREB2 gene expression (P = 3.0 × 10−11). The SNP is predicted to alter a miR-29 binding site on IREB2 gene and indeed the expression of miR-29 is inversely correlated with IREB2 expression in tumor tissues. We then determined the expression of serum miR-29a in 150 early-stage NSCLC patients and 172 healthy controls and found that miR-29a was significantly associated with higher risk of cancer (OR = 1.78, P = 0.03). By analyzing dietary intake information of the discovery population, iron intake was significantly associated with risk of NSCLC in logistic regression analysis and there was also evidence of a synergistic interaction with between the SNP and iron intake in modulating NSCLC risk (P for interaction = 0.01). Taken together, SNPs at miRNA binding sites of iron regulatory pathway genes and dietary iron intake may modify risk of NSCLC individually and jointly.
Citation Format: Liren Zhang, Yuanquing Ye, Huakang Tu, Michelle A.t. Hildebrandt, John V. Heymach, Jack A. Roth, Jian Gu, Xifeng Wu. Dietary iron intake, genetic variants in microRNA related iron regulatory pathway genes, and the risk of non-small cell lung 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 809.
Abstract 810: The CARRIERS consortium: Establishing refined breast cancer risk estimates in known predisposition genes
Authors: Lilyquist Jenna , Kraft Peter , Hart Steven N. , Hallberg Emily J. , Hu Chunling , Moore Raymond , Gnanaolivu Rohan , Domchek Susan M. , Weitzel Jeffrey N. , Nathanson Katherine L. , Goldgar David E. , Couch Fergus J. 
Published: July 2016

Abstract
Breast cancer is the most common type of cancer, and has a strong heritable component, with approximately 15 percent of new cases having family history of breast cancer. Genetic panel testing for patients with a family history of breast cancer has become a popular clinical resource. However, the risk of breast cancer associated with inactivating mutations in the predisposition genes is largely undefined, creating critical limitations in the interpretations of the results from panel testing and subsequent medical management. The Cancer Risk Estimates Related to Susceptibility Genes (CARRIERS) consortium was established to determine the risk of cancers associated with truncating mutations in the known predisposition genes and to extend these studies to the clinical classification of variants of uncertain significance (VUS) in the relevant genes.
CARRIERS involves screening of approximately 30,000 population-based breast cancer cases and 30,000 study matched controls for mutations in 28 established or proposed breast cancer predisposition genes. Population-based risks for breast cancer associated with mutations in each gene will be estimated. In parallel, 10,000 breast cancer cases from moderate and high-risk breast cancer families will be similarly screened for mutations and the penetrance of the mutations in high-risk families will be estimated. Furthermore, VUS identified by mutation screening will be characterized by functional and family-based studies and models for classification of the clinical relevance of VUS in each gene will be developed. These data are expected to lead to improvements in cancer risk assessment and improved management of patients found to carry mutations or VUS in breast cancer predisposition.
Citation Format: Jenna Lilyquist, Peter Kraft, Steven N. Hart, Emily J. Hallberg, Chunling Hu, Raymond Moore, Rohan Gnanaolivu, Susan M. Domchek, Jeffrey N. Weitzel, Katherine L. Nathanson, David E. Goldgar, Fergus J. Couch. The CARRIERS consortium: Establishing refined breast cancer risk estimates in known predisposition genes. [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 810.
Abstract 822: Role of c-Myc in prostate cancer stem-like cell inhibition by sulforaphane
Authors: Kim Su-Hyeong , Vyas Avani R. , Singh Shivendra V. 
Published: July 2016

Abstract
Chemopreventive efficacy of D,L-sulforaphane (SFN) against prostate cancer has been shown in a transgenic mouse model but the underlying mechanism is not fully understood. The present study demonstrates that c-Myc, which is an oncogenic transcription factor frequently upregulated in human prostate cancer, is a molecular target of SFN. Exposure of human prostate cancer cells (LNCaP, C4-2, and PC-3) and a cell line derived from prostate adenocarcinoma of a transgenic mouse (Myc-CaP) to SFN resulted in a marked decrease in c-Myc protein level. Naturally-occurring thio, sulfinyl, and sulfonyl analogues of SFN were also effective in causing suppression of c-Myc protein level. The c-Myc is a known regulator of cellular metabolism but basal glycolysis was not altered by SFN treatment in empty vector transfected or in c-Myc overexpressing PC-3 cells. The effect of SFN treatment on prostate cancer stem-like cells (pCSC) was also determined as c-Myc is implicated in their maintenance. Analysis of aldehyde dehydrogenase 1 activity, CD49f+ fraction, and sphere forming efficiency revealed dose-dependent inhibition of pCSC in SFN-treated cells. The pCSC inhibition by SFN was partially but significantly attenuated by overexpression of c-Myc. Expression profiling revealed upregulation of a set of stemness genes by c-Myc overexpression but their downregulation by SFN treatment. Finally, oral administration of SFN to Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice resulted in a marked decrease in c-Myc protein expression in the adenocarcinoma. In conclusion, this study indicates that c-Myc downregulation contributes to pCSC inhibition by SFN. This investigation was supported by grant CA115498 awarded by the National Cancer Institute.
Citation Format: Su-Hyeong Kim, Avani R. Vyas, Shivendra V. Singh. Role of c-Myc in prostate cancer stem-like cell inhibition by sulforaphane. [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 822.