bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2142: High variability of TIGIT expression in Hodgkin's lymphoma
Authors: Simon Ronald , Blessin Niclas C. , Kluth Martina , Fischer Kristine , Hube-Magg Claudia , Li Wenchao , Makrypidi-Fraune Georgia , Wellge Björn , Mandelkow Tim , Debatin Nicolaus F. , Sauter Guido , Wilczak Waldemar , Hinsch Andrea 
Published: August 2018

Abstract
Hodgkin's lymphoma (HL) is characterized by a high background of inflammatory cells which play an important role for the pathogenesis of the disease. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor and a putative target for novel immune therapies. To study patterns of TIGIT expression in the T cell background surrounding malignant cells including Hodgkin cells, Reed-Sternberg cells and histiocytic cells, a microenvironment (ME) tissue microarray (TMA) was constructed from tissue punches measuring 2 mm in diameter obtained from formalin-fixed tissue samples of Hodgkin lymphoma lymph nodes (n=40) and normal human tonsil (n=2) as a reference. The ME-TMA was stained with brightfield and multiplex fluorescence immunohistochemistry (IHC) in order to evaluate expression levels of TIGIT and PD-1 as well as standard lymphocyte markers (CD8, CD4, FOXP3) in the lymphocytic background. TIGIT and PD-1 expression was found in all (100%) analyzed HL samples. In general, TIGIT localized to the same cells as PD-1. IHC based identification of T cell subtypes revealed TIGIT and PD-1 expression on CD8+ cytotoxic T cells, CD4+ helper T cells and FOXP3+ regulatory T cells. Strikingly, expression levels of TIGIT and PD-1 were highly variable among the analyzed samples irrespective of the histological subtype of HL. Interestingly, highest levels of both proteins were found in one sample of nodular lymphocytic-predominant HL (NLPHL). The high variability of TIGIT and PD-1 expression was also independent from the T cell subtype. HL with high TIGIT/PD-1 expression on CD8 positive cells sometimes showed low TIGIT/PD-1 expression on CD4 or FOXP3 positive T cells and vice versa. However, the T cell subtypes differed with respect to the TIGIT:PD-1 ratio. In the majority of analyzed HL, FOXP3+ regulatory T cells expressed higher levels of TIGIT than of PD-1. This was different for CD8+ and CD4+ cells, where similar fractions of HL showed either more TIGIT as PD-1, or more PD-1 as TIGIT, or comparable levels of both receptors. In conclusion, TIGIT (and PD-1) expression is highly variable between patients with Hodgkin's lymphoma. TIGIT may play a particularly important role in FOXP3 regulatory T cells in the lymphocytic background.
Citation Format: Ronald Simon, Niclas C. Blessin, Martina Kluth, Kristine Fischer, Claudia Hube-Magg, Wenchao Li, Georgia Makrypidi-Fraune, Björn Wellge, Tim Mandelkow, Nicolaus F. Debatin, Guido Sauter, Waldemar Wilczak, Andrea Hinsch. High variability of TIGIT expression in Hodgkin's lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2142.
Abstract 2179: Population remodeling in the acquisition of endocrine resistance in breast cancer
Authors: Hu Rong , Sengupta Surojeet , Sevigny Catherine , Zhang Zhen , Wang Yue , Clarke Robert 
Published: August 2018

Abstract
The cell-cell interactions that occur within the breast tumor microenvironment are critical determinants of cancer cell fate. In the face of treatment, the theory of clonal evolution dominates current thinking. Thus, individual cells acquire a mutation(s) that provides a selection advantage where Darwinian selection acts at the single-cell level. We studied the effect of antiestrogen treatment on the population remodeling of admixtures of sensitive LCC1 (S) cells and resistant LCC9 (R) human breast cancer cells. R cells were derived from S cells by selection against antiestrogens. We labeled S cells with GFP and R cells with mCherry, mixed the cells in different ratios, and treated with antiestrogen or vehicle. Unlike other resistance phenotypes (e.g., MDR1-driven cytotoxic drug models), R cells do not outcompete S cells, nor do S cells restrain R cell growth. Rather, R cells protect S cells from treatment. Full communication of the resistance phenotype occurs at a 1:1 mixture of S:R; ~75% of the R phenotype transfer is evident at 10:1. These results reflect improved fitness conferred by population interactions, not clonal evolution. SILAC analysis of S and R cells (pure populations) implicate differential regulation of estrogen (E2) response-early; E2 response-late; glycolysis; fatty acid metabolism; mTORC1 signaling; peroxisome; unfolded protein response (UPR); oxidative phosphorylation in S vs. R cells. Clustering of iTRAQ-TAT data from pure and admixed S:R populations shows that the 1:1 and 5:1 treated, and the 1:1 untreated admixtures, cluster with pure R cells. Untreated 5:1 admixed cells cluster with untreated S cells. Thus, R and S cells alter each other's molecular signatures. Studies using scratch labeling and small-molecule inhibitors show that R cells communicate with S cells via both juxtacrine and paracrine interactions mediated by gap junctional intracellular communication and secreted microvesicles, respectively. The molecular features modified reflect our unifying hypothesis of signaling and cell function control in endocrine resistance.
Citation Format: Rong Hu, Surojeet Sengupta, Catherine Sevigny, Zhen Zhang, Yue Wang, Robert Clarke. Population remodeling in the acquisition of endocrine resistance in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2179.
Abstract 2194: Subclonal variation and evolutionary dynamics of BRAF mutations in cancer
Authors: Gopal Priyanka , Sarihan Elif I. , Abazeed Mohamed E. 
Published: August 2018

Abstract
Tumors have genetically distinct subclones that compete for space and resources and differentially resist efforts to make them extinct. We studied the intratumoral heterogeneity of BRAF mutations across several cancer types. We identified BRAF driver mutations as predominately clonal in some cancer types (e.g. melanoma) and subclonal in others (e.g. lung adenocarcinoma). Clonality corresponded to the amplification of BRAF and prevalence of V600 mutations in each cancer type. We mathematically and experimentally modeled the propagation and selection of tumors containing BRAF mutations and determined that the speed of clonal sweeps were associated with the extent of activation of MAPK signaling pathway and BRAF copy number. Consistent with these findings, tumors with "hard" sweeps were more likely to respond to BRAF and/or MEK inhibitors. Furthermore, some PDX models treated with cytotoxic therapy underwent BRAF mutant subclone expansion over time and this effect is mitigated by inhibitors of BRAF and/or MEK. Treatment strategies based on subclone composition resulted in significantly improved tumor control. Our study uncovers patterns of distinct BRAF clonal evolutionary trajectories and advances therapeutic strategies on the basis of BRAF mutation identity and subclone composition that merit testing in patients.
Citation Format: Priyanka Gopal, Elif I. Sarihan, Mohamed E. Abazeed. Subclonal variation and evolutionary dynamics of BRAF mutations in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2194.
Abstract 2200: Intratumoral heterogeneity of copy number variation in lung cancer harboring L858R via immunohistochemical heterogeneous staining
Authors: Hashimoto Takafumi 
Published: August 2018

Abstract
Background: Acquired resistance to EGFR-TKI is an inevitable event for advanced lung cancer patients harboring the EGFR-activating mutation. Although intratumoral heterogeneity is commonly observed in several cancers, such as renal cell carcinoma, few studies have shown its presence in EGFR-mutated lung cancer. We analyzed the intratumoral heterogeneity in EGFR-mutated (L858R) lung cancer through immunohistochemistry (IHC) for the primary site and targeted sequencing for specific cases in order to clarify the mechanism of acquired resistance.
Methods: Twenty resected primary lung cancers known to harbor EGFR L858R were analyzed. IHC was performed using an L858R mutant-specific rabbit monoclonal antibody (clone43B2; Japan) and the samples were scored by staining intensity (0-3) and proportion. For cases with heterogeneous L858R protein expression, the nucleic acids were extracted from each differently stained lesion, and targeted sequencing (Oncomine Cancer Research Panel) was performed. Single-nucleotide variations (SNVs) and copy number variations (CNVs) from each site were then analyzed. The cell proliferation and apoptosis were also evaluated by the ki-67 labeling index and TUNEL staining.
Results: Among 20 cases, 3 (15%) showed heterogeneous staining, defined as having both an L858R IHC-positive part and an IHC-negative one. Genetic analyses for cases with heterogeneous staining revealed an increase in the copy number of EGFR in the IHC-positive part (CNV 19.54) compared to the negative part (CNV 3.03), and an increase in the copy number of CCNE1 was observed in the IHC-positive part (CNV 18.59) compared to the negative part (CNV 2.59) in one case (case 1). In another case (case 2), an increase in the copy number of EGFR was observed in the IHC-positive part (CNV 8.21) compared to the negative part (CNV 2.90), and an increase in the copy number of MDM2 was observed in the IHC-positive part (CNV 6.65) compared to the negative part (CNV 1.37). Case 3 did not show any CNV. In three cases, no SNV changes were observed. An increase in the ki-67 labeling index in the L858R-positive part in case 1 and increased apoptosis in the L858R-positive part in case 2 were observed, suggesting the functional significance of CNV changes.
Conclusion: These cases exhibiting L858R IHC intratumoral heterogeneity suggest a heterogeneous effect on the cell activity due to CNV heterogeneity.
Citation Format: Takafumi Hashimoto. Intratumoral heterogeneity of copy number variation in lung cancer harboring L858R via immunohistochemical heterogeneous staining [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2200.
Abstract 2209: Lung cancer risk prediction using DNA methylation markers
Authors: Guida Florence , Nøst Therese H. , Relton Caroline , Brennan Paul , Sandanger Torkjel M. , Chadeau-Hyam Marc , Johansson Mattias 
Published: August 2018

Abstract
There is an urgent need to improve lung cancer risk assessment as current screening criteria miss a large proportion of cases and result in a high rate of false positives on low-dose CT screening. A fixed effect meta-analyses of 4 epigenome-wide association studies of lung cancer revealed differential DNA methylation at 16 CpG sites (FDR&lt;0.05). The current study aimed to evaluate the extent to which such methylation markers can improve upon smoking-based risk-discrimination among ever smokers. We used data on 662 ever smoking lung cancer case-control pairs from 4 individual prospective cohorts that measured DNA methylation using the Illumina Infinium HumanMethylation450 BeadChip in peripheral blood samples before diagnosis: The Italian part of the European Prospective Investigation into Cancer (EPIC) cohort, the Melbourne Collaborative Cohort (MCCS), the Norwegian Women and Cancer cohort (NOWAC) and the Northern Sweden Health and Disease Study (NSHDS). We adopted a training-testing design where the training was performed on MCCS and NSHDS (N=511 case-control pairs), and the testing on EPIC-Italy and NOWAC (N=151 case-control pairs). Logistic regressions with lasso penalties were performed in the training set to select the best set of CpGs jointly predicting lung cancer. A methylation score was trained by fitting a logistic regression model including the selected CpGs in the training set. A baseline score based on self-reported smoking information (duration, cigarettes/day for current smokers and time since smoking cessation for former smokers) was also developed. The discriminative performances of both scores, as well as integrated model where both smoking and methylation info was incorporated, were assessed by the AUC under the ROC curves in the validation set. The methylation score based on the 9 selected CpG sites yielded an AUC of 0.78 [0.73-0.84] compared to 0.73 [0.68-0.79] for the baseline-smoking score. The model integrating both scores yielded an AUC of 0.79 [0.73-0.84], a notable 0.06-increase in AUC from using the smoking score alone (P=0.008 for difference in AUC). In conclusion, specific methylation biomarkers have a strong potential to improve lung cancer risk assessment and current USPSTF criteria for CT-screening. During the conference, we will present absolute risk estimates based on the integrated risk prediction model.
Citation Format: Florence Guida, Therese H. Nøst, Caroline Relton, Paul Brennan, Torkjel M. Sandanger, Marc Chadeau-Hyam, Mattias Johansson. Lung cancer risk prediction using DNA methylation markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2209.
Abstract 2245: Deconvolution of diverse immune cell populations within tumors using ACE Transcriptome
Authors: Levy Eric , Boyle Sean M. , Milani Pamela , Luo Shujun , West John , Chen Richard 
Published: August 2018

Abstract
Comprehensive tumor immuno-genomic characterization is becoming an important tool for identifying new biomarkers correlated with patient response to immunotherapy. Both the abundance and composition of tumor-infiltrating lymphocytes have been associated with tumor progression and patient outcome. Prior studies have shown that an enrichment of cytotoxic immune cells, and depletion of immunosuppressive cells, can indicate better clinical outcome.
While common lab approaches are used to profile tumor samples for the presence and enumeration of immune cell types, these approaches can be limited by the number of markers and throughput. Thus, there is interest in using an accurate computational method leveraging NGS data to more comprehensively profile the distribution of immune cells in the tumor microenvironment. Through the use of marker genes that are expressed in a cell type specific manner, it is possible to computationally predict the fractions of multiple cell types in a mixed sample. This approach relies on an input of reference gene expression signatures, which are used to estimate the proportions of the cell types represented in the reference. The generation and validation of these reference signatures are critical for ensuring the accuracy of the results on a given platform.
We have used the ACE Cancer Transcriptome, from the ACE ImmunoID platform, to produce high-quality gene expression profiles of purified immune cells representing many lineages, including B cells, monocytes, NK cells, and T cells. These profiles were used to create reference signatures of immune cell type specific genes, enabling quantification of their cellular abundances. In addition, we test the accuracy of the deconvolution approach on mixtures of immune cells. Finally, we validate the approach on tumor samples with immune cells quantified by widely accepted orthogonal methods. Through these results, we show that deconvolution of TILs through our ACE Cancer Transcriptome can be a robust platform for elucidating the composition of immune cells in a tumor sample.
Citation Format: Eric Levy, Sean M. Boyle, Pamela Milani, Shujun Luo, John West, Richard Chen. Deconvolution of diverse immune cell populations within tumors using ACE Transcriptome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2245.
Abstract 2259: Prostate cancer molecular subtype impacts interpretation of clinical parameters
Authors: Liu Deli 
Published: August 2018

Abstract
Background: Molecular characterization of prostate cancer has revealed distinct subtypes with underlying genomic alterations. One of these core subtypes (SPOP mutant prostate cancer) has previously only been identifiable through DNA sequencing, making the impact on prognosis and routinely utilized risk stratification parameters unclear. We aimed to identify prostate cancer molecular subtypes from transcriptional data alone and determine associations with clinicopathologic outcomes and long-term prognosis.
Methods: We developed a novel gene expression signature, classifier (SCaPT), and decision tree to predict SPOP mutant subclass from RNA gene expression data and classify common prostate cancer molecular subtypes. We then validated and further interrogated the association of prostate cancer molecular subtypes with pathologic and clinical outcomes in retrospective and prospective cohorts of 8,158 patients. Associations with clinicopathologic variables, metastasis-free and prostate cancer-specific survival were the main outcomes.
Findings: The SCaPT model prediction showed high sensitivity and specificity in multiple cohorts across both RNA-seq and microarray gene expression platforms. We predicted 8~9% of cases to be SPOP mutant from both retrospective and prospective cohorts. Surprisingly, we found routine clinical risk factors were disconjugate when molecular subtype was considered. The SPOP mutant subclass was associated with lower frequency of positive margins, extraprostatic extension, and seminal vesicle invasion at prostatectomy. However, SPOP mutant cancers were associated with higher pretreatment serum prostate-specific antigen (PSA). The association between SPOP mutant status and higher PSA level was validated in three independent cohorts. Despite high pre-treatment PSA, the SPOP mutant subtype was associated with a favorable prognosis with improved metastasis-free survival, particularly in patients with “high-risk” preoperative PSA levels.
Interpretation: Using a novel gene expression signature to assign the SPOP mutant subclass and a decision tree algorithm to define prostate cancer molecular subclasses, we found the SPOP mutant subclass associated with higher preoperative PSA, less adverse pathological features, and favorable prognosis. These findings suggest a paradigm where interpretation of common risk stratification parameters, particularly PSA, must be modified to account for the molecular subtype of prostate cancer.
Citation Format: Deli Liu. Prostate cancer molecular subtype impacts interpretation of clinical parameters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2259.
Abstract 2263: The dysregulation of circadian genes across cancers
Authors: Liu Zexian , Lin Huan , Liu Zekun , Yu Kai , Zhao Qi , Zhang Xiaolong , Wang Yan , Zuo Zhixiang 
Published: August 2018

Abstract
As the daily oscillation in physiological processes, circadian is critical for health while disruption of the circadian rhythm has been associated with cancer in humans. Generally, circadian rhythm was proposed to play important roles in tumor suppression, while there were also evidences that disruption of canonical circadian pathway have anti-cancer effects. In this study, we systematically analyzed the aberrances including mutation, somatic copy number alternation, differential DNA methylation and differential expression of circadian genes across cancers based on TCGA data. It is observed that core circadian network genes (CCNGs) such as PER1/2/3, CLOCK, CRY1/2, ARNTL were highly mutated in a number of cancers such as uterine corpus endometrial carcinoma, skin cutaneous melanoma, stomach adenocarcinoma and colon adenocarcinoma. Generally, the expression for the majority of CCNGs was down regulated in a variety of the cancers such as bladder urothelial carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, cervical and endocervical cancers, prostate adenocarcinoma, glioblastoma multiforme and stomach adenocarcinoma, while the expression of a number of CCNGs were related with overall survival in various cancers. The alternations of somatic copy number and DNA methylation were observed to be consistent with the differential expression of these CCNGs. Furthermore, the PCA based circadian gene expression signature was found to be related with the overall survivals and immunophenotypes among cancers, which indicated that circadian rhythm might play critical roles in regulation of immune signaling state in tumor environment. Taken together, our study provided comprehensive analyses of the aberrances and functional roles of circadian genes in cancer, while the results should be helpful for further investigation of the molecular mechanisms and therapy development for cancer.
Citation Format: Zexian Liu, Huan Lin, Zekun Liu, Kai Yu, Qi Zhao, Xiaolong Zhang, Yan Wang, Zhixiang Zuo. The dysregulation of circadian genes across cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2263.