bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor profiling from whole-genome and whole transcriptome sequencing to uncover gene fusions and structural variations in clinically relevant cancer genes.
Authors: Gylfe Alexandra E , Shinbrot Eve , Kakaradov Boyko , Delport Wayne , Lau Corine K , Krishnan Subha , Perlina Ally , Natarajan Thanemozhi G , Sainger Rachana , Pelak Kimberly , Choppa Paul , Cooc Janine , Biggs William , Smith Heather L , Perkins Brad , Jones Daniel G , Nehring Ramlah B , Cohen Ezra E.W. , Bloom Kenneth Joel 
Published: September 2018

e23118 Background: Current targeted cancer therapies rely on the identification of clinically relevant somatic alterations in the tumor. Hotspot gene-panels and exome sequencing are designed to quickly assess somatic variations in frequently mutated regions and/or the coding regions of relevant genes, but they have limited ability to detect complex genomic rearrangements or novel structural variations. Here, we describe an integrative and comprehensive approach to fully characterize the genomic complexity of solid tumors using high throughput whole genome sequencing (WGS) and whole transcriptome sequencing (RNA Seq). Methods: We performed WGS and high-depth sequencing of known cancer genes in 14 paired tumor-normal samples of a variety of tumor types. Tumor-specific somatic alteration assessments included protein-coding mutations, copy number variations, gene fusions and structural variants. In addition, RNA Seq data was analyzed to identify expressed somatic alterations. Results: We identified 2 novel fusion genes as well as important structural alterations which could have clinical and therapeutic implications. We described a novel BRAF fusion gene in a cholangiocarcinoma devoid of other known driver mutations. BRAF fusions have not been described previously in cholangiocarcinoma; this fusion may represent an alternative mechanism for MAPK activation and could be a useful drug target. We also identified a novel NTRK3 fusion partner in a glioblastoma tumor. This fusion may imply a novel mechanism for NTRK3 activation. Finally, we identified numerous tandem duplications in an ovarian cancer. Recent advances describe tandem duplication hotspots in ovarian cancer as a potential driver mechanism characterizing a specific mutational signature. Conclusions: Comprehensive genomics assessment of paired tumor-normal samples through whole-genome and transcriptome sequencing can yield additional clinically actionable genomic characteristics that may not be detected in whole-exome or hotspot gene-panel sequencing. These findings have the potential to aid in clinical decision making.
HER2 activity in solid tumors.
Authors: Kujtan Lara Ann , Morris Scott , Subramanian Janakiraman 
Published: September 2018

e23121 Background: ERBB2 is a member of the human epidermal growth factor receptor family. HER2 expression that is immunohistochemistry (IHC) 3+ or IHC 2+ with copy number gain is an effective predictor for treatment with trastuzumab in breast and gastroesophageal cancers. Here we present an analysis on HER2 activity measured by IHC, mRNA expression and copy number variation (CNV) across a variety of solid tumors. Methods: The study population consists of patients diagnosed with solid tumors (n = 856) that underwent a Paradigm Diagnostic Cancer Test during 2016. We then analyzed tumor types that tested positive for HER2 by IHC (3+), CNV and/or mRNA expression. Results: We identified 365 (43%) patients positive for HER2 by IHC, 258 (30%) had high HER2mRNA expression and 41 (5%) had amplification by CNV. Seventy-five patients were HER2 IHC 3+ or 2+/CNV positive. The proportion of HER2 IHC 3+ or 2+/CNV positive tumors in each tumor type was as follows: breast cancer 41 (18.5%), NSCLC 10 (8.1%), colorectal 6 (6.7%), esophago-gastric 3 (10%,) urothelial/bladder 3 (16%), biliary 2 (28.6%), ovarian cancer 2 (5.1%) and pancreas 1 (3.1%). Using copy number gain as the gold standard, across all tumor types, an IHC of 3+ had a 90.2% sensitivity and a 95.6% specificity. In the same analysis with breast cancers omitted, the sensitivity was 75%, and specificity 96.8%. Whereas high mRNA expression had a sensitivity of 97.6% and specificity of 73.3%, omitting breast cancers, the sensitivity was 93.8% and specificity 73.2%. Conclusions: HER2 activity was identified in a wide variety of solid tumors and a small but significant proportion of these tumors maybe candidates for treatment with HER2 inhibitors such as trastuzumab. Our analysis also identified that HER2 activity in breast cancers has a distinctive pattern which was not seen in other tumor types. HER2 IHC 3+ expression was much less sensitive among other tumor types compared to breast cancer. mRNA expression, while remaining sensitive among other tumor types, is not specific, even among breast cancer patients. Our analysis also identified that HER2 activity in breast cancers has a distinctive pattern which was not seen in other tumor types.
Radiomics features of ground glass nodules tailored different pathological grades of lung adenocarcinoma.
Authors: Zhang C , Zhai Haoran , He Lan , Liu Zai-Yi , Wu Yi-Long , Zhong Wenzhao 
Published: September 2018

e23127 Background: Different pathological subtypes as well as different grades of adenocarcinoma based on the IASLC/ATS/ERS classification had been proven to be stage-independent predictor of survival. Radiomics features, as a novel analytic method, has been increasingly applied in variety cancer research and may be a potential predictor for preoperatively differentiating pathological grades of adenocarcinoma. Methods: Patients (pts) with radiological proved as solitary ground glass nodule were eligible in this study. Radiomics features derived from computed tomography (CT) images were extracted by Chinese Academy of Science. All pts will be categorized into three groups with lepidic predominance as low-grade, acinar and papillary predominance as intermediate-grade, micropapillary and solid predominance as high-grade. We used L1 penalized constrained continuation ratio model to select relevant radiomics features, and corresponding radiomics signature was constructed. Association between the radiomics signature and pathological grades of adenocarcinoma was explored using the Kruskal-Wallis test and C-index was performed to test the efficacy of differentiating. Results: 82 pts were included in this study. Low-grade, intermediate-grade and high-grade contained 15 (18.3%), 53 (64.6%), 14 (17.1%) pts respectively. 475 radiomics features were extracted from thin section CT image and 10 of them selected through L1 penalized constrained continuation ratio model composed radiomics signature which significantly associated with pathological grades (P < 0.0001). C-index for radiomics signature were 0.813 (95%CI 0.793-0.833). Since clinical characters including gender, age, smoking status, NSE, CEA and CYFRA21-1 were not associated with different grades of adenocarcinoma, we could not establish nomogram based on the radiomics signature and correlated clinical characters. Conclusions: Radiomics features only can be a potential predictor for preoperatively differentiating pathological grades of adenocarcinoma, which may be a more applicable clinical predictor for patients’ survival. Yet large sample sizes are warranted to confirm the results.
PAK4 as a potential therapeutic target in pancreatic ductal adenocarcinoma (PDAC).
Authors: Thillai Kiruthikah , Sarker Debashis , Wells Claire 
Published: September 2018

e23139 Background: PDAC is an aggressive cancer and metastatic spread requires reorganization of the actin cytoskeleton, a process dependent on Rho family GTPases and their interaction with downstream effectors. p21 activated kinases (PAK1-6) are effectors of Rho GTPases Cdc42 and Rac, and play a key role in cell migration and survival. PAK4 can be amplified in PDAC and can reciprocally activate the PI3K pathway. Hepatocyte growth factor (HGF), via c-Met, is an established activator of PAK4 and the PI3K pathway and may promote PDAC invasion. We hypothesized that there is a link between PAK4 and PI3K downstream of HGF and thus PAK4 is a potential therapeutic target in PDAC. Methods: Several invasive PDAC cell lines were used including PaTu 8988T, PaTu 8988S, Capan 1, Panc 1 and PaTu 8902. SiRNA transfection allowed transient loss of PAK4 and cell migration was measured using 2D time lapse microscopy. An organotypic model consisting of PDAC and stromal cells within an extracellular gel of collagen was developed to assess 3D invasion. Immunofluorescence staining of cytokeratin and smooth muscle actin allowed analysis of depth of invasion. Protein expression was measured using western blotting and protein interaction by pulldown assays. Results: Treatment with the c-Met ligand HGF increased migration speed, persistence of direction and importantly PDAC invasion. HGF also stimulated the phosphorylation of several proteins within the PI3K pathway including AKT and PRAS40. Loss of PAK4 expression resulted in a concomitant loss in PI3K signalling. Moreover, PAK4 directly binds to the p85α subunit of PI3K in PDAC cells. Reduced PAK4 expression in PDAC cells suppressed HGF-induced migration, and PAK4 depletion significantly inhibited the invasion response to HGF. Conclusions: We demonstrate a novel link between PAK4, PI3K and AKT, and show the significant effects of PAK4 on PDAC cell polarity, migration and invasion. Our results strongly support further investigation of PAK4 as a therapeutic target in PDAC, particularly given the minimal impact of PI3K-AKT pathway inhibitors in PDAC to date.
Understanding docetaxel and cabazitaxel modes of action in prostate cancer.
Authors: Nelius Thomas , Jarvis Courtney , Filleur Stephanie 
Published: September 2018

e23149 Background: Despite the approval of several new agents, taxanes remains the main treatment with survival benefits for castration-refractory metastatic prostate cancer/mCRPC. Still their mechanisms of action and therapeutic efficacy remain incompletely characterized. In the present study, we proposed to compare docetaxel/Doc and cabazitaxel/Cab, delivered as monotherapy or in combination with the anti-angiogenic and anti-tumoral Pigment Epithelium-Derived Factor/PEDF, on CRPC cells in vitro and in vivo. Methods: CRPCcells were assessed for cell growth, cell cycle, and apoptosis under taxane/control treatment by cytotoxicity, PI incorporation and TUNEL assays. CL1 cells that express PEDF/control were used in vivo. Tumor cells were injected s.c. into CB17-SCID mice. After two weeks, mice were randomized into groups: 1) Placebo; 2) Doc 5mg/kg i.p. d4; and 3) Cab 5-1-0.5-0.1mg/kg i.p. d4, d1-7, d2, daily. To assess the anti-tumor effect of the combination, tumor cell migration and phagocytosis were measured by Boyden chamber and confocal microscopy analyses of CL1-RAW264.7 macrophages co-cultures. Results: Cab was more cytotoxic than Doc in all the cell lines tested.This effect was concomitant to increased cell death, but was not due to autophagy or necrosis. Inversely, we showed that apoptosis was superior in Cab-treated cells than in Doc treatment. In vivo, while 0.5 and 0.1 mg/kg Cab did not improve PEDF efficacy on tumor growth, 1mg/kg was very toxic. In contrast, PEDF combined with 5mg/kg Cab lead to stabilization of the disease and was also found to be drastically more efficient than PEDF/Doc in delaying the disease. In vitro, PEDF/Cab inhibited tumor cell migration at a significant superior level compared to PEDF/Doc. Finally, tumor cells phagocytosis was induced in PEDF/Cab suggesting that the combination may target macrophages within the tumor microenvironment. Conclusions: Our data demonstrated the greater anti-tumor efficacy of Cab compared to Doc. They also insist on the fact that PEDF/Cab could be used as a novel combined therapy for CRPC, and emphasize on the importance in evaluating the cytotoxicity of the novel combination tested and investigating the role of the tumor microenvironment in the anti-tumor effect.
NAMPT inhibition is a novel synthetic lethal therapeutic approach exploiting nuclear-mitochondrial crosstalk in ERCC1-deficient populations.
Authors: Touat Mehdi , Sourisseau Tony , Friboulet Luc , Dorvault Nicolas , Chabanon Roman , Morel Daphné , Adam Julien , Sauvaigo Sylvie , Enot David , Bigot Ludovic , Pontoizeau Clément , Bouillaud Frédéric , Olaussen Ken , Pierron Gérard , Sarasin Alain , Lombès Anne , Ashworth Alan , Lord Christopher J. , Soria Jean-Charles , Postel-Vinay Sophie 
Published: September 2018

e23159 Background: ERCC1 (Excision Repair Cross-Complementation group 1) deficiency is the most frequent DNA repair defect in non-small cell lung cancers (NSCLC), making this enzyme an attractive therapeutic target for synthetic lethal (SL) approaches. Previous data support that DNA damage response is involved in regulation of metabolic homeostasis. We hypothesized that ERCC1 deficiency resulted in metabolic reprogramming of cancer cells that in turn generated specific vulnerabilities. Methods: High-throughput proteomic SILAC (stable isotope labeling by aminoacids in cell culture) and metabolomic (LC-MS, GC-MS, LC-QTOF) profiling were performed on a in-house generated NSCLC model of ERCC1 deficiency. Nicotinamide phosphoribosyltransferase (NAMPT) was selected as main hit and revalidated in low-throughput. Sensitivity to NAMPT inhibition was assessed in several NSCLC models. Potential SL interactions were investigated using functional DNA repair and metabolic assays, and transmission electronic microscopy (TEM). Results: We found marked metabolic rewiring in ERCC1-deficient populations, including decreased NAMPT and NAD+ levels and defects in the tricarboxylic acid cycle. These caused exquisite selective sensitivity to NAMPT inhibition in several in vitro and in vivoNSCLC models; these effects were reversed by the restoration of a functional ERCC1 isoform, establishing a causal link with the ERCC1 defective state. TEM, functional DNA repair and metabolic studies revealed structural and functional defects in the mitochondria of ERCC1-deficient cells, and allowed us to propose a model for this nuclear-mitochondrial SL link. A correlation between NAMPT expression and ERCC1 expression was observed in NSCLC patient samples. Conclusions: These findings open novel therapeutic opportunities that exploit a previously undescribed nuclear/mitochondrial SL link between ERCC1 deficiency and NAMPT inhibition in NSCLC. This highlights the potential for targeting DNA repair / metabolic crosstalk for cancer therapy, and support the evaluation of NAMPT inhibitors in ERCC1-deficient tumors.
Satellite alpha transcripts as a biomarker to predict the development of breast cancer with bilateral or multiple primary malignancies.
Authors: Kakizawa Nao , Suzuki Koichi , Yoshizawa Ayuha , Ichida Kosuke , Saito Masaaki , Futsuhara Kazushige , Rikiyama Toshiki 
Published: September 2018

e23202 Background: The impaired stability of chromosomal structure promotes the abnormal segregation of chromosomes, increasing the risk of carcinogenesis. Chromosomal stability during segregation is managed by appropriate methylation in the centromeric region of chromosomes. Satellite alpha transcripts (SatA) is a non-coding RNA transcribed from the centromere, which could be involved in this machinery. We reported that overexpression of SatA led to chromosomal instability, which was observed in not only cancer regions (CR) but also noncancerous regions (NCR). It was enhanced in NCR of patients with multiple primary malignancies (MPM), suggesting the involvement of SatA in genomic damage in regions where multiple cancers may arise. In this study, we determined whether SatA is involved in breast cancer development with bilateral or MPM. Methods: We constructed lentiviral vectors expressing SatA and control viruses, which were used to infect human mammary epithelial cells. SatA levels were determined by real-time quantitative PCR (qRT-PCR) and copy number alterations were evaluated by array comparative genomic hybridization (CGH). Then, we investigated the levels of SatA in clinical specimens in 135 breast cancer (BC) patients including 128 tumors and 83 matched normal tissues. Results: qRT-PCR showed higher expression levels of SatA in cells infected with SatA virus than in the control. Array CGH analysis indicated frequent copy number alterations at several specific chromosomes in infected cells, despite no alterations in the control. Among the 135 patients, 24 had bilateral breast cancer (BBC) and 18 had MPM. SatA was much higher in CR in BBC and in MPM than in SBC. SatA was also higher in NCR in MPM than without MPM. Considering human epidermal growth factor receptor type2 (HER2), hormone receptor (HR), family history and other factors, the levels of SatA in CR were a significant independent factor predicting the development of BBC patients. Conclusions: Chromosomal instability induced by SatA is involved in the development of BBC and BC with MPM.
In silico validation of a prostate cancer recurrence prognostic signature based on pathways related to stem cells.
Authors: Espinoza-Portocarrero Miguel Arturo , Araujo Jhajaira M. , Pinto Joseph A. , Casado Fanny Lys 
Published: September 2018

e23205 Background: Prostate cancer has the highest incidence in Peruvian male population with mortality close to 50% as opposed to countries with strong preventative programs were mortality is between 10-15%. Early detection and close follow up to avoid or detect recurrence as soon as possible is considered to be the best strategy to reduce this high mortality. However, this is not always the case due to limitations in prevention programs and cultural characteristics of male behavior. Therefore, there is a need to develop better biomarkers and targets. We hypothesize that recurrence occur due to the existence of cells that have acquired stem cell behavior that we denominate prostate cancer stem cell, which are not affected by first-line therapies. Methods: We curated a list of stem-cell genes meshing the WNT Signaling Pathway (KEGG entry: hsa04310) and the Signaling Pathways Regulating Pluripotency of Stem Cells (KEGG entry: hsa04550). We used data from 497 samples of primary tumors whose expression for 231 genes was quantified with NanoString from a public genomic information database (TCGA, provisional). The validation set (GSE21032) consisted of 131 primary tumors cases of prostate cancer. The stepwise multivariate survival analysis performed by the Cox proportional hazards mode selected FZD3, PLCB2, PLCB3 and TP53 as independent prognostic factors for distant recurrence-free survival (DRFS). We developed a four-genes signature using the regression coefficients for each gene. Results: The signature was: -0.363 × FZD3 + 0.432 × PLCB2 + 1.313 × PLCB3 - 0.237 × TP53. The percentile seventy-five score in the discovery set (0.6734) identified two subgroups with different DFRS (P < 0.05). The same score we used in the validation set and was also able to discriminate patients with different DRFS (P = 0.000003). Conclusions: Our in silico validation of a prostate cancer recurrence prognostic signature supports the involvement of stem cell-related pathways in prostate cancer genomics.
Lung cancer genomic alterations in cell free DNA in pleural effusion compared to plasma.
Authors: Zhou Zhenzhen , Chen Rongrong , Chu Yuxing , Hu Xingsheng , Yang Ling , Yi Xin , Zhang Hongbing , Zhang Dongmei , Xia Xuefeng , Liao Zhongxing X. 
Published: September 2018

e23206 Background: Circulating tumor DNA (ctDNA) in plasma has been shown to be informative of the genomic alterations present in lung cancer and has been used to guide tumor treatment and monitor tumor progression. However, patients with lung cancer, even in advanced stage, usually present with small numbers of cancer-related genetic aberrations and low mutation allele frequency (MAF) on average. Malignant pleural effusion is one of common complications for lung cancer patients in advanced stage. Cell free DNA (cfDNA) in pleural effusion may be extensively diluted once entering into the peripheral circulation system. Methods: We implemented targeted capture NGS with a gene panel of 180 lung cancer-relevant genes on 23 paired plasma ctDNA and matched pleural cfDNA samples extracted simultaneously from the same patient with advanced lung cancer (n = 23), including 17 adenocarcinoma. Results: Overall, actionable variations with on label, off-label, or experimental drugs available, were identified in 87% (n = 20) of pleural effusion samples, whereas plasma was 48% (n = 11). Median number of pleural somatic mutations was 4, predominantly located in TP53, EGFR, and ALK; while the median number was 2 in plasma samples. Of that, 39% and 74% of plasma ctDNA and pleural cfDNA samples were observed at an average MAF above 1%, respectively. In addition, 48% and 78% of plasma ctDNA and pleural cfDNA samples were observed with the highest MAF above 1%. The concordance rate for EGFR and ALK alterations with plasma NGS was 83% and 87%, respectively. Conclusions: Our results suggest that pleural effusion-derived cfDNA is more sensitive than plasma for advanced lung cancer patients. With higher MAF and detection rate of actionable variations, pleural effusion-derived cfDNA might guide more precise lung cancer treatment.
Clinical significance of FDG-PET/CT in assessment of recurrence in breast cancer patients before surgery.
Authors: Yoshizawa Ayuha , Futsuhara Kazushige , Suzuki Koichi , Okochi Tomohisa , Rikiyama Toshiki , Kakizawa Nao 
Published: September 2018

e23215 Background: FDG-PET/CT is widely used for the detection of primary breast cancer and metastasis, although its clinical significance is somewhat restricted to appropriate higher-risk populations. We attempted to apply maximum uptake values (SUVmax) of FDG-PET/CT to assess the malignant potential of breast cancer before surgery. Methods: We retrospectively reviewed 187 consecutive patients with invasive breast cancer and no distant metastasis recruited from 2009 to 2011 in our hospital who underwent PET/CT before surgery, and determined the representative PET imaging features by SUVmax. Correlation of SUVmax with several clinicopathological factors was evaluated by regression analysis. Relapse-free survival (RFS) and overall survival (OS) were compared among these factors and SUVmax using univariate and multivariate Cox analysis, Kaplan-Meier curves, and log-rank tests. Results: All patients were women of median age 60 years. The median follow-up period was 72 months. A logarithmic transformation was applied to SUVmax, which resulted in exclusion of 32 patients with no FDG uptake on PET/CT. Regression analysis revealed that SUVmax significantly correlated with ER (P = 0.0138), HER2 (P = 0.0153), lymph node metastasis (P < 0.0001), and tumor size (P < 0.0001). Multivariate analysis showed that tumor size was a significant independent factor. As regression analysis showed a strong correlation between SUVmax and tumor size < 5 cm (P < 0.0001), the 11 patients with tumor > 5 cm were excluded. Concerning the malignant potential of tumors, RFS was evaluated by univariate analysis whereby the median log SUVmax (0.6) was the only significantly independent factor to predict recurrence (P = 0.045). Patients with log SUVmax > 0.6 showed poor RFS (11 patients with recurrence) compared with log SUVmax < 0.6 (2 patients with recurrence) (P = 0.0064). OS showed no significant correlation. Conclusions: PET/CT is potentially a valuable modality to predict tumor recurrence in patients with breast cancer whose tumor size is < 5 cm and demonstrates uptake before surgery.