bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 320: Frequency and patient characteristics of homologous recombination deficiency in metastatic cutaneous melanoma
Authors: Kim Kevin B. , Millis Sherri Z. , Ross Jeffrey , Gay Laurie M. , Vosoughi Elham , Moretto John , Leong Stanley P. , Singer Mark I. , Parrett Brian M. , Minor David R. , Kashani-Sabet Mohammed 
Published: August 2018

Abstract
Purpose: In various cancer types, cells with a homologous recombination (HR) deficiency have been shown to be sensitive to PARP inhibitors. We investigated the frequency of HR pathway gene mutations in melanoma.Experimental Design: Next-generation sequencing analysis that included the entire coding sequence of 315 cancer-related genes was performed on formalin-fixed, paraffin-embedded melanoma samples. Clinical and pathologic characteristics of 62 patients with advanced melanoma were reviewed, and compared with a dataset of 1,986 melanoma patients with available molecular profiling data.Results: Nineteen (30.6%) patients had ≥1 functional HR mutation. The characteristics of patients with HR-deficient melanoma were: median age 69, male predominance (79%) and primary head and neck melanoma (53%). TMB was high in 12 (67%) patients and low in 1 (6%) patient. The most commonly mutated HR-associated gene was ARID2 (13%), followed by ARID1A, ATM, BRCA1, and FANCA (3% each). Among the 19 patients with HR mutation(s), concurrent NF1, NRAS, V600 BRAF, and KIT mutations were found in 7 (37%), 6 (32%), 5 (26%) and 1 (5%) patients, respectively. Presence of HR pathway mutation was associated with absence of ulceration at the primary site, high TMB and clinical response to checkpoint immunotherapy. A larger dataset analyzed by Foundation Medicine, Inc. (n=1,986) showed a similar frequency and pattern of HR mutations. Conclusions: HR pathway gene mutations are frequently observed in advanced melanoma. Melanomas with these alterations may represent a unique subset of patients who are more likely to benefit from checkpoint blockade, and also may be targeted with PARP inhibitors.
Clinical and pathologic characteristics of patients with genetic HR mutationsHR mutation (n=19)Non HR mutation (n=43)p-valueUlceration statusn=16*n=33*0.0050Present2 (12.5%)18 (54.5%)0.0114Absent14 (87.5%)15 (45.5%)0.0479Tumor mutation burdenn=18*n=38*0.0114Low1 (5.6%)17 (44.7%)Intermediate5 (27.8%)8 (21.1%)High12 (66.7%)13 (34.2%)Response to anti-PD-1 antibody inhibitors (+/- ipilimumab)n=12*n=23*0.0479Response10 (83.3%)10 (43.5%)Early Progression1 (8.3%)10 (43.5%)Stable disease1 (8.3%)3 (13.0%)
Citation Format: Kevin B. Kim, Sherri Z. Millis, Jeffrey Ross, Laurie M. Gay, Elham Vosoughi, John Moretto, Stanley P. Leong, Mark I. Singer, Brian M. Parrett, David R. Minor, Mohammed Kashani-Sabet. Frequency and patient characteristics of homologous recombination deficiency in metastatic cutaneous melanoma [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 320.
Abstract 3216: H2AX is a novel prognostic marker of breast cancer
Authors: Katsuta Eriko , Ouchi Mutsuko , Ouchi Toru , Takabe Kazuaki 
Published: August 2018

Abstract
INTRODUCTION: Phosphorylation of histone variant H2AX, termed gamma-H2AX, is well known for its role in DNA damage repair. On the other hand, clinical relevance of expression of H2AX in breast cancer remains to be elucidated. Previously we found that H2AX determines clonogenic cell survival under metabolic oxidative stress and cellular levels of Reactive Oxygen Species (ROS). In this study, we investigated the impact of H2AX expression on breast cancer patients' survival, as well as underlying mechanisms.
METHODS: Breast cancer patients in The Cancer Genome Atlas (TCGA) dataset were classified as either high or low expression of H2AX. Overall Survival (OS) and Disease-Free Survival (DFS) as well as Gene Set Enrichment were compared between these two groups. Gene expression of each cell lines was analyzed by RNA-seq. Radiation sensitivity was quantified using cells from patient-derived xenograft (PDX). Gene expression level after neoadjuvant chemo-radio therapy was compared using publically available database (GSE25113).
RESULTS: H2AX expression level is higher in triple negative breast cancers (TNBC) than non-TNBC (p&lt;0.001) and in HER2 positive tumors than negative tumors (p=0.048) as well as advanced Stage tumors (Stage I vs Stage II/III/IV, p=0.029). H2AX high expressing tumors showed significantly worse OS (p=0.007) as well as DFS (p=0.001) and this was the case only in advanced Stage tumors (Stage I vs Stage II/III/IV, p=0.029). There were more H2AX high tumors with advancement of Stage (Stage I: 2.8%, Stage II: 5.5%, Stage III/IV 7.4%). In agreement, breast cancer cell line clones that develop metastasis expressed higher H2AX compared from their parental cells (4T1 vs 4T1.2; p&lt;0.001, MDA-MB-231 vs LM2-4; p=0.042). Gene Set Enrichment Analysis (GSEA) demonstrated that not only DNA repair (p&lt;0.001) and ROS related gene set (p=0.011), but also Myc target related gene sets (p=0.002) as well as UV response related gene set (p&lt;0.001) were significantly enriched in H2AX high patients. We also demonstrated that H2AX high expressing cells from PDX showed significantly higher sensitivity to radiation therapy with higher ROS production. Indeed, tumors that demonstrated pathological completely response (pCR) after neoadjuvant chemo-radiation therapy had a trend to have higher H2AX levels compared to non-pCR tumors (p=0.093).
CONCLUSIONS: Advanced Stage breast cancers that express high levels of H2AX associated with worse OS and DFS, but showed higher sensitivity to radiation. H2AX can be a prognostic biomarker for recurrent tumor that may be sensitive to radiation therapy.
Citation Format: Eriko Katsuta, Mutsuko Ouchi, Toru Ouchi, Kazuaki Takabe. H2AX is a novel prognostic marker of 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 3216.
Abstract 3293: Solid tumors have frequent mutation, copy number variation and differential mRNA expression of GPCRs: Are such GPCRs functional oncogenes
Authors: Sriram Krishna , Moyung Kevin , Corriden Ross , Insel Paul 
Published: August 2018

Abstract
G protein-coupled receptors (GPCRs), the largest family of membrane receptors, regulate numerous cellular functions and are drug targets for many disorders but not generally in cancer. We analyzed The Cancer Genome Atlas (TCGA) for GPCR mutations, copy number variation (CNV) and mRNA expression in 20 categories of solid tumors. We found that numerous GPCRs are frequently mutated, in particular, certain adhesion GPCRs (e.g.,GPR98 and GPR112), which appear to have a higher density of mutation events than other genes of similar length. Tumors with high mutational burden show a high frequency of such GPCR mutations that may result from DNA damage. CNV (especially amplifications and single-copy deletions) of GPCRs is widespread. In certain tumor types, particular GPCRs (e. g., GPR160) show high-level amplification in &gt;30% of tumors. However, CNV does not appear to be a major factor in determining differential expression (DE) of GPCRs in tumors.
Compared to RNA expression in normal tissues (GTEX database), most solid tumor types (including those accounting for the most annual deaths) differentially express &gt;50 GPCRs, including 77 GPCRs with increased expression in at least one tumor type that are targets for approved drugs, providing opportunities for drug repurposing. DE of GPCRs is largely independent of tumor stage/grade, largely insensitive to specific driver mutations, and similar in primary and metastatic tumors, which both have high expression of numerous GPCRs in nearly all members within tumor populations. Cancer cells highly express most GPCRs overexpressed in tumors, making such GPCRs (especially those that are druggable) attractive candidates for further validation and functional studies. Multiple published studies provide functional data for certain such GPCRs.
These findings imply a previously unappreciated role for GPCRs in solid tumors. Overexpressed GPCRs in tumors may regulate tumor biology as “functional oncogenes” and are potentially novel biomarkers and therapeutic targets, including for approved drugs.
Citation Format: Krishna Sriram, Kevin Moyung, Ross Corriden, Paul Insel. Solid tumors have frequent mutation, copy number variation and differential mRNA expression of GPCRs: Are such GPCRs functional oncogenes [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 3293.
Abstract 3318: Frequent promoter hypermethylation correlates with better prognosis in pharyngeal cancer
Authors: Nakagawa Takuya , Matsusaka Keisuke , Misawa Kiyoshi , Fukuyo Masaki , Takane Kiyoko , Hanazawa Toyoyuki , Matsubara Hisahiro , Okamoto Yoshitaka , Kaneda Atsushi 
Published: August 2018

Abstract
The incidence of Human Papilloma Virus (HPV) associated oropharyngeal cancer is dramatically increasing in developed countries, due to mainly HPV 16. Whereas viral infection status could affect molecular subtypes in other cancers, molecular features of HPV(+) and HPV(-) OPSCCs including epigenetic aberrations are not fully clarified. We here performed genome-wide DNA methylation analysis of OPSCC. We identified 144 candidate methylation-associated silencing genes using Infinium 450k analysis of 13 OPSCC samples, 4 normal mucosal samples and two HNSCC cell lines with/without 5Aza/TSA. Re-expression of the hypermethylated genes by 5-aza-2-deoxycytidine was confirmed by RNA-seq. Among the 144 candidate genes, 9 genes were selected and their methylation status was analyzed in 70 pharyngeal SCC cases including 55 OPSCC and 15 hypopharyngeal SCC cases using pyrosequencing. HPV(+) samples showed higher methylation level within all the samples (P=0.0002, t-test) and within OPSCC (P=0.001, t-test). While HPV infection significantly correlated with positive staining of p16 in immunohistochemistry, HPV(+) as well as p16(+) status significantly correlated with better prognosis (P = 0.005 and 0.002, log-rank test). The aberrant hypermethylation of an identified marker gene also correlated with better prognosis significantly when all the cases were analyzed (P = 0.04). Interestingly, the its hypermethylation status also correlated with better prognosis within p16(-) cases (P = 0.03). Our data suggest that aberrant DNA methylation might be involved in genesis of OPSCC, that DNA methylation might associate with HPV infection, and that methylation marker might work as prognostic marker. To elucidate the correlation between DNA methylation and OPSCC including HPV(+) and HPV(-) OPSCCs, we additionally performed genome-wide DNA methylation analysis of OPSCC using Infinium 450k analysis of 83 OPSCC samples, and integrated our data with 81 OPSCC data from the Cancer Genome Atlas (TCGA). HPV(+) and HPV(-) OPSCCs were mainly classified into two epigenotypes, respectively. Analyzing the correlation with clinicopathological data, we created a new classification strategy for OPSCC.
Citation Format: Takuya Nakagawa, Keisuke Matsusaka, Kiyoshi Misawa, Masaki Fukuyo, Kiyoko Takane, Toyoyuki Hanazawa, Hisahiro Matsubara, Yoshitaka Okamoto, Atsushi Kaneda. Frequent promoter hypermethylation correlates with better prognosis in pharyngeal 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 3318.
Abstract 3334: CREB is required for KRAS-driven lung tumorigenesis
Authors: Lee Jong woo , Slack Frank J. , Nestler Eric J. , Herbst Roy S. , Koo Jaseok Peter 
Published: August 2018

Abstract
The aberrant constitutive activation of the transcription factor, cyclic-AMP response element- binding (CREB) protein, has been associated with poor prognosis and chemotherapeutic resistance in KRAS-mutated human cancers, one of which includes non-small cell lung cancer (NSCLC). However, the role of CREB in KRAS-driven lung tumorigenesis has not been fully understood. Using adenoviral delivery of Cre specifically to the mouse lung, we generated a new transgenic lung cancer mouse model driven by Kras activating mutation G12D and concomitant with Creb loss (KrasLSL-G12D/+; CrebFlox/Flox). In this study, we used this model to show that a proto-oncogenic transcription factor CREB, is required for KRAS-driven lung tumorigenesis. Loss of Creb (Creb-/-) in the mice harboring Kras-mutated lung tumors significantly suppressed tumor development, and thus, dramatically prolonged mouse survival when compared to either wild (Creb+/+) or heterozygous (Creb+/-) deletion of Creb. Mechanistically, we identified a few novel CREB target gene. These data suggest that CREB is essential for KRAS-driven lung tumorigenesis and that CREB could be a potential target for therapeutic treatment for individuals suffering from KRAS-mutant lung cancers.
Citation Format: Jong woo Lee, Frank J. Slack, Eric J. Nestler, Roy S. Herbst, Jaseok Peter Koo. CREB is required for KRAS-driven lung tumorigenesis [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 3334.
Abstract 3342: Truncated glioma-associated oncogene homolog 1 (tGLI1) is a novel mediator of mesenchymal subtype of glioblastoma and a novel transcriptional activator of CD44
Authors: Rimkus Tadas K. 
Published: August 2018

Abstract
The subpopulation of stem-like cells, or glioma stem cells (GSCs), is a key driver of tumor initiation, recurrence, and chemoresistance. Recently, patient-derived GSC lines were identified to contain two mutually exclusive subtypes termed proneural and mesenchymal. Mesenchymal GBM and GSCs were found to be more aggressive and radioresistant; however, the molecular pathways supporting mesenchymal GBM and mesenchymal GSCs are not well understood. To address this knowledge gap, we examined truncated glioma-associated oncogene homolog 1 (tGLI1) for its role in mesenchymal subtypes of GBM and GSCs. Discovered in our laboratory, tGLI1 is a novel alternatively spliced, gain-of-function variant of GLI1 zinc-finger transcription factor with an in-frame deletion of 41 codons retains all of the known functional domains of GLI1, but gains the ability to activate genes not regulated by GLI1. In this study, we report for the first time that tGLI1 is a tumor-specific transcription factor that facilitates GBM growth, enriches in the mesenchymal subtype of GBM and GSCs, and promotes mesenchymal GSCs via transcriptionally activating CD44 expression. Using an orthotopic GBM xenograft mouse model, we observed that tGLI1-overexpressing tumors grew more aggressively, with increased proliferation and angiogenesis, compared to control and GLI1-overexpressing xenografts. IHC analysis using tGLI1- and GLI1-selective antibodies we developed showed that tGLI1 was significantly expressed in GBM specimens but undetectable in normal brains whereas GLI1 was expressed in both tissues. Datamining further showed that tGLI1 activation signature (tGAS) was correlated with glioma grade, tumor angiogenesis, and poor overall survival, and that GBMs with high tGAS were enriched with mesenchymal GBM and GSC gene signatures. Neurospheres contained increased levels of tGLI1, but not GLI1, compared to the monolayer culture. Mesenchymal GSCs expressed more tGLI1 than proneural GSCs. Ectopic tGLI1 expression significantly enhanced the ability of GSCs to yield neurospheres in vitro and form aggressive tumors in mouse brains. Finally, we examined the ability of tGLI1 to regulate stemness genes and found that tGLI1 binds to and transactivates the promoter of the CD44 gene, a marker and mediator for mesenchymal GSCs. Collectively, these findings advanced our understanding of GBM biology by establishing tGLI1 as a novel transcriptional activator of CD44 and a novel mediator of mesenchymal GBM and GSCs.
Citation Format: Tadas K. Rimkus. Truncated glioma-associated oncogene homolog 1 (tGLI1) is a novel mediator of mesenchymal subtype of glioblastoma and a novel transcriptional activator of CD44 [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 3342.
Abstract 3377: Extensive subclonal mutations in human colorectal cancers detected by duplex sequencing
Authors: Loeb Lawrence A. , Loubet-Senear Kaitlyn J. , Kohrn Brendan F. , Schmitt Michael W. , Bronner Mary P. , Beckman Robert A. 
Published: August 2018

Abstract
The accumulation of somatic mutations is a defining hallmark of cancer. Human colorectal cancers (CRC) contain thousands of mutations that are detected at frequencies greater than 1%. Some of these are “driver mutations” that have been positively selected during tumor progression. In addition, subclonal mutations—those occurring only in a fraction of malignant cells—are randomly distributed and contribute to phenotypic and morphologic heterogeneity of cancer cells within a tumor. Cells containing specific subclonal mutations may be present prior to therapy and can be positively selected and account for the rapid emergence of therapeutic resistance. The extent of subclonal mutations in cancer, however, has been difficult to quantify, as the high error rate of next-generation sequencing precludes reliable detection of mutations present in fewer than 1-5% of cells. Here, we apply the highly accurate duplex sequencing methodology to quantify the extent of subclonal mutations in CRC. We analyzed somatic mutations in genes encoding replicative DNA polymerases (POLδ and POLε) as well as in genes reported to be frequently mutated in CRC. Duplex sequencing was carried out at depths varying from 500X-30,000X and an accuracy of 10-8. We find that CRCs with DNA repair deficits harbor an unexpectedly large complement of unique subclonal mutations; indicating that the mutational diversity of CRCs has been greatly underestimated. The frequency of subclonal mutations in normal colonic mucosa and CRC is greater than reported for clonal mutations. The burden of tumor-associated subclonal mutations does not correlate with age and the spectrum of single-nucleotide substitutions is different from that in nonmalignant cells, indicating that different mechanisms of mutation accumulation are operative in normal and CRC. Our data are consistent with a mutation rate of 1.1 x 10 per base pair, indicating that each malignant cell and its daughter encoded genomic DNA differs by more 3,000 nucleotides. The linearity of subclonal mutation accumulation as a function of sequencing depth, using DNA obtained from five different tumors, is in accord with a neutral model of tumor evolution. We calculate that the probability of mutations at any type is so high that it is likely that every possible somatic point mutation is present by the time a tumor is clinically detectable, and this could account for the high frequency by which tumors become resistant to therapeutic agents.
Citation Format: Lawrence A. Loeb, Kaitlyn J. Loubet-Senear, Brendan F. Kohrn, Michael W. Schmitt, Mary P. Bronner, Robert A. Beckman. Extensive subclonal mutations in human colorectal cancers detected by duplex sequencing [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 3377.
Abstract 3378: Variance in the distance between chromosome territories 9 and 22 in lymphocytes from peripheral blood healthy subjects: A proof of concept for a possible risk factor in chronic myeloid leukemia
Authors: Vallejo David G. , Fabian Eunice , Herrera Luis A. 
Published: August 2018

Abstract
The objective of our study was to assess the variations in the 3D organization of Chromosome Territories (CT) of chromosomes 9 and 22 in lymphocytes from healthy subjects. The differences in the distances of CTs 9 and 22 between subjects may provide a new perspective in the predisposition for specific chromosome translocations. We quantified the intra- and inter-subject variation in the distance of CT 9 and 22 as a proof of concept for new questions on the physiological and pathological effects of these differences. Methods: Blood samples from healthy subjects were processed for the isolation of lymphocytes with Ficoll as the gradient media. After the isolation, we fixed the cells directly onto coverslips for a 3D Fish protocol with 9 and 22 whole chromosome probes. Our protocol has been standardized to maintain the integrity of the nucleus with only minor changes in its volume. After the hybridization, we used the Elyra System of Zeiss to obtain super resolution images in Z stack. The images were processed with the Imaris software for its 3D reconstruction, measurement (distances, volumes and colocalization) and analysis. Results: The CTs 9 and 22 behave differently in peripheral blood lymphocytes. The CT 22 has a more internal position (closer to the center of the nucleus) in comparison with the CT 9, which can be seen most of the times in contact with the border of the nucleus. The CT 22 occupies a smaller volume than CT 9, which has almost a twice as larger volume. The CTs 9 have a polarized distribution inside the nucleus, therefore the distance between the CT 9-9 was larger (~7.3 μm ± 0.9) than the distance between CT 22-22. Although the position of the CTs was highly variable in cells from the same individual, we found a statistically significant difference in the inter-individual distance between CT 9-9 and the minimal distance between CT 9-22. Conclusion: Our study suggests that there are differences in the distribution of CT in lymphocytes isolated from peripheral blood between our subjects. These differences could prove to be a new individual characteristic with important implications in the predisposition for specific diseases, mainly to those related with chromosomal rearrangements.
Citation Format: David G. Vallejo, Eunice Fabian, Luis A. Herrera. Variance in the distance between chromosome territories 9 and 22 in lymphocytes from peripheral blood healthy subjects: A proof of concept for a possible risk factor in chronic myeloid leukemia [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 3378.