bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2138: Whole genome cfDNA profiles reveal common signatures of Immune checkpoint inhibition response in kidney, melanoma, and lung cancers
Authors: Donnella Hayley , Zhang Yue , Wang Irving , Vallania Francesco , Louie Maggie , Lin C. Jimmy 
Published: July 2021

Abstract
Immune checkpoint inhibition (ICI) via anti-PD-1/PD-L1 and anti-CTLA4, has improved clinical outcomes for multiple cancers, including non-small cell lung cancer (NSCLC), kidney cancer, and melanoma. Despite this success, response rates remain low, highlighting the need for more robust predictive biomarkers. In this study, we used cell-free DNA (cfDNA) profiles from patients undergoing ICI therapy to identify common signatures associated with responses shared among the three cancers. Whole-genome sequencing (mean coverage=18X) of cfDNA was performed on pre-treatment plasma samples from 126 patients across three cancers (NSCLC, n=91; kidney, n=21; melanoma, n=14). Transcriptional activation for protein-coding genes was then inferred by modeling fragment distribution around each transcription start site (TSS-GAP). Transcription factor binding activity (TFBA) was estimated by measuring binding site accessibility across the genome.
To delineate potential signatures of response, we performed a gene set enrichment analysis (GSEA) based on weighted average effect sizes of TSS-GAP levels between response groups across the three cancer types. GSEA results showed an enrichment of DNA repair and cell cycle genes in non-responders and of EMT processing genes in responders. To identify shared signatures of ICI response, we performed a meta-analysis by (1) computing the effect size between response groups for TFBA and TSS-GAP features in each cancer type; (2) calculating a weighted-average effect size across cancer types; (3) performing gene selection based on the degree of heterogeneity among cancer types, followed by false discovery rate correction and assessment of significance through Monte Carlo permutation testing. This analysis identified 13 transcription factors and 269 genes consistently enriched in response groups across these cancer types. Notably, this analysis revealed significantly higher accessibility in STAT5A (p=0.02), JUN (p=0.02) and JUNB (p=0.03) in non-responders, suggesting JAK/STAT-pathway dependency as a common feature in ICI resistance.
Using our platform that detects both tumor and non-tumor-derived signals, we identified common signatures of ICI response, revealing a potential pathway of resistance through JAK/STAT signaling and a possible EMT signature of response in kidney, melanoma, and NSCLC. These findings warrant further investigation into using cfDNA signatures for patient stratification and response monitoring.
Citation Format: Hayley Donnella, Yue Zhang, Irving Wang, Francesco Vallania, Maggie Louie, C. Jimmy Lin. Whole genome cfDNA profiles reveal common signatures of Immune checkpoint inhibition response in kidney, melanoma, and lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2138.
Abstract 2151: Neuroendocrine cancer cells have changed HOX code during trans-differentiation
Authors: Cheng Siyuan , Yang Shu , Shi Yingli , Shi Runhua , Yeh Yunshin , Yu Xiuping 
Published: July 2021

Abstract
Background: HOX genes encode Homeobox-containing proteins. There are 39 HOX genes organized into 4 clusters in human. The nested and partially overlapping expression of HOX genes in an anatomic region can determine its tissue specificity, which is termed as “HOX code”. In this study, we examined the expression of HOX genes in neuroendocrine prostate cancer (NEPCa), an aggressive subtype prostate cancer that arises from prostate adenocarcinoma (AdPCa) trough trans-differentiation.
Methods: The HOX genes expression data were extracted from Cancer Cell Line Encyclopedia (CCLE) dataset. All in silico analysis were performed by using R language. Immunohistochemistry (IHC), dual immunofluorescence staining, Western blot and RT-qPCR were conducted to access the expression of HOXs.
Results: Using the HOXs' mRNA expression data from CCLE, we generated HOX codes for 25 different types of tissues. These HOX codes were validated in TCGA pan cancer. By calculating the Pearson correlation, we were able to use 9 HOX codes including prostatic HOX code to identify the tissue origins of the cancer samples. Further, we found that in prostate cancer, the NEPCa samples have lost prostatic HOX code while majority of the AdPCa samples maintain the prostatic HOX code. The expression of HOXB13, the most prominent HOX expressed in prostatic tissues, was increased in AdPCa along with PCa progression but was decreased in NEPCa. Similarly, we found that in breast cancer, a sub-group of samples correlated well with the HOX code of mammary gland, but the rest did not. By comparing the differentially expressed genes in these two subgroups of samples, we found that the neuroendocrine markers including CHGA, CHGB and SYP were higher in HOX code-negative samples compared with HOX code-positive ones. Additionally, we observed a similar phenomenon in colorectal cancer samples: The expression of neurogenesis genes were enriched in HOX code-negative subgroup.
Conclusions: 1) The expression of HOXB13 is decreased in NEPCa. 2) NEPCa has changed HOX code, suggesting the loss of prostatic identity in these samples. 3) The association of neuroendocrine phenotype with the changes in HOX code is not limited to prostate cancer but also is observed in other types of cancer.
Significance: The HOX codes we established can be used in pan cancer research to identify the tissue origins of cancer samples and to study the trans-differentiation of cancer cells.
Funding: This study is supported by: The LSUHS Office of Research SEED awards, NIH R01 CA226285 and Feist-Weiller Cancer Center.
Citation Format: Siyuan Cheng, Shu Yang, Yingli Shi, Runhua Shi, Yunshin Yeh, Xiuping Yu. Neuroendocrine cancer cells have changed HOX code during trans-differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2151.
Abstract 2156: Genomics and molecular analysis of Aurora kinase B (AURKB) in response to antiretroviral (ARV) treatment in lung cancer
Authors: Marima Rahaba Makgotso , Hull Rodney , Dlamini Zodwa , Penny Clement 
Published: July 2021

Abstract
Aurora kinase B (AURKB) is essential for normal physiological processes. However, aberrant AURKB expression has been reported in various cancers, including lung cancer. Lung cancer is a leading non-AIDS defining cancer (NADCs) and the relationship between the use of antiretrovirals (ARVs) and lung cancer is poorly understood. The anti-proliferative effects of Efavirenz (EFV) and Lopinavir/ritonavir (LPV/r) have also been documented. This study aimed at determining the genomic and molecular roles of AURKB in lung cancer in response to ARV treatment. For this purpose, cellular (xCELLigence RTCA), molecular (RT-qPCR) and bioinformatics tools were used in normal fibroblasts (MRC-5) and adenocarcinoma (A549) lung cells. Real-Time Cell Analysis (RTCA) data confirmed the anti-proliferative effects of ARVs in a time-dependent manner. AURKB gene expression was elevated in A549 compared to MRC-5 in non-ARV treated. Interestingly, p53 and CASP3 gene expression was downregulated. Contrarily, ARV treatment resulted in the formation of a negative signaling loop due to AURKB being downregulated, while CASP3 and p53 were upregulated. KEGG analysis demonstrated AURKB, CASP3 and p53 as cell cycle related genes. STRING database searches showed a strong protein-protein interaction (PPI) between AURKB and p53, and CAP3 and p53, but a weak PPI between AURKB and CASP3. Gene Ontology (GO) analysis revealed a decline in serine/threonine kinase (AURKB) activity in cancer cells in response to ARV treatment. Although not yet confirmed, AURKB displays oncogene features, while its overexpression has been shown to deregulate p53. The association between the use of ARVs and lung carcinogenesis remains to be fully comprehended and targeting AURKB signaling may help shed light on this relationship.
Citation Format: Rahaba Makgotso Marima, Rodney Hull, Zodwa Dlamini, Clement Penny. Genomics and molecular analysis of Aurora kinase B (AURKB) in response to antiretroviral (ARV) treatment in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2156.
Abstract 2159: Oscillating p53 temporal dynamics enable proliferative recovery of cells following DNA damage
Authors: Lu Dan , Jimenez Alba , Jambhekar Ashwini , Lahav Galit 
Published: July 2021

Abstract
The transcription factor and tumor suppressor protein p53 regulates cellular outcomes (e.g. cell cycle arrest, senescence or apoptosis) following DNA damage. Cellular outcomes can be influenced by modulating the temporal expression dynamics of p53, which in turn alters target gene mRNA expressions patterns. However, it is not clear how changes in such mRNA dynamics would eventually results in differences in temporal protein expression dynamics, which ultimately determines the cell outcome. By quantifying mRNA and protein by RNA-Seq and mass-spectrometry, respectively over time, we systematically categorized the different dynamics which could arise of p53 target mRNAs and proteins. We show that while p53 target proteins plateaus under pulsatile dynamics, the majority of target proteins are enhanced and accumulates under sustained dynamics including many regulators of terminal cell fates such as apoptosis and senescence. Next we derived synthesis and degradation rates based on empirical measurements to model how different p53 dynamics could lead to the assortment of subsequent target protein dynamics. We show that target protein dynamics are highly governed by protein degradation rate, implying the temporal selection of target gene expression is not pre-determined by the initiating stress signal, but rather through differences in the inherent protein degradation rates. Furthermore, we identify multiple unique signaling network motifs which results in target protein accumulation only under sustained (persistent) but not pulsatile (oscillatory) p53 dynamics. Our results highlight the diversity of mechanisms cells evolved to decode transcription factor dynamics as well as the role of p53 in governing cellular outcome, important both in understanding cellular information processing as well as therapeutic implications for cancer treatments.
Citation Format: Dan Lu, Alba Jimenez, Ashwini Jambhekar, Galit Lahav. Oscillating p53 temporal dynamics enable proliferative recovery of cells following DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2159.
Abstract 2164: Overexpression of the TERT binding proteins GABPA/B in Glioblastoma
Authors: Timmer Marco , Papazacharias Efthymios , Goldbrunner Roland 
Published: July 2021

Abstract
Enhanced expression of TERT in gliomas is a result of two hotspot mutations, C228T and C250T, at the promoter region. GA-binding proteins selectively bind at these positions, respectively causing an activation of the promoter and overexpression of TERT. GABP is a multimeric protein consisting of GABPA and GABPB with its isoforms GABPB1, GABPB1-L, GABPB1-S, GABPB2. In this study, we investigated the mRNA expression and association between TERT and GABPA/B isoforms in tumor samples of different glioma grades. The expression was determined by quantitative real-time PCR and the results were statistically analyzed. We present that TERT is mainly expressed in primary glioblastomas. All GA-binding proteins progress through the glioma grades and have the highest expression levels in secondary glioblastomas. In secondary glioblastomas after chemotherapy, GABPB1 and GABPB1-L are lower expressed than without treatment. In high grades, TERT and GABPA, GAPB1, GABPB1-L, GABPB1-S are upregulated compared to low grades. Between primary and secondary glioblastomas with and without chemotherapy, TERT is elevated in the former while GABPB1 is increased in the secondary glioblastomas. GABPA and GABPB1, GABPB1-L and GABPB1-S positive correlate in primary glioblastomas. The present study confirms the upregulation of TERT in primary glioblastomas while all GABP proteins rise with the malignancy of the gliomas. TERT and all GABP proteins seem to play a key role in the gliomagenesis.
Citation Format: Marco Timmer, Efthymios Papazacharias, Roland Goldbrunner. Overexpression of the TERT binding proteins GABPA/B in Glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2164.
Abstract 2178: Spectrum of pathogenic germline mutations in Chinese esophageal squamous cell carcinoma patients through next-generation sequencing
Authors: Cai Ruijun , Zheng Yating , Xie Wenzhuan , Huang Mengli 
Published: July 2021

Abstract
Background: Esophageal Squamous Cell Carcinoma (ESCC) is one of the leading cause of cancer death in China, while the nature of genetic factors related to ESCC has not been well-studied. The purpose of this study is to assess the inherited genetic factors regarding pathogenic germline mutations in Chinese ESCC population.
Methods: Tumor tissue samples from Chinese patients with ESCC were analyzed using next generation sequencing (NGS) (panel on 381/733-gene). MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was evaluated using immunohistochemistry (Dako 22C3). TMB was defined as total number of somatic non-synonymous mutations in coding region.
Results: Genomic profiling of DNA of 271 ESCC patients were analyzed using NGS, of which 251 (92.6%) harbored 354 pathogenic or very likely pathogenic germline mutations in 94 genes. In ESCC patients with germline mutations, the most frequently germline mutated genes were CYP2C19 (54.18%), followed by UGT1A1 (41.04%), RAC1 (35.06%), VEGFA (34.66%), DPYD (33.47%), CD74 (31.47%), MGMT (31.08%), CYP2D6 (29.88%), BCL2L11 (12.35%), FANCA (7.97%), ALK (7.57%), APC (7.17%), and BARD1 (5.98%). Of all the 94 germline mutated genes, 26.6% (n=25) lay in the DNA damage repair (DDR) pathways. The most frequently germline mutated DDR genes were FANCA (7.97%), followed by BARD1 (5.98%), FANCG (5.98%), BLM (5.58%), BRCA2 (5.18%), BRCA1 (4.78%), FANCD2 (4.78%), POLD1 (3.98%), ATM (3.59%), and POLE (3.58%). MSI status analysis was performed in 246 of 251 ESCC patients with germline mutated genes, and the results showed that all the patients with germline mutated genes were determined to be MSS. In addition, among 251 ESCC patients with germline mutated genes, 163 of them were tested for PD-L1. The results showed that 45 (27.6%) of the ESCC patients were PD-L1 positive (CPS≥10) and 118 (72.4%) were PD-L1 negative. Of the 247 ESCC patients with germline mutations that could be evaluated for TMB, 60 (24.29%) patients had TMB≥10Muts/Mb.
Conclusions: As the first study to explore the pathogenic germline mutation profile of Chinese ESCC patients, our study provides valuable clues for the assessment and clinical management of genetic susceptibility to ESCC patients.
Citation Format: Ruijun Cai, Yating Zheng, Wenzhuan Xie, Mengli Huang. Spectrum of pathogenic germline mutations in Chinese esophageal squamous cell carcinoma patients through next-generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2178.
Abstract 2205: Molecular subtypes of head and neck cancer in patients with African ancestry
Authors: Mezghani Nadia , Yao Alexandria G. , Taylor Alison M. , Momen-Heravi Fatemeh 
Published: July 2021

Abstract
Epidemiological data identifies disparities in black patients for head and neck squamous carcinoma (HNSCC) screening, detection, treatment, and survival. Although socioeconomic and environmental factors play a role in the existing racial disparities, HNSCC incidence and survival rates in the black population cannot be attributed to these factors alone. To investigate the role race plays in the genomics of head and neck cancer, we examined HNSCC samples from 49 black and 446 white patients in the Cancer Genome Atlas (TCGA). We used computationally-derived ancestry identifications to correlate race with HNSCC molecular features. We then characterized the extent to which genomic alterations in black patients impact their clinical outcomes. We found that black patients lived significantly fewer disease-free months and had a poorer overall survival than white patients. Black patients showed a higher frequency of human papillomavirus (HPV)-negative than HPV-positive tumors compared to white patients. Black patients were found to suffer higher rates of metastasis and more aggressive lymph node involvement. Differences in patient primary tumor site were also identified, with black patients having a higher prevalence of tumors in the larynx and lower prevalence of tumors in the tongue compared to white patients. We also found higher frequencies of RUNX1T1, KMT2D, and UNC13C mutations and lower frequency of PIK3CA mutations in black patients. We found a significant enrichment of MYC signaling and amplifications in the tumors of black patients compared to white patients. Novel data uncovered by this project brings us closer to understanding the racial disparities in HNSCC, and advances research aimed at eliminating those disparities. Unique tumor mutations and molecular signatures show promising clinical utility in providing more targeted, individualized screening diagnostic, and treatment modalities to reduce outcome disparities in the black population.
Citation Format: Nadia Mezghani, Alexandria G. Yao, Alison M. Taylor, Fatemeh Momen-Heravi. Molecular subtypes of head and neck cancer in patients with African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2205.
Abstract 2215: Landscape of RET fusion identified by next-generation sequencing in a Chinese multi-cancer retrospective analysis
Authors: Lei Ting , Wang Weiran , Wang Danhua , Fu Junfeng , Wang Yu , Wang Ze , Fan Zhe , Lv Zhenyang , Ma Tonghui 
Published: July 2021

Abstract
Background: Fusion of RET with several partner genes has been detected in papillary thyroid, lung, colorectal, pancreatic and breast cancers. FDA has approved Retevmo (Selpercatinib) for lung and thyroid cancers with RET gene mutations or fusions. Here we focused on the prevalence of RET fusions in a Multi-cancer cohort (besides lung and thyroid cancers) for patients (pts) whom might benefit from RET inhibitors in clinical development.
Methods: Genomic profiling was performed on 12,888 lung cancer pts, 2,848 colorectal cancer pts, 1,785 liver cancer pts, 1,169 Gastric cancer pts and 232 thyroid cancer pts from Jan. 2017 to Dec. 2019 using next-generation sequencing (NGS), which covers all exons of RET and specific intron 7-11 containing the break points of fusions. The fusion patterns of RET were analyzed.
Results: A total of 165 RET fusions were identified in approximately 0.86% (163/18,922) of this Chinese multi-cancer cohort. The RET fusion-positive rates were 1.05% (135/12,888) in lung cancer pts, 0.39% (11/2,848) in the colorectal cancer pts, 0.06% (1/1,785) in liver cancer pts, 0.09% (1/1,169) in the 1169 Gastric cancer pts and 6.03% (15/232) in the 232 thyroid cancer pts tested. The most common partners were KIF5B (62.04%) and CCDC6 (21.17%) in lung cancer, NCOA4 (45.45%) and CCDC6 (27.27%) in colorectal cancer, and CCDC6 (93.33%) and NCOA4 (6.67%) in thyroid cancer. The most frequent regions of RET fusions were intron 11 (140/165) and intron 10 (15/165). The common fusion partners detected in different cancers are variable, indicating that the same oncogene has different carcinogenic mechanisms in cancers, and the sensitivity of these fusions to RET inhibitors in different cancers needs to be further studied.
Conclusions: This study revealed the molecular features of RET rearrangement in Chinese cancer pts, which might result in more effective personalized diagnoses and therapies.
Citation Format: Ting Lei, Weiran Wang, Danhua Wang, Junfeng Fu, Yu Wang, Ze Wang, Zhe Fan, Zhenyang Lv, Tonghui Ma. Landscape of RET fusion identified by next-generation sequencing in a Chinese multi-cancer retrospective analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2215.
Abstract 2216: Exploration of the genomic features of pan-neuroendocrine tumors in a Chinese retrospective analysis
Authors: Ye Jinyan , Wang Weiran , Wang Danhua , Ma Tonghui 
Published: July 2021

Abstract
Background: A neuroendocrine tumor (NET) begins in the specialized cells of the body's neuroendocrine system. Most NETs take years to develop and grow slowly. However, some NETs can be fast-growing. NETs can occur in any part of the body, including gastrointestinal (GI) tract (43%), lung (30%), pancreas (7%) and other organs. Here, we reported an analysis of genomic features in 16 GI tract, 45 lung and 13 pancreas NETs.
Methods: Patients (pts) with neuroendocrine tumors were enrolled, and surgical tumor tissues or plasma samples were collected. Mutation profiling was performed by next-generation sequencing (NGS).
Results: Compared with GI tract NETs patients (Age±SD, 52±11.2), lung NETs patients (Age±SD 62±8.4, P&lt; 0.001) occurred in older patients, and the median age (±SD) of pancreas NETs patients was 58 (±10.8). Mutations were identified in 66 of NETs patients (89.19%), including 12 GI tract (75%), 43 lung (95.56%) and 11 pancreas (84.62%) NETs. Mutations of TP53 (43.85%, 7/16), APC (31.25%, 5/16) and KRAS (25%, 4/16) in GI tract NETs; TP53 (80%, 36/45), LRP1B (24.44%, 11/45) and EGFR (20%, 9/36) in lung NETs and MEN1 (30.77%4/13) in pancreas NETs were observed as the most commonly genetic variations in different type of NETs, which located in different signal pathways and suggested different pathogenesis. Meanwhile, there was no MEN1 mutations and only one LRP1B or EGFR mutation (6.25%, 1/16) occurring in GI tract NETs, one MEN1 mutation (2.22%, 1/44) occurring in lung NETs, and one TP53, KRAS or LRP1B mutation (7.69%, 1/12) and no APC or EGFR mutations occurring in pancreas NETs. In total, although gastrointestinal tract, lung and pancreas NETs all begin in the cells, which have traits of both hormone-producing endocrine cells and nerve cells, the mutation spectrums are very different. On the contrary, the mutations carried by NETs in different locations are related to the organ.
Conclusions: In summary, genomic characterization of NETs may offer insights into tumorigenesis and identify potential therapeutic targets in this disease.
Citation Format: Jinyan Ye, Weiran Wang, Danhua Wang, Tonghui Ma. Exploration of the genomic features of pan-neuroendocrine tumors in a Chinese retrospective analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2216.