bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1697: Molecular features of refractory metastatic breast cancer
Authors: Chen Zhanhong , Zhang Yuzi , Zhao Jing , Cai Shangli , Yin Yongmei 
Published: August 2019

Abstract
Background: Breast cancer is the most frequently diagnosed cancer in women worldwide and metastatic disease remains generally incurable, indicating a need for new drug discovery for metastatic breast cancer. In this study, we investigated the molecular features of refractory metastatic breast cancer.
Methods: 74 metastatic refractory breast cancer patients who received molecular screening using next generation sequencing (NGS) between 2015 and 2017 were included in this analysis. Clinical and pathologic characteristics of these patients were reviewed.
Results: Among the 74 patients, 27%, 51.4%, 10.8%, 10.8% had hormone receptor (HR)-negative HER2-negative, HR-positive HER2-negative, HR-positive HER2-positive, HR-negative HER2 positive. 54.1%, 48.6%, 9.5%, 47.3% had liver, lung, brain, bone metastasis. The most significantly mutated genes in refractory HR-positive breast tumors included TP53 (54.3%), PIK3CA (52.2%), CCND1 (19.6%) and ESR1 (15.2%). The most significantly mutated genes in refractory HR-negative breast tumors included TP53 (82.1%), PIK3CA (50%), MYC (14.3%), NF1 (14.3%) and KRAS (10.7%). Genes in PI3K/AKT/mTOR pathway were significantly mutated in 76.1% of HR-positive and 82.1% of HR-negative refractory breast tumors, respectively. Mutation of genes involved in DNA damage response pathway were observed in 23.9% of HR-positive tumors and 32.1% of HR-negative tumors. 21.7% of HR-positive tumors and only 3.6% of HR-negative tumors harbored at least one gene alteration in FGFR pathway (P = 0.04). 30.4% (17/74) of HR-positive tumors and 10.7% (3/28) of HR-negative tumors carried at least one gene alteration in CDK pathway (P = 0.50). 63.6% of tumors with alterations in FGFR pathway concurrently harbored alterations in CDK pathway. Alterations in FGFR or CDK pathway were significantly correlated with liver metastasis (P = 0.001). In addition, TP53 mutation was significantly correlated with brain metastasis (P = 0.022).
Conclusions: These results provide a better understanding of molecular targets in refractory metastatic breast cancer which may lead to an improvement in the development of novel therapeutic strategies.
Citation Format: Zhanhong Chen, Yuzi Zhang, Jing Zhao, Shangli Cai, Yongmei Yin. Molecular features of refractory metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1697.
Abstract 1706: High-quality whole-genome sequencing and analysis of FFPE samples from multiplecancer types
Authors: Bailey Shannon T. , Lund James , Ekram Muhammad , Yu Wanfeng , Williams Richard T. , Sun Hongye , Gulcher Jeffrey R. 
Published: August 2019

Abstract
Next-generation sequencing analysis of formalin-fixed, paraffin-embedded (FFPE) samples has the potential to lead to major advances in cancer treatment and prevention. However, whole-genome sequencing (WGS) of these samples has remained challenging due to the difficult process of isolating high-quality DNA and distinguishing true variant calls from artifacts. As evidence of these challenges, only four WGS studies of FFPE samples have been published to date. Previous work has attempted to overcome these challenges by using whole-exome sequencing or smaller exon panels at high coverage depths with publications reporting success from less than half to most samples. Thus, there has not been widespread adoption of using FFPE samples for next-generation sequencing.
We developed a novel DNA extraction and library prep protocol for whole-genome sequencing of FFPE tissue samples. This method produces larger DNA fragments that can be successfully used for WGS. We previously presented results of a large esophageal cancer cohort where we sequenced over 1,000 samples in tumor-normal pairs with data equivalent to that generated from fresh-frozen tissues. We recently expanded the tumor types, ages, and sources and achieved similar results. We have assayed FFPE tissues derived from breast cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, and melanoma. These samples were sourced from several different labs, which have used variations on the standard fixation protocol. Some of these FFPE samples were over 15 years old. Variant calling provides excellent results without excessive C&gt;T mutations. The coverage uniformity was very good, and CNV calls were made with results comparable to published TCGA data. These samples have been analyzed for MSI and TMB, and the results are comparable to those using fresh tissues.
Our method makes new types of clinical studies possible utilizing FFPE samples that have been generated as part of standard hospital procedures. This method also facilitates performing studies comparing primary and recurrent cancers easier to establish and run as recurrent cancer cases can be enrolled and stored FFPE primary samples used to establish a cancer baseline.
Citation Format: Shannon T. Bailey, James Lund, Muhammad Ekram, Wanfeng Yu, Richard T. Williams, Hongye Sun, Jeffrey R. Gulcher. High-quality whole-genome sequencing and analysis of FFPE samples from multiplecancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1706.
Abstract 1718: Down-regulation of p16INK4a by hYSK1 promotes cancer cell migration under hypoxic conditions
Authors: Lee Mee-Hyun , Shim Jung-Hyun , Dong Zigang , Surh Young-Joon , Choi Bu Young 
Published: August 2019

Abstract
The alteration expression of p16INK4a, a well-known cyclin-dependent kinase inhibitor involved in cancer cell cycle control, is unclear, especially under hypoxic conditions. To evaluate p16INK4a regulation, we performed a protein microarray analysis. Among 1,800 proteins, we identified hYSK1 as a novel protein that interacts with the tumor suppressor p16INK4a. hYSK1, a member of the Ste20 family of serine/threonine protein kinases, promotes cell migration & tumorigenesis and is activated by oxidative stress. However, the molecular mechanisms underlying the oncogenic potential of hYSK1 remain elusive. Here, we report here that hYSK1 interacts with p16INK4a under hypoxic conditions like tumors, where it negatively regulates p16INK4a, enhancing cancer cell migration. Hypoxic stimulation of hYSK1 reduces p16INK4a accumulation through p16 promoter regulation to interact with unphosporylated SP-1 & increases matrix metalloproteinase-2 (MMP-2) expression by activating the MMP-2 promoter associated with cell migration and proliferation.Conversely, knocking down hYSK1 expression activated p16INK4a expression & suppressed MMP-2 expression.Thus, hYSK1 is necessary as a trigger for inactivating p16INK4a & activating MMP-2 during tumor migration, suggesting that hYSK1 is a specific negative regulator of the tumor suppressor p16INK4a may represent a novel molecular target for reactivation of tumor suppressor genes in humans.
Citation Format: Mee-Hyun Lee, Jung-Hyun Shim, Zigang Dong, Young-Joon Surh, Bu Young Choi. Down-regulation of p16INK4a by hYSK1 promotes cancer cell migration under hypoxic conditions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1718.
Abstract 1721: FOXO1, a downstream substrate of AKT, function as tumor suppressor in HCC carcinogenesis
Authors: Zhang Shu , Chen Xin 
Published: August 2019

Abstract
Hepatocellular carcinoma (HCC) represents the fifth most common tumor types in the world and the third leading cause of cancer-related death. However, the signaling pathways underlying hepatic pathogenesis are still poorly understood, hence lacking of effective targeted therapy. Activation of PI3K/AKT signaling cascade has been implicated in HCC development. It has been well-established that the mammalian target of rapamycin complex 1 (mTORC1), is a major downstream effector of AKT. The reason why mTORC1 can be consistently activated is partly due to inactive mutations of a negative element regulating mTORC1, tuberous sclerosis 2 (TSC2), found in 10% human HCCs. Beyond TSC2, forkhead Box O transcription factor 1 (FOXO1), is another AKT substrate. It has been proved that FOXO1 plays a crucial role in the insulin signal pathway and liver regeneration relying on AKT isoforms. However, the role of FOXO1 in HCC development has not been well established. Here we report, by using TCGA database the mRNA level of FOXO1 significantly decreases among the FOXO family, comparing tumor tissue to the surrounding tissue. The overall survival rate favors patients with high FOXO1 expression level. The inhibition efficacies of a pan-AKT inhibitor, in both TSC2 wide type cells and TSC2-null ones, indicating TSC2 is not the only target downstream of AKT. Protein analysis shows the activity of mTORC1 can still be inhibited as well as the phosphorylation of FOXO1 in TSC2-null cells. Therefore, we hypothesize that in the presence of TSC2, AKTi can suppress the activation of mTORC1 directly through TSC2. Otherwise, in the absence of TSC2, AKTi can still inhibit mTORC1 via activation of FOXO1. Furthermore, we overexpress the activated FOXO1 (FOXO1 AAA) in TSC2-null HCC cell lines. Cell growth are significantly prohibited, implicating FOXO1 is a tumor suppressor in HCC cells. Over expression of activated FOXO1 can also delay mTORC1 activation based HCC in AKT/Ras FVB mice model.Lesions consist mainly of clear-cell hepatocytes, owing to an increase in glycogen and fat storage. Proliferation is nearly the same within the neoplastic nodules. Activated AKT occurs both in the cytoplasm and on the membrane. Interestingly, FOXO1AAA escapes into the cytoplasm instead of remaining in the nuclei where it should stay. In a conclusion, AKT/mTORC1 can be a classic molecular pathway for HCC pathogenesis. Nevertheless, the parallel substrate of AKT, FOXO1, may also be an important factor in a TSC2 independent way.
Citation Format: Shu Zhang, Xin Chen. FOXO1, a downstream substrate of AKT, function as tumor suppressor in HCC carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1721.
Abstract 1723: Elucidation of novel therapeutic targets for acute myeloid leukemias with RUNX1-RUNX1T1 fusion
Authors: Yun Jae Won , Bae Yoon Kyung , Cho So Yeong , Kim Hee-Jin , Nam Do-Hyun , Kim Sun-Hee , Chun Sejong , Joo Kyeung Min , Lee Hye Won , Park Woong-Yang 
Published: August 2019

Abstract
The RUNX1-RUNX1T1 fusion is a frequent chromosomal alteration in acute myeloid leukemias (AMLs). Although RUNX1-RUNX1T1 fusion protein has pivotal roles in the development of AMLs with the fusion, RUNX1-RUNX1T1 fusion protein is difficult to target since it lacks kinase activities. Here, we used a sophisticated bioinformatic tool to elucidate targetable signaling pathways in AMLs with RUNX1-RUNX1T1 fusion. After analysis of 93 AMLs from the TCGA database, the expressions of 293 genes were significantly correlated with the expression of the RUNX1-RUNX1T1 fusion gene. Based on the 293 genes, the COX, VEGFR, PDGFR, and FGFR pathways are predicted to be specifically activated in AMLs with RUNX1-RUNX1T1 fusion. Compared with the AML cells without the fusion, the specific activations of the AML cell lines with RUNX1-RUNX1T1 fusion were confirmed by the increased phosphorylation of VEGFRs, PDGFRs, and FGFRs. Moreover, the in vitro proliferation of AML cells with RUNX1-RUNX1T1 fusion decreased significantly more than that of AML cells without the fusion when the pathways were inhibited pharmacologically. The results indicate that novel targetable signaling pathways could be identified by the analysis of the gene expression features of AMLs with non-targetable genetic alterations. The elucidation of specific molecular targets for AMLs that have a specific genetic alteration would promote personalized treatment of AMLs and improve treatment outcomes for AML patients in clinic.
Note: This abstract was not presented at the meeting.
Citation Format: Jae Won Yun, Yoon Kyung Bae, So Yeong Cho, Hee-Jin Kim, Do-Hyun Nam, Sun-Hee Kim, Sejong Chun, Kyeung Min Joo, Hye Won Lee, Woong-Yang Park. Elucidation of novel therapeutic targets for acute myeloid leukemias with RUNX1-RUNX1T1 fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1723.
Abstract 1728: Overactivation of tumor suppressor P53 in hepatocytes promotes hepatocarcinogenesis
Authors: Makino Yuki 
Published: August 2019

Abstract
Aim: p53 is a tumor suppressor and its dysfunction promotes carcinogenesis of several organs including the liver. Meanwhile, p53 is reported to be overactivated in non-tumorous liver tissues of patients with chronic liver diseases, presumably due to several stressful stimuli to hepatocytes, including viral infection, ethanol exposure, fat accumulation. The aim of this study is to clarify the impact of p53 overactivation on hepatocarcinogenesis.
Methods: To induce hepatocyte-specific overactivation of p53 in liver cancer models, hepatic Mdm2, a negative regulator of p53, was genetically ablated in diethylnitrosoamine (DEN)-treated mice (Alb-CreMdm2fl/fl) and liver-specific constitutive-active Kras-mutant knock-in mice (Alb-CreKrasLSL-G12DMdm2fl/fl called as KrasG12DΔMdm2 mice). To analyze the significance of p53, hepatic p53 was deleted in Mdm2-wild KrasG12D mice (Alb-CreKrasLSL-G12DMdm2+/+p53fl/fl) and KrasG12DΔMdm2 mice (Alb-CreKrasLSL-G12DMdm2fl/flp53fl/fl).
Results: Mdm2 deletion significantly elevated serum ALT levels and increased tumor penetrance in both DEN-treated mice and Kras-mutant mice, suggesting that p53 overactivation accelerated hepatocarcinogenesis. KrasG12DΔMdm2 mice upregulated hepatic expressions of pro-apoptotic molecules (p16, p21, Bax, Noxa), number of TUNEL positive hepatocytes and serum caspase-3/7 levels, indicating accelerated hepatocyte apoptosis. They also increased the number of β-galactosidase positive hepatocytes and upregulated hepatic inflammatory cytokines (Tnf, Ccl2, Il-1β), suggesting senescence-associated secretory phenotype (SASP). Expressions of hepatic progenitor cell (HPC) markers (Afp, Epcam, Ck7, Ck19, Cd90, Cd133, Dlk1) were up-regulated in their liver. HPC marker staining suggested that liver tumors in KrasG12DΔMdm2 mice may originate from HPCs. All the phenotypes including accelerated hepatocyte apoptosis, SASP and emergence of HPCs in KrasG12DΔMdm2 mice were significantly alleviated by p53 deletion. Most importantly, deletion of p53 significantly decelerated hepatocarcinogenesis in those mice, indicating that p53 overactivation was responsible for the accelerated hepatocarcinogenesis. In sharp contrast, p53 deletion significantly accelerated hepatocarcinogenesis in Mdm2-wild Kras-mutant mice, confirming the tumor suppressive role of normal level of p53 in the liver.
Conclusion: Whereas p53 deletion accelerated hepatocarcinogenesis, p53 overactivation induced liver injury and activation of HPCs, leading to the acceleration of hepatocarcinogenesis. p53 overactivation in hepatocytes might be associated with liver cancer development in patients with chronic liver diseases.
Citation Format: Yuki Makino. Overactivation of tumor suppressor P53 in hepatocytes promotes hepatocarcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1728.
Abstract 1731: Functional genomics approach reveals distinct neo-morphic activities and co-driver mutations of different missense mutant TP53 that promote breast cancer heterogeneity and progression
Authors: Pal Anasuya , Pal Anasuya 
Published: August 2019

Abstract
Phenotypic and molecular profiling of breast cancer demonstrates a high degree of heterogeneity in the breast tumors. TP53 tumor suppressor is mutated in 30% of all breast tumors and 80% of the basal-like subtype with numerous co-existing somatic mutations in other genes. We hypothesize that tumor heterogeneity is a result of combination of neo-morphic functions of specific TP53 driver mutations and functionally important but distinct co-mutations (or ‘co-drivers’) for each type of TP53 mutation. We thus ectopically expressed 10 most common missense p53 mutant proteins found in breast cancer patients in normal-like mammary epithelial cells and examined their phenotypes associated with various hallmarks of cancer. Supporting our hypothesis, a wide spectrum of phenotypic changes in cell survival, resistance to apoptosis and anoikis, cell invasion and cell polarity across the 10 mutant cell lines were observed compared to those of WT p53 expressing cells. Integrated analysis of ChIP-seq and RNA-seq showed distinct promoter binding profiles of different p53 mutant proteins, implying that non-canonical transcriptional activity of mutant p53 proteins may contribute to the phenotypic heterogeneity in TP53-mutated tumor. Further, enrichment and model-based pathway analyses revealed the key biological pathways associated with invasion of cells expressing different p53 mutant proteins. As a proof-of-concept for screening co-drivers of mutant p53, when PTEN was deleted in non-invasive cells expressing p53-Y234C mutant using CRISPR-Cas9 system, an increase in cell invasion was observed. A genome-wide CRISPR library-based screen on p53-Y234C and p53-R273C cells identified completely different candidate co-driver mutations that promoted cell invasion. The top candidates included several known mutated genes in breast cancer patients harboring TP53 mutations and were associated with cytoskeletal and apoptosis resistance pathways. Overall, our combined approach of molecular profiling and functional genomics screens highlighted distinct sets of genes and co-driver mutations that can lead to heterogeneous phenotypes and promote aggressive behaviors of cells with different TP53 mutant backgrounds, which can guide development of novel targeted therapies.
Citation Format: Anasuya Pal, Anasuya Pal. Functional genomics approach reveals distinct neo-morphic activities and co-driver mutations of different missense mutant TP53 that promote breast cancer heterogeneity and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1731.
Abstract 1733: Role of the SIX1 oncofetal protein in endometrial basal cell metaplasia and carcinogenesis following neonatal exposure to diethylstilbestrol
Authors: Suen Alisa A. , Jefferson Wendy N. , Wood Charles E. , Kenan Anna C. , Williams Carmen J. 
Published: August 2019

Abstract
Early-life exposure to estrogenic chemicals can increase cancer risk, likely by disrupting normal patterns of cellular differentiation. In a model of this process, female mice exposed to the potent synthetic estrogen diethylstilbestrol (DES) on postnatal days 1-5 develop endometrial adenobasal carcinoma as adults. Neoplastic glands are comprised of abnormal populations of basal cells (cytokeratin (CK)14+), luminal cells (CK18+), and low numbers of "mixed” basal/luminal cells (CK14+/18+), all of which express the oncofetal protein sine oculis homeobox 1 (SIX1). We hypothesized that DES-induced SIX1 expression is necessary for aberrant endometrial differentiation patterns and carcinogenesis. To test this hypothesis, a conditional knockout model was generated in which floxed Six1 was excised in the uterus using progesterone receptor (Pgr) cre. The most prominent change in DES-exposed SIX1 knockout (DES-Six1d/d) mice was the absence of basal cells in the uterine horns. There was a greater than 10-fold decrease in CK14 labeling in the uterine horns of DES-Six1d/d mice compared to DES-exposed SIX1 wildtype (DES-Six1+/+) mice as determined by quantitative image analysis. However, DES-Six1d/d mice exhibited a 42% increase in cancer incidence compared to DES-Six1+/+ mice at 6 months of age (16/18 DES-Six1d/d vs. 7/15 DES-Six1+/+). Interestingly, mixed cells were still present in DES-Six1d/d mice. These findings demonstrate that SIX1 is a cellular differentiation factor necessary for DES-induced basal cells but not mixed cell development or cancer. Furthermore, these data suggest that DES-induced SIX1 expression decreases endometrial carcinogenesis by facilitating basal cell differentiation. Studies investigating the mixed cell population as a putative cancer progenitor cell population are ongoing. Interestingly, mixed cells were present in 35% (63/181) of malignant human endometrial tissue biopsies and in 0% (0/29) of normal endometrial tissue biopsies, suggesting that the DES mouse model has significant similarities to human endometrial cancer.
Citation Format: Alisa A. Suen, Wendy N. Jefferson, Charles E. Wood, Anna C. Kenan, Carmen J. Williams. Role of the SIX1 oncofetal protein in endometrial basal cell metaplasia and carcinogenesis following neonatal exposure to diethylstilbestrol [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1733.