bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1083: GAP43, a novel potential metastases promoter in non-small cell lung cancer
Authors: Zhang Fanrong , Jin Jiaoyue , Wu Junzhou , Chen Kaiyan , Huang Minran , Yu Herbert , Ying Lisha , Su Dan
Published: August 2018

Metastasis is a serious sequela with dismal prognosis in non-small cell lung cancer (NSCLC). To identify novel biomarkers for predicting NSCLC metastasis, we performed high-throughput Luminex assays to profile the transcriptional level of 36 genes in 37 operable NSCLC patients who had distant metastases within 3 years after surgery and 33 paired patients without relapse after operation. Among the 36 genes, growth associated protein 43 (GAP43), an axonal membrane protein, was identified related to distant metastases. Multivariate cox regression analysis showed that NSCLC patients with elevated GAP43 had a 3.71-fold increase in risk for metastasis than those with low levels (95% confidence interval 1.69-8.14, P = 0.001). Analysis of a patient cohort of 1,926 NSCLC revealed that patients with high levels of GAP43 had worse progression-free and overall survival. In vitro experiments showed that GAP43 knockdown suppressed NSCLC cell migration and invasion, while GAP43 overexpression facilitated their migration and invasion. Immunofluorescence assay indicated that the linear polymer microfilament F-actin became cracked after GAP43 knockdown. Furthermore, animal studies using left ventrical injection demonstrated that GAP43 silenced NSCLC cells were less likely to metastasize to brain and bone than the controls. Together, our findings suggest that GAP43 may be an independent predictor for NSLCL metastasis, and it may facilitate distant metastasis through targeting F-actin.

Citation Format: Fanrong Zhang, Jiaoyue Jin, Junzhou Wu, Kaiyan Chen, Minran Huang, Herbert Yu, Lisha Ying, Dan Su. GAP43, a novel potential metastases promoter in non-small cell lung 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 1083.
Abstract 110: PPARγ loss increases the metastatic potential of HER2+ breast cancer
Authors: Lightbody Elizabeth D. , O'Connell Kathleen MJ , Newton Hailey T. , Rubino Rachel R. , Apostoli Anthony J. , Ren Kevin , SenGupta Sandip K. , Nicol Christopher J.
Published: August 2018

Breast tumors that overexpress human epidermal growth factor receptor 2 (HER2+) grow and spread faster than HER2-negative tumors, resulting in poor patient prognosis. Peroxisome proliferator-activated receptor (PPAR)γ is a nuclear transcription factor that controls the expression of genes essential for normal metabolism of fats and sugars in the body. Our laboratory previously showed that PPARγ expression suppresses environmental carcinogen DMBA-mediated breast tumor progression in vivo, and PPARγ-activating drugs further enhance this effect. However, the role of PPARγ and PPARγ agonists on HER2+ breast tumorigenesis and patient survival is unclear. We hypothesized that PPARγ loss enhances HER2+ breast tumor progression. To test this, this study generated a novel mouse model referred to as NIC:PPARγ-KO, which has targeted PPARγ deletion in the same HER2+ transformed mammary epithelial cells that drive breast tumorigenesis. Compared to NIC:PPARγ-WT mice, NIC:PPARγ-KO mice have increased mammary tumor incidences and lung metastases. Protein analysis of NIC:PPARγ-KO tumors shows PPARγ loss is inversely correlated with increased HER2 phosphorylation at tyrosine 877 (pY877HER2) in primary and metastatic tumorigenic tissue. Immunofluorescence also showed HER2 H-scores were significantly highest among tumors from NIC:PPARγ-KO mice, but also correlated with targeted PPARγ loss in DMBA-induced primary and metastatic mammary tumors among PPARγ-WT and PPARγ-KO mice (p<0.05). To further investigate the role of PPARγ in the metastatic process, we established cell lines from the freshly isolated lung metastatic tumors harvested from the NIC:PPARγ-KO model (NIC:PPARγ-KO-lmet). In vitro analysis of several human HER2+ breast cancer cells lines and our NIC:PPARγ-KO-lmet cells shows migration, invasion and tumorsphere-forming potential were significantly increased after epidermal growth factor (EGF, 20ng/mL) treatment and, more interestingly, that co-treatment with a PPARγ-activating drug (rosiglitazone, 10μM) significantly abrogated these effects (p<0.05). Together, these data provide the first evidence that PPARγ may be a useful prognostic/predictive biomarker for HER2+ breast tumors, and suggest that the novel inclusion of PPARγ-activating drugs may benefit a subset of HER2+ breast cancer patients.

Citation Format: Elizabeth D. Lightbody, Kathleen MJ O'Connell, Hailey T. Newton, Rachel R. Rubino, Anthony J. Apostoli, Kevin Ren, Sandip K. SenGupta, Christopher J. Nicol. PPARγ loss increases the metastatic potential of HER2+ 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 110.
Abstract 1103: Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche through macrophage polarization in liver metastasis
Authors: Shao Yingkuan , Chen Ting , Zheng Xi , Zheng Shu
Published: August 2018

Liver metastases develop in more than half of patients with colorectal cancer (CRC) and indicate a poor prognosis. In this study, we aim to investigate CRC-derived small extracellular vesicles (CRC-sEVs) participating in liver-specific metastasis. Fluorescence-labeled CRC-sEVs were found to accumulate in macrophages in mouse liver and prime macrophage polarization toward an interleukin-6 (IL-6)-secreting pro-inflammatory phenotype (macrophage expresses different programs in response to different microenvironmental signals called macrophage polarization). By analyzing miRNA expression profiles of the CRC-sEVs and their parental cells (SW480 and SW620), we identified miR-21-5p (miR-21) as the top ranked miRNA that was highly upregulated both in the sEVs and their parental CRC cells. The majority of macrophage-secreted inflammatory signaling pathways are activated by Toll-like receptor (TLR). Macrophages treated with miR-21 analogs exhibited enhanced expression of pro-inflammatory cytokines such as IL-6 and TNF-α. Silencing either miR-21 in CRC-sEVs, or the Toll-like receptor 7 (TLR7) in macrophages which miR-21 binds to, abolished the effect of CRC-sEVs in inducing pro-inflammatory macrophage polarization. Upon intravenous injection, CRC-sEVs promoted miR-21 expression and macrophage infiltration in the mouse liver, followed by the up-regulation of inflammatory genes. Accordingly, the multiplicity of liver metastases was increased upon transplantation of CRC cells in mice treated with CRC-sEVs. Furthermore, miR-21 expression in plasma-derived sEVs positively correlated with tumor stage and liver metastasis in CRC patients. Finally, co-expression of the miR-21 and IL-6 macrophages markers was observed in liver metastatic tissues from CRC patients. Together, our data point to a pivotal role of CRC-sEVs in inducing an inflammatory pre-metastatic niche through the miR-21-TLR7-IL6 axis. Moreover, sEVs-miR-21 represents a potential prognostic marker and therapeutic target for CRC patients with liver metastasis.

Citation Format: Yingkuan Shao, Ting Chen, Xi Zheng, Shu Zheng. Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche through macrophage polarization in liver metastasis [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 1103.
Abstract 1118: DOT1L epigenetically regulates cancer stem cell properties and tumor progression in glioblastoma brain tumor stem cells
Authors: Bozek Danielle , Hao Xiaoguang , Luchman H. Artee , Weiss Samuel
Published: August 2018

The median survival for patients diagnosed with Glioblastoma (GBM) is only 14 months, due to recurrence, despite current treatment options of surgery, radio- and chemo-therapies. Brain tumor stem cells (BTSCs) are thought to underlie disease recurrence and lethality as they exhibit self-renewal, multipotency and tumorigenesis. The epigenetic regulation of BTSCs are relatively un-characterized and unlike genomic mutations are potentially reversible. Disrupter of telomeric silencing-1-like (DOT1L) is the only known histone methyltransferase responsible for histone-3-lysine-79 methylation (H3K79me), an epigenetic mark associated with active gene transcription. Previous studies investigating the therapeutic implications of targeting DOT1L in cancer have shown that its inhibition in leukemia results in cancer cell death and, in solid cancers, decreases metastasis. We investigated the role of DOT1L in GBM BTSCs. We find that short-term DOT1L inhibition in BTSCs in vitro has limited effects on viability but alters growth morphology, as neurospheres become flattened and adherent. Furthermore, inhibition decreases BTSC invasion and promotes differentiation. Long-term inhibition of DOT1L had a more pronounced effect on sphere morphology and decreased BTSC proliferation and survival. Pre-treatment with the DOT1L inhibitor EPZ-5676 followed by orthotopic xenografts of BTSCs led to slowed tumor growth and improved overall survival. Initial H3K79me2 ChIP-sequencing and RNA-sequencing results show that H3K79me2 levels and gene expression are decreased for stem and progenitor cell markers SOX2 and OLIG2 respectively, in BTSCs treated with EPZ-5676. These results suggest that DOT1L may be an important regulator of GBM cancer stem cell properties and tumor progression. Current studies aim to further investigate how DOT1L regulates BTSCs by overlaying H3K79me2 ChIP-sequencing, RNA-sequencing and ATAC-sequencing in a panel of BTSCs following DOT1L inhibition and overexpression. These findings highlight the potential clinical implications of epigenetic targeted therapies for GBM.

Citation Format: Danielle Bozek, Xiaoguang Hao, H. Artee Luchman, Samuel Weiss. DOT1L epigenetically regulates cancer stem cell properties and tumor progression in glioblastoma brain tumor stem cells [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 1118.
Abstract 1129: Sox2 drives ST6Gal-I expression and activity to promote a CSC phenotype in ovarian cancer
Authors: Dorsett Kaitlyn A. , Bellis Susan L.
Published: August 2018

This study elucidates ST6Gal-I, a sialyltransferase, as a functional driver of a cancer stem cell (CSC) phenotype regulated by the stem cell transcription factor Sox2. ST6Gal-I is upregulated in 98% of ovarian cancers (OC); it functions to add an α2-6 sialic acid, a large, negatively charged sugar, to N-glycosylated proteins bound for the cell surface. Normal differentiated epithelia have very low expression of ST6Gal-I, however, expression is turned on in stem cell compartments and transformed tissues. Furthermore, our work has shown that ST6Gal-I plays a causal role in conferring hallmark CSC properties including greater tumor-initiating capabilities, promotion of recurrence, and resistance to tumor-associated stressors like chemotherapies, serum deprivation, and hypoxia. Even given this stark upregulation and apparent functional import of ST6Gal-I in cancers, very little work has been done to identify the transcriptional driver of ST6Gal-I expression. We identified that Sox2 and ST6Gal-I are both part of one of the most commonly enriched amplicons in human cancer, amplicon 3q26. We then examined the TCGA database and found that these two genes are co-amplified in 48/73 cancer cohorts, including ovarian cancer. In addition to being genetically co-amplified, Sox2 has been shown to bind to the promoter of ST6Gal-I, though no further analyses have been performed to assess a functional link. Herein we address a novel, glycosylation-dependent mechanism that drives a CSC phenotype. We hypothesize that Sox2, a key stem-associated transcription factor in CSCs, directly induces expression of ST6Gal-I. In our ovarian cancer cell model systems, we forced overexpression or knockdown of Sox2 and found that Sox2 expression directly correlated with ST6Gal-I expression. Overexpression or knockdown of Sox2 resulted in up- or down- regulation of CSC markers Oct4 and Nanog respectively. We then forced ST6Gal-I knockdown to inhibit the Sox2-induced ST6Gal-I upregulation and found that this prevented the enhanced expression of Oct4 and Nanog. Here we show that Sox2 requires ST6Gal-I expression to promote a CSC phenotype.

Citation Format: Kaitlyn A. Dorsett, Susan L. Bellis. Sox2 drives ST6Gal-I expression and activity to promote a CSC phenotype in ovarian 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 1129.
Abstract 1130: The role of TET2 in mammary stem cell fate decision
Authors: Wu Meng-Ju , Chang Chun-Ju
Published: August 2018

Epigenetic mechanisms, including DNA methylation, has an essential role in governing the stem cell fate decision. The Ten-Eleven-Translocation (TET) protein family serves as a primary epigenetic regulator responsible for catalyzing the conversion of the modified genomic base 5-methylcytosine into 5-hydroxymethylcytosine to mediate DNA demethylation. It has been shown that loss of TET2 promotes aberrant stem cell self-renewal in hematopoietic malignancy.

Interestingly, our recent study has revealed that expression of TET2 directs the breast cancer stem cell-like population to the differentiation cell fate in vitro. Since aberrant stem cell fate is often associated with tumorigenesis, delineating the role that a critical epigenetic regulator (e.g., TET2) plays to govern the mammary stem cell (MaSC) fate will likely provide new strategies used for breast cancer treatment.

Thus, to determine the physiological and pathological roles of TET2 in the regulation of MaSC fate and mammary gland development using a mouse model with mammary specific deletion of the Tet2 gene (MMTV-Cre; Tet2fl/fl). Our data show that deletion of Tet2 in mouse mammary gland leads to disrupted mammary epithelial morphology, defective lobular-alveolar development, along with aberrant mammary stem cell fate decision, contributing to an expansion of the MaSC population and development of mammary lesions. Together, the data demonstrate that TET2 plays an important role in controlling MaSC fate decision to maintain epithelial homeostasis, and loss of TET2 may contribute to the development of mammary malignancies.

Citation Format: Meng-Ju Wu, Chun-Ju Chang. The role of TET2 in mammary stem cell fate decision [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 1130.
Abstract 1147: Developing an individualized human colonic crypt cell culture as an ex vivo model for immunotherapy
Authors: Cheah Peh Yean , Low Yee Syuen , Lo Michelle , Tang See Aik , Ng Alphaeus , Tang Choong Leong , Wong Siew Heng
Published: August 2018

Colorectal Cancer (CRC) is the third leading cause of cancer death worldwide. Majority of mortality is attributable to metastasis to distal organs. Current treatment targeting the ERK/MAPK pathway used monoclonal anti-EGFR antibody after the first line of chemotherapy fails. However these treatments are only effective for a small percentage of patients with wild-type KRAS, and these same patients eventually develop resistance. Small molecule drugs are toxic and have limited success. A combination of antibodies is an attractive alternative. This study aims to investigate whether anti-KRAS antibody can enter live cells in an individualized ex vivo culture system and whether it can bind and inactivate KRAS. The transient culture has advantages over cell line study as it better mimics the human colonic environment and tumors can be compared to their matched normals to partially address the problem of heterogeneity. Samples were obtained from patients' resected tumour and matched mucosa, cultured ex vivo, and immunostaining performed. We show that anti-KRAS antibody is internalized in both the cultured mucosa and tumor crypt cells prior to fixation. Subcellular localization of the internalized antibody in the mucosa cells is similar in the pre-fixed and post-fixed cells. In contrast, the internal cell membrane staining observed in post-fixed tumor cells appear more cytoplasmic and 'punctated' in the pre-fixed tumors, mimicking that of the mucosa cells suggesting that the internalized anti-KRAS may have altered the sub-cellular localization and hence cycling of KRAS. Furthermore, staining with anti-keratin antibody indicates that live tumor cells treated with anti-KRAS has partial reversal of the phenotype to become more like the regular striated pattern of the matched mucosa. Preliminary double labelling of cultured tumours with monoclonal anti-KRAS prior to fixation and polyclonal anti-KRAS post-fixation revealed punctate staining of KRAS in the cytoplasm that were mainly non-overlapping suggesting that the punctate structures are in different compartments.

Citation Format: Peh Yean Cheah, Yee Syuen Low, Michelle Lo, See Aik Tang, Alphaeus Ng, Choong Leong Tang, Siew Heng Wong. Developing an individualized human colonic crypt cell culture as an ex vivo model for immunotherapy [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 1147.
Abstract 1148: Promising preclinical platform for evaluation of immuno-oncology drugs using Hu-PBL-NSG lung cancer models
Authors: Lim Sun Min , Pyo Kyoung-Ho , Kim Jae Hwan , Lee Ji Min , Kim Seong Keun , Kim Sung Eun , Jo Ha Ni , Cho Jae Soek , Kim Hye Ryun , Cho Byoung Chul
Published: August 2018

Introduction: With the advance of immunotherapy, treatment of non-small-cell lung cancer (NSCLC) has revolutionized by having anti-PD-1 therapy in front-line setting. In this era of cancer immunotherapy, humanized mouse models which recapitulate human immune system, are needed for predicting immunotherapy response in patients. We established a Hu-PBL-NSG mouse model which can be used as a preclinical testing platform for assessing efficacy of different immunotherapeutic agents.

Methods: Hu-PBL-NSG mouse model was established by engrafting human peripheral blood lymphocytes (PBLs) into NOD-scid (NSG) mice. The 6-7 week-old NSG mouse was transfused with 1 x 107 cells of PBL via tail vein, and human immune cells were characterized after 24 hours, and weekly thereafter. Cytokine array was performed to assess serological similarity between patient and the Hu-PBL-NSG mouse, and microscopic immune cell infiltration was observed in various organs mouse model. Human anti-PD-1 therapy was treated for assessing drug efficacy in patient-derived tumor.

Results: hCD3+hCD45+ T-cells and antigen presenting cells (dendritic cells, macrophages, and MDSC) increased in the serum of Hu-PBL-NSG mouse 24 hour after the transfusion of human PBLs, and CD3+ T cells were observed in lung, liver, kidney, spleen sections. Cytokine arrays of human and Hu-PBL-NSG mouse revealed high similarity of Th1, Th2, Th17-related cytokines. A tumor xenograft was engrafted from an EML4-ALK patient, and Hu-PBL-NSG mouse was sacrificed for histological analyses. hCD3+ T cells were infiltrated within the tumor, and CD11c+ cells, which represent antigen-presenting capability, were seen in spleen, lung, liver and kidney. When anti-PD-1 Ab was treated intraperitoneally, xenograft tumor showed significant reduction in volume after day 6, and increased expression of immune response-related genes on microarray analysis in the tumor. Mostly IFN-gamma and its related gene sets were significantly changed (FDR < 0.25, GSEA).

Conclusion: Hu-PBL-NSG mouse model which highly resembles human immune system was successfully established. This model could be a strong preclinical model for testing efficacy of immunotherapeutic agents, and also for pursuing novel immunotherapy treatment strategies in advanced NSCLC.

Citation Format: Sun Min Lim, Kyoung-Ho Pyo, Jae Hwan Kim, Ji Min Lee, Seong Keun Kim, Sung Eun Kim, Ha Ni Jo, Jae Soek Cho, Hye Ryun Kim, Byoung Chul Cho. Promising preclinical platform for evaluation of immuno-oncology drugs using Hu-PBL-NSG lung cancer models [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 1148.
Abstract 1149: Humanized knock-in mouse models for evaluating in vivo efficacy of immune-oncology drugs targeting inhibitory immune checkpoint molecules
Authors: Zhang Baozhu , Guo Chaoshe , Shen Yuelei , Guo Yanan
Published: August 2018

Recently, increasingly attention has been paid to the development of immuno-oncology (IO) drugs, due to the promising clinical results acquired by CTLA-4, PD-1 and PD-L1 antibodies. However, along the IO drug development process, in vivo efficacy models have always been a rate-limiting step. Mouse surrogate antibodies were often used in immune-competent mice with murine syngeneic tumor models to evaluate in vivo efficacy of the IO drugs. However, the efficacy of a surrogate antibody cannot fully represent the human drug in the clinical scenario. In most cases, a human monoclonal antibody does not have mouse cross-reactivity. Therefore, we generated humanized knock-in mouse to evaluate the in vivo efficacy of human IO antibodies. For example, human PD-1 knock-in (B-hPD-1) mice were generated with a chimeric PD-1 receptor, which is recognizable by human PD-1 antibodies, and can be used to test human PD-1 antibody in vivo efficacy. Mouse cancer cell lines including colon cancer MC38, melanoma B16F10 and lung cancer LLC1 were genetically modified with over-expression of hPD-L1 and knock-out of mPD-L1, and used to evaluate the in vivo efficacy of human PD-L1 antibodies. Additionally, more knock-in mice targeting inhibitory immune checkpoint molecules were developed, such as B-hPD-L1, B-hCTLA-4, B-hLAG3, B-hTIM3, B-hTIGIT, B-hBTLA, B-hSIRPa et al,. Humanized knock-in mice, pairing with genetically modified mouse cancer cells, represent a promising in vivo efficacy model for the development of IO drugs, and contribute to the clinical translation of animal studies.

Citation Format: Baozhu Zhang, Chaoshe Guo, Yuelei Shen, Yanan Guo. Humanized knock-in mouse models for evaluating in vivo efficacy of immune-oncology drugs targeting inhibitory immune checkpoint molecules [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 1149.
Abstract 1156: New spontaneous and carcinogen-induced mouse-derived isograft (MDI) tumor models for immune therapeutic approaches
Authors: Jantscheff Peter , Beshay Janette , Lemarchand Thomas , Obodozie Cynthia , Schaechtele Christoph , Weber Holger
Published: August 2018

First findings in the late 1990s and the early 2000s, that blockade of immune checkpoint inhibitors (ICI) by antibodies could induce rejection of established tumors and induce immunity also to secondary exposure with these tumor cells, led again to a stronger focus of experimental studies on syngeneic tumor models in immunocompetent animals. The availability of such models, however, is mainly limited by the small number of genetically-modified (GEM) or long-term passaged cell line-derived tumor models. We here describe establishment and first characterization of a new type of animal tumor models, named Mouse-Derived-Isografts (MDI), from spontaneously appearing or carcinogen-induced syngeneic tumors in both sexes of various mouse strains (C3H/HeN, CBA/J, BALB/C, DBA/2N and C57BL/6N). The tumors were obtained from animals during long-term observation (≥ 1-2 years) of normally fed, otherwise untreated animals (spontaneous - sMDI) or during short-term observation (3-9 month) of once subcutaneously, intramuscularly, intraperitoneally or orally methylcholanthrene (MCA) or methyl-nitroso-urea (MNU) treated animals (carcinogen - cMDI). Criteria to perform a primary necropsy were critical weight loss, bad general conditions or externally observable tumor growth in monitored animals. At this first step, tissues were assessed only macroscopically, and conspicuous ones were transplanted (in PDX-like manner) as small pieces into sex-matched syngeneic animals. If possible tissue/tumor pieces were also frozen and stored in 10% DMSO freezing medium at -80°C. In a second step these re-transplanted, outgrowing tumors were amplified once again in syngeneic mice for freeze storing, and then the models were finally established by re-transplantation and testing outgrowth of the frozen stored tumor pieces in the syngeneic animals. The tumors appear phenotypically stable, as far as routine standard HE stained sections could show. General characteristics of these models are; they are primary spontaneous or carcinogen-induced tumors, of low passage number (<10), propagated as tissue pieces only in mice without tissue culturing, and thus with conserved original tumor characteristics as assessed microscopically and intra-tumoral immune cell populations analyzed by flow cytometry.

Citation Format: Peter Jantscheff, Janette Beshay, Thomas Lemarchand, Cynthia Obodozie, Christoph Schaechtele, Holger Weber. New spontaneous and carcinogen-induced mouse-derived isograft (MDI) tumor models for immune therapeutic approaches [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 1156.
Abstract 1181: Structure and evolution of double minutes in a pediatric high-grade glioma
Authors: Xu Ke C. , Ding Liang , Chang Ti-Cheng , Wang Shuoguo , Wang Yong-Dong , Mulder Heather , Shao Ying , Easton John , Zhang Jinghui , Baker Suzanne J. , Wu Gang
Published: August 2018

Double minutes (DMs) are circular extrachromosomal DNA frequently found in brain tumors, often associated with overexpression of oncogenes. To understand the evolution of DMs, we developed a graph-based method to identify simple cycles in a directed graph consisting of highly amplified copy number alteration (CNA) segments and structural variants (SVs) found at the boundaries of each segment. With this method, we presented a case of DM evolution in a pair of diagnosis and relapse whole genome sequencing (WGS) samples from a pediatric high-grade glioma patient, followed by validation with Chromium linked-read sequencing. Using an empirical value of CNA threshold, we extracted 44 and 29 highly amplified CNA segments from the diagnosis and relapse samples respectively. We then identified 29 and 19 unique SVs associated with these CNA segments from the two samples. We constructed five major DMs in the diagnosis sample and five major DMs in the relapse sample, covering all the CNA segments and the SVs. One DM harboring EGFR is identified in both samples. Two of the five relapse DMs are also found in the diagnosis sample but in a trace amount, suggesting a shifting from minor clones in the diagnosis to dominant clones in the relapse. Two major DMs, one carrying MYC and the other carrying CDK6, were only identified in the relapse sample. Analysis of mutations on the DMs revealed that new somatic mutations were acquired on sub-populations of the DMs. Importantly, for the EGFR-carrying DM shared in both samples, we identified an 8-bp deletion at a splicing site of EGFR that has 2% allele frequency in the diagnosis but reached 96% in the relapse. This deletion leads to a mRNA transcription skipping of exon 16 with an 87 fold up-regulation of EGFR compared with other high-grade gliomas, suggesting a possible drug resistance mechanism and positive selection of tumor cells resulting from the mutated DM. We propose an evolutionary model that simultaneously involves a branching model for DM formation and a selection model for mutations on DM. We applied the same methods to the WGS data from two adult glioblastoma patients in TCGA, and found that our proposed model could also explain the DM evolution in these patients. Therefore, our study reveals that DMs follow an evolutionary trajectory independent of linear chromosomes and contribute to tumor heterogeneity.

Citation Format: Ke C. Xu, Liang Ding, Ti-Cheng Chang, Shuoguo Wang, Yong-Dong Wang, Heather Mulder, Ying Shao, John Easton, Jinghui Zhang, Suzanne J. Baker, Gang Wu. Structure and evolution of double minutes in a pediatric high-grade glioma [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 1181.
Abstract 1195: Incidence rates of head and neck cancer across Thailand and the USA
Authors: Argirion Ilona , Rentschler Katie , Vatanasapt Patravoot , Sriplung Hutcha , Rozek Laura S.
Published: August 2018

Background: Head and neck cancer is the sixth most common cancer in the world, with the largest burden occurring in developing countries. Although the primary risk factors have been well characterized, little is known about the temporal trends in head and neck cancer across Thailand. Using population based registries from three Thai provinces (Songkhla, Lampang and Khon Kaen), we have characterized the age-standardized incidence rates of head and neck cancer by sex and age and compared them to those observed in the United States. Methods: Cancer cases diagnosed between 1990 and 2014 were selected by ICD-10 code directly from the Songkhla, Lampang and Khon Kaen Cancer Registries as well as the Surveillance, Epidemiology, and End Results Program (SEER) for the following sites: oral cavity (00, 03-06), tongue (01-02), pharynx (09-10, 12-14), and larynx (32). The data were analyzed using R software (3.1.1) and Joinpoint Regression Software (4.4.0) to determine age-standardized incidence rates and trends of annual percent change. Incidence rates were standardized using the Segi (1960). Additional exploratory analyses using stratified linear regression models were conducted to assess temporal trends in head and neck cancer across 10-year age groupings. Results: Overall head and neck cancer rates are decreasing across all registries except Khon Kaen, where there is an observed, albeit not statistically significant, increase among males (APC: 0.53, p=0.3). Subsite analyses demonstrate consistent decreases in both larynx and oral cavity cancers, but suggested increases in pharynx and tongue cancers among both genders in the US (APC: 1.9 and 1.6, p<0.05 respectively) as well as pharynx cancer in Khon Kaen males (APC: 2.1, p<0.05). Furthermore, age-stratified APC analyses showed increased incidence in tongue cancer among Khon Kaen females age 30-39, Khon Kaen males age 30-59, Lampang males age 50-59, Songkhla females age 30-49, US females age 30-49 and 70-85+, as well as US males age 40-79. Pharynx cancers were seen to increase in Khon Kaen males age 40-59 and US males age 50-59. Conclusions: Although overall trends in head and neck cancer do seem to be decreasing across both Thailand and the United States, there is reason to believe that the etiological shift affecting both pharynx and tongue cancers in the US may be similarly presenting in Thailand. While disparities across gender and region do still exist, further investigation into the increased rates of early onset cancer is needed.

Citation Format: Ilona Argirion, Katie Rentschler, Patravoot Vatanasapt, Hutcha Sriplung, Laura S. Rozek. Incidence rates of head and neck cancer across Thailand and the USA [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 1195.
Abstract 1198: Rare isn't rare: Rare cancers compose over 50% of all U.S. diagnoses
Authors: Arline Katherine , Zeme Emily , Treuting Robert L. , Bravo Rodrigo , Barber Jamie , Higginson Christopher , Goetz Jon , Siders William , Kaplan Johanne
Published: August 2018

Rare cancers are an understudied and deadly public health problem. Estimates for the percentage of cancer diagnoses that are rare vary depending upon the source cited and the definition of what constitutes a rare cancer. A frequently cited report states that 25% of all adult cancers are rare. However, given the ever-changing landscape of cancer biology and as a result of changes in disease classification, oft-cited percentages underestimate the burden of rare cancers. To address this discrepancy, we reviewed the most recent publicly available data regarding the incidence of all cancers in the United States. Following the NCI definition of a rare disease as one affecting fewer than 15 persons per 100,000 per year, for 2017, a cancer affecting 48,952 or fewer is classified as rare. We considered each cancer individually, acknowledging subtypes based upon the criteria of scientifically accepted definitions, treatments, and histology. We then compiled statistics for each type and subtype. By this method, the total number of estimated new cancer patients in 2017 was 1,685,346, which differed only 0.2% from the Cancer.gov's publicly available estimate of 1,688,780. However, in contrast to previously published data that indicated that 60 of 71 cancer types were rare, we identified a total of 347 cancers, of which 337 were rare. The estimate for rare cancer diagnoses in the U.S. per year was therefore 875,084. Ultimately, 51.9% of all cancer diagnoses are classified as rare cancers by this method. In addition, of 52 major groupings of cancer, 35 (67.3%) disproportionately affect minorities in terms of incidence or overall survival. Seven groupings exclusively or almost exclusively affect women, and 7 additional groups display disproportionate incidence or negative outcomes in women. In addition, while many cancers affect children, and while all cancer in children is rare, at least 55 cancers exclusively or frequently affect children. This analysis clearly shows that the incidence of rare cancer in the United States is widely misunderstood and that cancer in total disproportionately affects historically underserved populations. Treatment options are needed for each form of cancer and should be developed based on a thorough understanding of each disease's biology. In addition, efforts to understand and address the origins of demographic disparities can help reduce disease burden.

Citation Format: Katherine Arline, Emily Zeme, Robert L. Treuting, Rodrigo Bravo, Jamie Barber, Christopher Higginson, Jon Goetz, William Siders, Johanne Kaplan. Rare isn't rare: Rare cancers compose over 50% of all U.S. diagnoses [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 1198.
Abstract 1199: Adult Hispanic males experience a higher incidence of acute lymphoblastic leukemia compared to non-Hispanic Whites
Authors: Espinoza-Gutarra Manuel R. , Munoz Edgar , Shah Dimpy P. , Karnad Anand , Mesa Ruben A. , Ramirez Amelie G.
Published: August 2018

Introduction: Acute leukemia is an important cause of morbidity and mortality with differences in incidence and outcomes between patients of different ethnic backgrounds. We conducted this study to examine the ethnic disparities in incidence of ALL as well as other types of acute leukemia in the Latino population in South Texas.

Methods: Data were obtained from the U.S. Surveillance, Epidemiology and End Results 18 (SEER) Program and the Texas Cancer Registry (TCR) under Limited-Use Data Agreements between sources and authors. Adult patients (15 years or older) were identified in both SEER and TCR databases from 2000 to 2014 and ICD-O-3 codes were used to select specific malignancies: ALL (9727-9729, 9835-9837), acute promyelocytic leukemia (APL) (9866) and non-APL acute myeloid leukemia (AML) (9840, 9861, 9867, 9870-9874, 9891, 9895-9897, 9910, 9920, 9930, 9931). Ethnicity was classified as Hispanic (H) and non-Hispanic White (NHW) per the North American Association of Central Cancer Registry (NAACR) Hispanic Identification Algorithm. Cases were obtained from SEER 18 and TCR, including Texas and the 38 counties of South Texas. Comparisons used the SEER population of NHW as reference. We used SEER*Stat software v 8.3.4 (SEER*Stat, NIH), to generate 2000-2014 average annual age-specific and age-adjusted acute leukemia incidence rates (per 1000000), rate ratios (RR) and 95% confidence interval (CI) for Hispanic and NHW populations in SEER, Texas, and South Texas.

Results: Table 1 shows Hispanic males in South Texas had significantly higher RR for development of ALL (p<0.05), and lower for non-APL AML; there was no statistical difference for APL RR compared to NHW. Males (15-39 and 70-79 years) had higher rates of ALL.

Conclusion: Latinos in South Texas experience a higher incidence of ALL and a lower incidence of non-APL AML compared to NHW. Future studies are needed to identify specific risk factors associated with this higher burden in Hispanic population.

Table 1SEERTCRTexasSouth TexasHNHWRR (95%CI)HNHWRR (95%CI)HNHWRR (95%CI)ALL213744421.50 (1.42-1.59)9789851.43 (1.33-1.53)3771071.63 (1.46-1.81)Non-APL AML3398047190.77 (0.75-0.80)216375930.41 (0.40-0.43)8488980.48 (0.45-0.51)APL77022241.22 (1.11-1.33)3094720.90 (0.80- 1.02)109510.94 (0.77- 1.14)

Citation Format: Manuel R. Espinoza-Gutarra, Edgar Munoz, Dimpy P. Shah, Anand Karnad, Ruben A. Mesa, Amelie G. Ramirez. Adult Hispanic males experience a higher incidence of acute lymphoblastic leukemia compared to non-Hispanic Whites [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 1199.
Abstract 1207: A systematic literature review of the prevalence of PIK3CA mutations and mutation hotspots in HR+/HER2- metastatic breast cancer
Authors: Mollon Lea , Aguilar Alejandra , Anderson Elizabeth , Dean Joni , Davis Lisa , Warholak Terri , Aizer Ayal A. , Platt Emma , Bardiya Aditya , Tang Derek
Published: August 2018

Introduction: Clinical research on the predictive value of PIK3CA mutations in hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2–) metastatic breast cancer (mBC) has advanced in recent years. However, knowledge of epidemiological prevalence has not been systematically evaluated. This study aimed to report prevalence of PIK3CA mutation using different biopsy techniques as well as specific hotspot mutations across the available literature.

Methods: A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and select conference abstracts was performed by two independent researchers that included, but was not limited to, keywords: “breast neoplasm”, “PIK3CA protein”, “hormone receptor positive”, and “metastases”. English-language studies in HR+, HER2– mBC detailing the prevalence of PIK3CA mutations and published between January 1993 through August 2017 were included. Content analysis was employed to quantify collected data elements.

Results: Of 558 studies included for full-text review, 36 met inclusion criteria. Most included studies (n = 18) were observational in nature. A total of 4,247 samples were tested for genetic mutations. Most studies used tissue biopsy samples (n = 33; 89%). Tumor samples accounted for 84.6% of all samples (n = 3597). Liquid biopsies were performed in 4 studies (11%) and accounted for 15.3% of all samples (n = 650). One study reported both liquid and tumor biopsy data. Overall, reported prevalence of the PIK3CA mutation ranged from 13.3% to 61.5%. Median prevalence was 36.4% (25th percentile = 28.6%; 75th percentile = 48.4%). Among studies using tissue biopsies, the majority reported prevalence from 16.7% to 61.5%. Among studies using liquid biopsies, the majority (n = 3) reported prevalence from 43.3% to 46.8%; one other study reported 13.3%. The most commonly tested hotspot mutations were H1047R and E545K. Among studies reporting specific hotspot mutation prevalence (n = 9), the H1047R hotspot mutation prevalence in these studies ranged between 25% and 75% while the E545K prevalence ranged between 11.1% and 50%.

Conclusions: Although discrepancies exist with respect to mutation prevalence estimated across various tissue vs. liquid biopsy techniques, PIK3CA mutations and mutation hotspots (specifically H1047R and E545K) frequently occur in HR+/HER2– mBC.

Citation Format: Lea Mollon, Alejandra Aguilar, Elizabeth Anderson, Joni Dean, Lisa Davis, Terri Warholak, Ayal A. Aizer, Emma Platt, Aditya Bardiya, Derek Tang. A systematic literature review of the prevalence of PIK3CA mutations and mutation hotspots in HR+/HER2- metastatic 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 1207.
Abstract 1214: Nasopharyngeal carcinoma clinical stage, histologic grade and biomarker status at presentation are usually of poor prognostic characteristics: A clinicopathologic study in a low-resource setting
Authors: Olusanya Aralola A. , Ogun Gabriel O. , Adeyemo Adebolajo
Published: August 2018

Introduction: Nasopharyngeal carcinoma (NPC) is the 8th commonest malignancy in men and the commonest head and neck tumor in Ibadan Cancer Registry (IBCR).

Methods: Clinical files and records of all nasopharyngeal carcinoma diagnosed at the Department of Pathology, University College Hospital affiliated with IBCR between January 2007 and December 2016 were reviewed for demographic data, clinical presentation, clinical stage, histologic grade, LMP-1 and EGFR status.

Results: A total of 71 cases of nasopharyngeal carcinoma were diagnosed during the study period, comprising 44 males and 27 females with a male:female ratio of 1.6. Age ranged from 12 years to 80 years, the modal age group was 40-49 and the modal age was 45 years. Sixty-three percent of cases were non-keratinizing undifferentiated tumors, 31% were non-keratinizing differentiated, 4.2% were keratinizing tumors and 1.4% basaloid squamous cell carcinoma. In all, non-keratinizing undifferentiated tumors constituted 64% of tumors in males and 63% in females. Conversely, non-keratinizing differentiated tumor was commoner in males, accounting for 34% of tumors compared to only 26% in females. Also, keratinizing tumor was twice as common in females than males; there was only a single basaloid squamous cell carcinoma recorded. The age group 30-39 years had the highest incidence of non-keratinizing undifferentiated tumor while non-keratinizing differentiated tumor was more common in the 40-49 age group. Patients presented most frequently with stage II disease, which accounted for 62% of cases. About 20% of these patients presented with stage IV disease. Nasal and aural symptoms accounted for the commonest presenting complaint, occurring in 38% of patients. Thirty-six percent presented with nasal symptoms alone while 13% had a combination of nasal, aural and visual symptoms; this group was mainly patients with stage IV disease. LMP-1 positivity was observed in as many as 99% of all cases. EGFR was positive in 94% of cases, indicating that NPCs are usually of poor prognosis in our practice setting at presentation.

Conclusion: In our practice, nasopharyngeal carcinoma is characterized by late-stage presentation, high-grade histologic characteristics and have biomarker indicators of poor prognosis.

Citation Format: Aralola A. Olusanya, Gabriel O. Ogun, Adebolajo Adeyemo. Nasopharyngeal carcinoma clinical stage, histologic grade and biomarker status at presentation are usually of poor prognostic characteristics: A clinicopathologic study in a low-resource setting [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 1214.
Abstract 1246: A family history of CRC confers protection against other cancers in a cohort of patients at risk for CRC
Authors: Tobi Martin , Antaki Fadi , Rambus MaryAnn , Lawson Michael , Ezekwudo Daniel
Published: August 2018

Risk for colorectal cancer (CRC) confers susceptibility to other cancers such as small bowel, breast, prostate, and female genital. However, these cancer family histories (F/H) have not been studied systematically.

Methods: 1,948 patients at increased CRC risk were followed to determine if the biomarker outcome was related to personal cancer prevalence or a cancer F/H by risk questionnaire which categorized patients as: Group 0 (no family history of cancer), Group 1 (F/H of breast cancer), Group 2 (F/H CRC), and Group 3 (P/H uterine/ovarian cancers).

Results: Demographics (age, sex, race, obesity) and NSAID use were similar in all groups and 88% were males. The proportion of cancer incidence in Group 1 is statistically greater [RR 1.36 (1.08-1.72) p = 0.014] compared to group 0 (Figure). Conversely, group 2 had statistically less cancer [RR 0.72 [0.52-0.99], p=0.045]. There was no significance difference between Group 0 and Group 3. About half the tumors in this older group of Veterans were prostatic. There was a wide variety of other cancers. In the entire cohort of the 5 tumors the most common tumor was prostate (n=222) followed by lung (n=61); CRC (n=53); bladder (n=23) and breast (n=20).

Conclusions: These differences may be explained by the effect of exosomes which play a major role in CRC and other cancers. Exosomes are nano-lipid particles of 30-100 nm released into the extracellular compartment. The ability of exosomes to facilitate cell-cell communication could be used to inhibit tumorigenic pathways. Exosomes may be endogenous in the case of CRC cell release or exogenous, found in breast milk containing microRNA moieties relevant to inhibition of carcinogenesis of cancers. Many of these mutated genes may inhibit tumorigenic process of cancers thus conferring protection against incipient cancers thus explaining our observation in Group 2. A commonality between CRC and endometrial cancer genetics potentially explains the reduced cancer prevalence in Groups 2 & 3. Breast cancer does not share BRCA “founder genes” with CRC and in contrast to CRC, K-ras mutations are not major events and thus F/H does not confer protection. This hypothesis remains to be proven but in the interim, timely screening for common cancers in patients with a family history of breast cancer may be effective.

Citation Format: Martin Tobi, Fadi Antaki, MaryAnn Rambus, Michael Lawson, Daniel Ezekwudo. A family history of CRC confers protection against other cancers in a cohort of patients at risk for CRC [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 1246.