tbuckley/cabot-search huggingface dataset:
Abstract 4708: Comprehensive analysis of 71 <i>VHL</i> germline deletions and rearrangements
Authors: Cathy D. Vocke, Christopher J. Ricketts, Laura S. Schmidt, Mark W. Ball, James Peterson, Lindsay A. Middelton, W Marston Linehan
Journal: Cancer Research (2020)

Abstract An estimated 35% of von Hippel-Lindau (VHL) disease patients possess a gross germline deletion of one, two, or all three exons of VHL. In this study, 71 germline deletions have been extensively characterized, including 59 partial deletions (PD) and 12 complete VHL deletions (CD). VHL patients possessing germline VHL deletions were enrolled on an IRB-approved protocol. An Agilent custom high-definition comparative genomic hybridization array (aCGH) including 21 probes within the VHL gene at an average probe density of 2 probes per kb was used to map most VHL deletions; 4 patients were evaluated using CLIA-approved VHL deletion/duplication analysis. Primers were designed adjacent to the estimated deletion boundaries, and the breakpoints were mapped by Sanger bidirectional sequencing. Fifty eight deletions (55 PD and 3 CD) have been mapped to the exact breakpoint. Nearly all (55 of 58) deletions involve Alu repeats at both breakpoints. Several novel observations have been made in this cohort, including two cases that have complex rearrangements involving both deletion and inversion, two cases that have inserted extra Alu-like sequences, three cases that involve breakpoints in Alu repeats situated in opposite orientations, and a “hotspot” PD of exon 3 involving the same pair of Alu repeats that is observed in 12 families. In conclusion, this is the largest study to date of germline deletions in VHL patients. Deletions almost always involve Alu repeats, which are enriched in and near the VHL gene. In two cases, both a deletion and an inversion are observed, implying that it may be possible for an inversion to occur in the absence of deletion. Citation Format: Cathy D. Vocke, Christopher J. Ricketts, Laura S. Schmidt, Mark W. Ball, James Peterson, Lindsay A. Middelton, W Marston Linehan. Comprehensive analysis of 71 VHL germline deletions and rearrangements [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4708.
Abstract 1008: Characterizing the post-translational regulation of programmed death-ligand 1 (PD-L1) in triple-negative breast cancer: Role of EphA3/Fes/Fer
Authors: Min Ling, Wenqi Wang, Xiaolong Yang
Journal: Cancer Research (2020)

Abstract Background: The programmed death ligand-1 (PD-L1) is a cell surface protein expressed on a variety of antigen-presenting cells for the purpose of controlling the immune response. As such, the role of PD-L1 expression on the surface of cancer cells has been proven to contribute to cancer immune evasion and tumor progression. Triple negative breast cancer has the most abundant tumor infiltrating lymphocytes (TILs) and PD-L1 is found highly upregulated in TNBC, allowing blockade immune checkpoint therapy a potentially effective treatment. However, the overall response rate is less than 20-30%. Over the past years, the literature that implicated the regulation of PD-L1 was primarily on transcription levels. The objective of our present study is to further characterize the post-translational modification of PD-L1 in efforts to better target it in TNBC immunotherapy. Methods and Results: By proteomic screen utilizing tandem affinity purification of interacting proteins using SFB (S, Flag, and Streptavidin binding peptide)-tagged PD-L1, we identified a number of novel interactions between PD-L1 and 67 candidates. A number of exclusive kinases have also shown high-confidence binding with PD-L1 in the proteomic screen. The primary hits were shortlisted and validated by means of co-immunoprecipitation (co-IP). The co-IP has confirmed a number of hits identified in the proteomic screen, including receptor tyrosine kinases (ephrin receptors, EphA3), and non-receptor tyrosine kinases (Fes and Fer) which have been explored in tumor progression and immune cell development. To test whether our candidate kinases can directly phosphorylate PD-L1 in vitro, His tagged-PD-L1 was mixed with active EphA3/Fes/Fer kinases. Phosphorylated PD-L1-His was detected by WB using PNBM treatment and anti-thiophosphate antibody. Kinase assays showed that EphA3/Fes/Fer can directly phosphorylate PD-L1. We also found that Fes/Fer were able to up-regulate PD-L1 protein expression in a dose-dependent manner. Conclusions: PD-L1 exhibits interactions with tyrosine kinases, which suggests PD-L1 phosphorylation as a novel post-translational modification. Our findings provide a rationale for the development of combination kinase inhibitors and immunotherapy in TNBC. Citation Format: Min Ling, Wenqi Wang, Xiaolong Yang. Characterizing the post-translational regulation of programmed death-ligand 1 (PD-L1) in triple-negative breast cancer: Role of EphA3/Fes/Fer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1008.
Abstract 1922: Tamoxifen detection by molecular fluorescence in breast cancer patients as a screening for metabolizer classification
Authors: Lorenna Larissa Ferreira Costa, Daniel Lucas Dantas de Freitas, Kassio Michell Gomes de Lima, Tirzah Braz Petta Lajus
Journal: Cancer Research (2020)

Abstract Breast cancer patients with polymorphic changes in the CYP2D6 gene show considerable variations in tamoxifen (TMX) bioavailability due to the need for bioactivation of this drug. Therefore, patients with such allelic changes have a worse prognosis compared to controls. Biospectroscopy allows the analysis of biofluids, providing the complete characterization of all molecules present in the biological matrix. Among spectroscopic techniques, molecular fluorescence stands out for its high analytical sensitivity in the broad identification of information obtained by the excitation-emission fluorescence matrix (EEM). This allows the specific measurement of fluorescent species in the sample. Quantification of TMX by fluorescence spectroscopy provides a phenotypic assessment of the patient's pharmacological metabolizing status, leading to a personalized and effective pharmacological therapy. We applied fluorescence spectroscopy to blood samples from n=20 women, who had genotyping of the CYP2D6*4_g.1846G&amp;gt;A allele, which confers decreased protein activity. We were able to demonstrate that the fluorescence signal generated by the TMX structure in plasma solution could be detected using our methodology. The data collected exhibited signal interference due to the numerous molecular species present in this matrix. However, using multivariate statistical algorithms we could extract relevant information from the analyte, improving the signal / noise of the emission-excitation matrix. Finally, we were able to demonstrate that low cost method, which can be performed rapidly, may allow for a simple point of care stratification of patients by the CYP2D6 status, which in turn may allow for increased personalization of tamoxifen therapy for breast cancer patients. Citation Format: Lorenna Larissa Ferreira Costa, Daniel Lucas Dantas de Freitas, Kassio Michell Gomes de Lima, Tirzah Braz Petta Lajus. Tamoxifen detection by molecular fluorescence in breast cancer patients as a screening for metabolizer classification [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1922.
Abstract 3557: Genetic algorithms to identify homologous recombination deficiency (HRD) in pancreas adenocarcinoma
Authors: Wungki Park, Jiapeng Chen, Joanne F. Chou, Christine Iacobuzio-Donague, Nadeem Riaz, Eileen M. O'Reilly
Journal: Cancer Research (2020)

Abstract Introduction: Homologous recombination deficiency (HRD) is an emerging biomarker for DNA-damage-response (DDR)-targeted therapies in pancreatic cancer (PDAC). There are different methods available to identify HRD in other cancers, however these have not been evaluated comprehensively in PDAC for their response prediction to first-line platinum-based therapies (1L-platinum). Methods: Patients with advanced (stage 3-4) PDAC who had germline and somatic MSK-IMPACT were included. We evaluated genetic methods for HRD and their association with clinical outcomes on 1L-platinum or 1L-non-platinum therapies. Homologous recombination (HR)-genes included: ATM, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, PALB2, RAD50, RAD51, RAD51C, RTEL1. We evaluated the status of pathogenic HR-gene mutations (HRm): (1) germline vs. somatic HRm; (2) core HRm (cHRm) (BRCA1, BRCA2, PALB2) vs. non-core (ncHRm); (3) zygosity (monoallelic vs. biallelic HRm). Additionally, HRD genetic signatures using large-scale state transition (LST) and signature 3 (Sig3) were evaluated. Results: Two-hundred and sixty-two patients with advanced PDAC who received care at Memorial Sloan Kettering were included. There was no difference in overall survival (OS) for patients with either germline or somatic HRm, hence they were analyzed together as HRD. Median [95% CI] follow-up among surviving patients (n=75) was 21.9 [1.4-57.0] months, median OS was 15.5 [14.6-19] months, and median progression-free survival (PFS) was 7 [6.1-8.1] months. The effect of HRD on PFS was dependent on whether the patient received 1L-platinum or not. After controlling for stage at diagnosis, patients with HRD had a reduced risk of progression or death compared to patients without HRD when treated with 1L-platnium (HR: 0.44 [95%CI: 0.29-0.67], p&amp;lt;0.01). Biallelic HRm and cHRm were associated with higher LST and tumor mutation burden. Sig3-positive patients were also associated with improved PFS compared to Sig3-negative patients when treated with 1L-platinum. Conclusion: Patients who have PDAC with HRD defined by HRm had better OS irrespective of 1L-platinum, although they had better PFS when treated with 1L-platinum compared to 1L-non-platinum. Among methods to identify HRD, pathogenic HR-gene mutations remain the standard when using a targeted-sequencing approach. Further investigation is warranted. Citation Format: Wungki Park, Jiapeng Chen, Joanne F. Chou, Christine Iacobuzio-Donague, Nadeem Riaz, Eileen M. O'Reilly. Genetic algorithms to identify homologous recombination deficiency (HRD) in pancreas adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3557.
Abstract 10: Sclareol induces apoptosis and inhibits notch signaling in hamster oral carcinogenesis
Authors: Aiyavu Chinnaiyan, Anandhi Nallu, Suresh Kathiresan
Journal: Cancer Research (2020)

Abstract The Notch signaling pathway is an evolutionarily conserved cell signaling pathway. It plays a central role in cell fate decisions and differentiation. The bioavailability of sclareol has been widely studied due to its anti-carcinogenic and antioxidant effects. However, chemo preventive effects of sclareol on notch signaling in 7, 12-dimethylbenz [a] anthracene (DMBA) induced hamster buccal pouch(HBP) carcinogenesis remain to be fully elucidated. In the present study, tumors were induced by applying 0.5% DMBA topically to HBP thrice a week for 14 weeks and sclareol was orally administered at a dose of 20mg/kg body weight on alternate days of DMBA painting. We analyzed expression of Notch signaling in DMBA induced oral squamous cell carcinoma (OSCC) in experimental oral carcinogenesis and inhibition of notch signaling by sclareol. This study thus observed up regulation of Notch1, Notch2, Jagged1, Hes1 and Hey1 in DMBA alone induced hamsters. Furthermore, oral administration of sclareol led to reduced Notch1, Notch2 activation and expression of Jagged-1 and its downstream targets of Hes-1 and Hey-1 in tumor bearing hamsters. In addition, sclareol treatment increased pro-apoptotic and decreased anti-apoptotic proteins survival indicating apoptosis through activation of caspase 3, and promoting cell death by dysregulation of cyclin D1 levels in tumor bearing hamsters. Immunohistochemical examination showed that Notch intracellular domain accumulates in the nucleus of cells in DMBA induced hamster buccal pouch carcinogenesis, and Jagged1 was found to be dysregulated in sclareol treated tumor animals. In conclusion, the results provide an important new insight of Notch signaling pathway for a potential therapeutic target for oral cancer. Citation Format: Aiyavu Chinnaiyan, Anandhi Nallu, Suresh Kathiresan. Sclareol induces apoptosis and inhibits notch signaling in hamster oral carcinogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 10.
Abstract 2501: Delineating mutational lineages with single cell DNA sequencing using multi-patient specific panels
Authors: Jake Leighton, Min Hu, Alexander Davis, Emi Sei, Yong Wang, Nicholas Navin
Journal: Cancer Research (2020)

Abstract Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high rates of metastasis. Although copy number aberrations (CNAs) and genome doubling have been extensively studied in relation to TNBC initiation, little is known regarding the timing and impact of point mutations during tumor initiation, outside of TP53. A major challenge in sequencing mutations in single cells is the significant cost of unbiased whole-exome analysis of many cells. To address this challenge, we developed an approach called multi-patient-panel (MPP) sequencing which involves first performing bulk deep-exome sequencing of many patient's tumors, after which hundreds of mutations are identified and pooled across patients to design a targeted panel for high-throughput single cell DNA sequencing. We applied MPP sequencing to profile 330 mutations across 23,000 single cells from 5 TNBC patients using a microdroplet system (Mission Bio). From this data we identified 1-4 major clonal subpopulations in each tumor which shared a common evolutionary lineage. Copy number data was inferred from the targeted panel coverage depth, which showed that CNAs were correlated with different subpopulations in the tumor. By integrating both the mutation and copy number data, we inferred phylogenetic lineages and identified the timing of mutations during primary tumor growth, which detected early truncal mutations (in addition to TP53) that were involved in the initiation of TNBC tumors. The MPP approach provides a powerful method to scale-up single cell DNA sequencing to tens of thousands of cells to detect mutations and infer cancer lineages and clonal substructure. Citation Format: Jake Leighton, Min Hu, Alexander Davis, Emi Sei, Yong Wang, Nicholas Navin. Delineating mutational lineages with single cell DNA sequencing using multi-patient specific panels [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2501.
Abstract 2766: Potassium channel expression in cervical cancer models
Authors: Ana Ramírez, María de Guadalupe Chávez-López, Eunice Vera, Jaime de la Garza, Patricio Gariglio, Javier Camacho
Journal: Cancer Research (2020)

Abstract Introduction. Cervical cancer is a public health problem in developing countries, and the fourth leading cause of cancer death in women worldwide. Most human cervical cancer cases are associated with high-risk human papillomavirus (HR-HPV) infection, but different cofactors including long-term use of oral contraceptives and multiple pregnancies increase the risk for cervical cancer in HPV-positive women. Ion channel expression and/or function differ between healthy and tumor cells. This alteration confers proliferation, progression, and survival advantages to tumor cells, making ion channels promising targets for cancer therapy and diagnosis. Here, we studied the mRNA expression of two potassium channels in human keratinocytes stably transfected with either E6 or both E6/E7 oncogenes of HPV16, and in a K14E7 transgenic mouse model of cervical cancer. These mice express the HPV16-E7 oncogene and develop cervical cancer after 6 months of treatment with 17β-estradiol (E2). Methods. Human normal keratinocytes and keratinocytes transfected with either E6 or E6/E7 oncogenes of HPV16 were cultured. In addition, we used the K14E7-transgenic mice-cervical cancer model; some animals were treated with E2. Continuous-release pellets delivering daily 0.05 mg of E2 were implanted into 4–6-week old female mice for either 3 months to produce low-grade cervical dysplasia or 6 months to produce cervical cancer. Total RNA extraction and subsequent quantification by qPCR of Kv3.4 and KCa3.1 mRNA channel levels were performed both from cultured cells and the mice cervical tissue. Results. Significantly higher KV3.4 and KCa3.1 channel mRNA expression was observed in keratinocytes transfected with either the E6 or E6/E7 HPV oncogenes in comparison with normal keratinocytes. In the cervical cancer mouse model, E2 treatment for 6 months increased the mRNA levels of KV3.4 and KCa3.1 channels both in the transgenic and the non-transgenic mice in comparison with the rest of the groups. The highest mRNA relative expression was observed for the KV3.4 channels in the transgenic mice displaying cervical cancer (K14E7+E2 group). Conclusion. KV3.4 channel expression may serve as a cervical cancer biomarker. This work was partially supported by Conacyt grant A1-S-9783. Citation Format: Ana Ramírez, María de Guadalupe Chávez-López, Eunice Vera, Jaime de la Garza, Patricio Gariglio, Javier Camacho. Potassium channel expression in cervical cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2766.
Abstract 2440: The epigenetic influence of maternal diet on prevention of high-fat diet induced obesity and breast cancer in later life
Authors: Yuanyuan Li, Min Chen, Trygve Tollefsbol
Journal: Cancer Research (2020)

Abstract Breast cancer is one of the most lethal diseases in women. Individual epigenetic profiles that are initially established in utero and postnatal environmental exposures contribute to later-life breast cancer incidence. Intervention on environmental factors such as diets during these sensitive periods provides excellent opportunities to re-program epigenetic profiles leading to cancer prevention. The bioactive dietary compound, genistein (GE) enriched in soybean products such as soymilk, soy protein and tofu, has been widely accepted as a potent anticancer reagent through regulation of epigenetic mechanisms. Our pilot study indicates that maternal dietary GE exposure effectively prevents later-life breast cancer development through epigenetic reprogramming in transgenic breast cancer mouse models. More importantly, we found that maternal GE significantly inhibited a postnatal overnutrition stimulus such as high-fat diet (HFD)-induced breast cancer promotion and metabolic disorders in mouse offspring. Diets with high saturated fat such as the Western diet and its related obesity are considered major risk factors for breast cancer. Importantly, we found that maternal dietary GE reversed HFD-induced lipid panel abnormalities, reduced obesity-related biomarkers and influences gut microbiome profiles through epigenetic regulations. Overnutrition-induced metabolic disorders such as overweight and obesity are a global epidemic that impair human life quality and increases risk of development of many human diseases including breast cancer. Elucidation of the key mechanisms and interactions between nutrition stress and breast cancer and exploration of a novel in utero preventive strategy through natural bioactive products will have global impact. Citation Format: Yuanyuan Li, Min Chen, Trygve Tollefsbol. The epigenetic influence of maternal diet on prevention of high-fat diet induced obesity and breast cancer in later life [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2440.
Abstract 5062: Modeling NK cells activities in full human immune system mouse models
Authors: Kiave Yune Ho Wang Yin
Journal: Cancer Research (2020)

Abstract The cytotoxic potential of NK-cells for the elimination of cancer cells represents the basis for many important ongoing clinical efforts. These efforts can now be supported by the humanized immune system mouse models (Hu-Mice), which offer an improved in vivo system for translating therapies to the clinic. Using hydrodynamic injection of human IL-15, TransCure bioServices has developed a NK boosted hu-Mice (CD34+ engrafted NCG) providing sufficient and functional human NK cells. The transient and physiological expression of IL-15 allow the expansion of human NK cells in the context of a full and stable human immune system bringing numerous advantages compared to the NK infused mouse model in IL15 transgenic mouse models. One week after boost, three times more NK cells are present in peripheral blood of IL15-boosted hu-Mice and this level is stable up to five weeks, providing sufficient time to engraft tumor cells and test drug efficacy. A better infiltration of the tumor by human NK cells is also visible in IL-15 boosted mice. Furthermore, the efficacy of ADCC dependent drugs (administered prophylactically or therapeutically) have been highlighted in IL-15 boosted hu-Mice engrafted with melanoma and multiple myeloma cells. In conclusion, the IL-15 boosted hu-Mice provide a reliable and validated in vivo model to better assess the efficacy and MOA of drug depending on NK cell activity. Citation Format: Kiave Yune Ho Wang Yin. Modeling NK cells activities in full human immune system mouse models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5062.