bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 299: Large tandem duplications in cancer resulting from transcription and DNA replication collisions
Authors: Yang Yang , Badura Michelle , O’Leary Patrick , Egusa Emily , Robinson Troy , Zhong Xiaoming , Swinderman Jason , Kim Minkyu , Li Haolong , Ashworth Alan , Feng Felix , Chou Jonathan , Yang Lixing 
Published: April 2023

Abstract
Somatic structural variations (SVs) are common in cancer. Although a small fraction of SVs in breast and ovarian cancers can be attributed to homologous recombination deficiency, the underlying molecular mechanisms for the vast majority of somatic SVs remain unclear. Here, we focus on the roles of transcription and DNA replication collisions in genomic instability in cancer. Such collisions are unavoidable in cells since both transcription and replication use the same DNA as template. We hypothesized that transcription replication collisions (TRCs), if not properly repaired, would lead to collapsed replication forks and result in SVs. To this end, we studied somatic SVs in 5994 high-coverage whole-genome sequenced primary and metastatic tumors from three independent pan-cancer cohorts. A total of 12 conserved SV signatures, representing independent molecular mechanisms, were deconvoluted from these cohorts using non-negative matrix factorization approach. We detected replicated-strand bias, the expected footprint of transcription-replication collision, in large tandem duplications (TDs) across multiple cohorts. This bias was only observed in expressed genes, consistent with TRCs depending on transcription activity. Large TDs were abundant in female-specific (breast, ovarian and uterus), upper gastric-intestinal tract and prostate cancers. They were associated with worse patient survival and TP53 and CDK12 mutations. CDK12 is a cyclin-dependent kinase (CDK) and a key regulator of transcription elongation. Deleting or suppressing CDK12 using CRISPR-Cas9 in prostate cancer cell lines not only increased RNA:DNA hybrids (R-loops), but also promoted TRCs, suggesting a mechanism by which dysregulation of a transcriptional CDK may lead to genomic instability. Finally, using existing large-scale drug screening data, we found that cancer cell lines with abundant large TDs were significantly more sensitive to the WEE1 inhibitor, MK-1775, which we experimentally validated in prostate cancer cells lacking CDK12. In summary, our data suggest that large TDs in cancer form due to impaired TRC repair and can be used as a biomarker for prognosis and treatment.
Citation Format: Yang Yang, Michelle Badura, Patrick O’Leary, Emily Egusa, Troy Robinson, Xiaoming Zhong, Jason Swinderman, Minkyu Kim, Haolong Li, Alan Ashworth, Felix Feng, Jonathan Chou, Lixing Yang. Large tandem duplications in cancer resulting from transcription and DNA replication collisions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 299.
Abstract 2993: Unmutated tumor antigens are abundant and contribute to tumor control in melanoma
Authors: Apavaloaei Anca , Zhao Qingchuan , Hesnard Leslie , Vincent Krystel , Hardy Marie-Pierre , Durette Chantal , Lanoix Joël , Laverdure Jean-Philippe , Larouche Jean-David , Cuevas Maria Virginia Ruiz , Ehx Grégory , Lemieux Sébastien , Thibault Pierre , Perreault Claude 
Published: April 2023

Abstract
Recognition of MHC-I-associated tumor antigens (TAs) by CD8+ T cells is central to antitumor immunity. Owing to the elevated tumor mutational burden (TMB) in melanoma, the marked efficacy of immune checkpoint blockade (ICB) has been attributed to the recognition of mutated TAs. However, recent reports showed that response to ICB in melanomas with low TMB is associated with CD8+ T-cell reactivity against melanocyte lineage-associated antigens (LSAs). Here, we systematically evaluated the contribution of all TA classes, i.e., mutated and unmutated, canonical and non-canonical, to the antigenic landscape of melanoma. We characterized the TAs from melanoma biopsies and patient-derived cell lines using proteogenomics. Out of 79450 MHC-I-associated peptides (MAPs) identified from 19 samples, we found 557 unmutated TAs classified as tumor-specific (TSA), tumor-associated (TAA), or LSAs. These TAs most often derived from annotated open-reading frames, followed by ncRNAs and intergenic regions. By contrast, only 6 MAPs were mutated and tumor-specific, which could be partially explained by a decreased expression of mutations within MAP-generating genomic regions. While the number of unmutated TAs with predicted presentation (TApres) in melanoma patients was similar between responders and non-responders pre-ICB, non-responders showed marks of inefficient antigen presentation. In consequence, only responders lost TApres upon treatment, in tandem with an expansion in tumor-infiltrating lymphocytes. These results reveal a previously underappreciated contribution of unmutated TAs to tumor control in melanoma and suggest that enhancing their recognition could improve the ICB efficacy in non-responders.
Citation Format: Anca Apavaloaei, Qingchuan Zhao, Leslie Hesnard, Krystel Vincent, Marie-Pierre Hardy, Chantal Durette, Joël Lanoix, Jean-Philippe Laverdure, Jean-David Larouche, Maria Virginia Ruiz Cuevas, Grégory Ehx, Sébastien Lemieux, Pierre Thibault, Claude Perreault. Unmutated tumor antigens are abundant and contribute to tumor control in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2993.
Abstract 2996: CT26 neoantigen presentation and immunogenicity
Authors: Nyayapathy Seeta , Jones Richard , Ford Michael , Doty Micah , Rumble Julie M. 
Published: April 2023

Abstract
The foundation of personalized cancer therapy is teaching a patient’s own immune system to directly kill the cancer cells. Vaccination against tumor antigens is one method being explored to generate immune responses against tumors, and may be particularly effective in conjunction with therapies currently in the clinic, such as checkpoint inhibition. Identification of antigens for use in a vaccine is the pinch point of this method, and many algorithms have been developed in an attempt to predict what epitopes will be both presented and immunogenic. Importantly, both public (common to multiple individuals/cancer types) and private (single individual) epitopes may contribute to the development of effective vaccines. Experimental identification of presented and immunogenic epitopes is crucial to building effective anti-cancer vaccines. Using immunopeptidome profiling, we have narrowed a collection of published potential neoantigens to those which were presented by MHC class I in the CT26 mouse colorectal cancer cell line. These peptides were synthesized and used to immunize BALB/c mice. The immunogenicity of the peptide mix was then evaluated by ELIspot to assess IFN-gamma responses in immunized mice. These experiments support a complete workflow for selection of potential cancer neoantigens which experimentally exhibit both MHC presentation and immunogenicity.
Citation Format: Seeta Nyayapathy, Richard Jones, Michael Ford, Micah Doty, Julie M. Rumble. CT26 neoantigen presentation and immunogenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2996.
Abstract 3012: Increased lung cancer risk and associated risk factors in tuberculosis survivors: a Korean population-based study
Authors: Park Dong Won , Moon Seong Mi , Choi Hayoung , Kim Sang Hyuk , Kang Hyung Koo , Jung Jin Hyung , Han Kyungdo , Shin Dong Wook , Lee Hyun 
Published: April 2023

Abstract
Background: Although studies have suggested an association between previous tuberculosis (TB) infection and increased lung cancer risk, there are limited data comprehensively evaluating the effects of smoking and chronic obstructive pulmonary disease (COPD) on the association.
Methods: This population-based cohort study enrolled TB survivors (n=75,467) ≥20 years of age between 2010-2017 and 1:1 age- and sex-matched controls (n=75,467). Subjects were followed for one year after the date of TB diagnosis to the date of the incidental lung cancer, death, or December 2018.
Results: During a median follow-up duration of 4.8 (interquartile range, 2.9-6.6) years, the incident lung cancer risk was 1.71-fold (95% confidence interval [CI], 1.49-1.97) higher in TB survivors than in the controls. Compared to never-smoker, non-TB infected controls, TB survivors who were current smokers with ≥20 pack-years showed the highest risk of lung cancer (adjusted hazard ratio [aHR], 6.78; 95% CI, 5.26-8.74). In terms of COPD, the risk of lung cancer was higher in TB survivors with COPD compared to non-COPD, non-TB-infected controls (aHR, 2.43; 95% CI, 2.03-2.91). However, smoking as well as COPD did not have significant interaction on the association between TB and lung cancer development (p for interaction&gt;0.05 for both). Risk factors related to incident lung cancer among TB survivors were pulmonary TB, age &gt;60 years, smoking, and the presence of COPD or asthma.
Conclusions: Previous TB infection is an independent risk factor for lung cancer without significant interaction with smoking status or amount and COPD.
Citation Format: Dong Won Park, Seong Mi Moon, Hayoung Choi, Sang Hyuk Kim, Hyung Koo Kang, Jin Hyung Jung, Kyungdo Han, Dong Wook Shin, Hyun Lee. Increased lung cancer risk and associated risk factors in tuberculosis survivors: a Korean population-based study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3012.
Abstract 3031: Pilot study of EGFR inhibition with erlotinib in liver fibrosis for hepatocellular carcinoma prevention
Authors: Tanabe Kenneth K. , Zahrieh David , Strand Carrie A. , Hoshida Yujin , Flotte Thomas J. , Della’Zanna Gary , Umar Asad , Limburg Paul 
Published: April 2023

Abstract
BACKGROUND: Effective approaches for prevention of hepatocellular carcinoma (HCC) will have a significant impact on HCC-related mortality. Data from preclinical models strongly support epidermal growth factor receptor (EGFR) as a target for chemoprevention of HCC. Erlotinib is a small-molecular EGFR tyrosine kinase inhibitor that is FDA-approved for cancer treatment. The side effects of erlotinib observed in patients receiving the oncology dose (150 mg/day) render it unacceptable as a chemoprevention agent at this dose.
OBJECTIVE: The objective of this clinical trial was determination of a safe and minimum effective dose of erlortinib for which a ≥50% reduction phospho-EGFR immunohistochemical staining in the liver was observed.
RESULTS: 46 participants were pre-registered and 25 participants were registered in this multicenter trial. In a dose de-escalation trial design, cohorts of participants received a 7 day course of erlotinib 75 mg/day, 50 mg/day or 25 mg/day with liver tissue acquisition prior to and after erlotinib. A ≥50% reduction phospho-EGFR immunohistochemical staining in the liver was observed in a minimum of 40% of participants at each of the dose levels. Erlotinib was very well tolerated with few side effects observed, particularly at the dose of 25 mg/day. A favorable modulation of the Prognostic Liver Signature was observed in participants that received the higher erlotinib doses (50 and 75 mg/day).
CONCLUSION: These data support the selection a dose of 25 mg/day of erlotinib for a longer intervention to assess for evidence of efficacy as an HCC chemoprevention drug.
Citation Format: Kenneth K. Tanabe, David Zahrieh, Carrie A. Strand, Yujin Hoshida, Thomas J. Flotte, Gary Della’Zanna, Asad Umar, Paul Limburg. Pilot study of EGFR inhibition with erlotinib in liver fibrosis for hepatocellular carcinoma prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3031.
Abstract 3079: Characterization of ER-AF2 inhibitors in breast cancer
Authors: Foo Jane , Gentile Francesco , Lee Joseph , Morin Helene , Massah Shabnam , Guo Maria , Smith Jason , Ban Fuqiang , Cherkasov Artem , Lallous Nada 
Published: April 2023

Abstract
Up to 80% of breast cancers (BCa) rely on the estrogen receptor (ER) for their growth and progression. This dependence on ER has led to many hormonal therapies that target this receptor. However, almost 40% of these cancers will acquire resistance over the course of the treatment period. One potential cause of resistance is mutations in the estrogen binding site (EBS) of ER. As such, there is an increasing need for novel inhibitors that targets ER at a site separate from the EBS. Here, we propose targeting the activation-function (AF2) pocket of ER that is important for cofactor binding and transcription activation. Billions of compounds were screened through an in-silico deep docking method, and potential AF2 inhibitors were then validated in cell-based and biophysical assays. We tested the effect of potential AF2 inhibitors on ER transcriptional activity using luciferase reporter assay in ER-positive T47D-kbluc cells. We then evaluated the effect of molecules on cell viability of ER-positive T47D and ER-negative MDA-MB-231 cells using PrestoBlue assays in order to exclude off-target effects. From these cell-based assays, we identified several inhibitors that effectively reduced transcriptional activity and viability in ER-positive T47D cells at low micromolar concentrations. We conducted PGC-1α peptide displacement assay to confirm their AF2 binding and estradiol displacement assays to exclude any binding to the EBS. Proximity ligation assay (PLA) showed disruption of the interaction between ER and coactivator SRC-3 upon treatment with ER-AF2 inhibitors in T47D cells. Current work focuses on confirming the direct binding between the compounds and recombinant ER-ligand binding domain by various biophysical assays (MST, BLI, and ITC). Future work aims to solve the structure of ER-LBD in a complex with our lead compound by X-ray crystallography. We predict that the use of potent ER-AF2 inhibitors along with current treatments, will provide a novel tactic that can act as a complementary therapeutic to target treatment resistance in ER+ BCa.
Citation Format: Jane Foo, Francesco Gentile, Joseph Lee, Helene Morin, Shabnam Massah, Maria Guo, Jason Smith, Fuqiang Ban, Artem Cherkasov, Nada Lallous. Characterization of ER-AF2 inhibitors in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3079.
Abstract 3092: Optimization of deferiprone for the treatment of triple-negative breast cancer
Authors: Johnston Alexis , Oyelere Adegboyega K. 
Published: April 2023

Abstract
Triple-negative breast cancer (TNBC) is the leading cause of new cancer cases and the second leading cause of cancer deaths in American women. TNBC is one of the most difficult cancers to treat due to the lack of three receptors, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), found in regular forms of breast cancer (BCa). Currently, there is no targeted therapy for TNBC and treatment options to manage this lethal disease include surgery, adjuvant chemotherapy and radiotherapy. A better understanding of TNBC etiology has aided in unraveling the roles of two additional cellular targets - androgen receptor (AR) and histone lysine demethylase (KDM) - in the viability and survival of TNBC. Interestingly, AR overexpression is the most important driver of prostate cancer (PCa). A class of current medications used to treat PCa act as androgen receptor (AR) antagonists (or antiandrogens). It is therefore plausible to repurpose and optimize these antiandrogens for TNBC therapy. The proposed therapeutics are dual-acting antiandrogen-KDM inhibitors. The antiandrogen moiety of these agents will enable TNBC cell-targeting and translocation of the drug into the nucleus where inhibition of KDM will prevent transcription of KDMs that promote tumor. The three pharmacophores of these agents are (i) a surface recognition cap, (ii) a linker, and (iii) an Fe2+-binding group. Two classes of these compounds, alkyl-derivative and benzyl-derivative, vary in the design of the surface recognition cap. To optimize these agents, the linker length is varied from 2-7 methylene groups in each class and the optimal length will be determined through in vitro studies. The compounds are tested on five cancer cell lines: TNBC cell lines (MDA-MB-231, low AR+; and MDA-MB-453, high AR+), and ER+ BCa (MCF-7) while PCa cell lines (LNCaP PCa, AR+; and DU 145, PCa, AR-) serve as controls for AR dependency of the effects of test compounds. Longer linker length compounds exhibited low micromolar cytotoxicity and selectivity for MDA-MB-231 (TNBC) and LNCaP (PCa) cell lines due to the presence of the AR. Western blot analysis on lead compounds supported significant downregulation of AR in MDA-MB-231 cells confirming the predicted mechanism of action. Thus far, the designed dual-acting therapeutics have potential to revolutionize the design of anticancer drugs and improve treatment outcome for TNBC patients.
Citation Format: Alexis Johnston, Adegboyega K. Oyelere. Optimization of deferiprone for the treatment of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3092.
Abstract 3133: Loss of the Y chromosome as a candidate driver in solid tumors
Authors: Qi Meifang , Rheinbay Esther , Lane Andrew A. , Pang Jiali , Mitsiades Irene 
Published: April 2023

Abstract
It has long been recognized that certain cancer types afflict female and male patients disproportionately. The reasons for this disparity include differences in male and female physiology, effect of sex hormones, risk behavior and environmental exposures, and different copy number of the sex chromosomes X and Y. Loss of Y (LOY) is common in peripheral blood cells in aging men, and this phenomenon is associated with several diseases. However, the frequency and role of LOY in tumors is little understood. Here, we present a comprehensive catalog of LOY in about 5,000 primary tumors from male patients in the TCGA. We show that LOY rates vary by tumor type, and provide evidence for LOY being either a passenger or driver event depending on context. LOY in uveal melanoma specifically is associated with age, survival and is an independent predictor of poor outcome. LOY creates common dependencies on DDX3X and EIF1AX in male cell lines, suggesting that LOY generates unique vulnerabilities that could be therapeutically exploited.
Citation Format: Meifang Qi, Esther Rheinbay, Andrew A. Lane, Jiali Pang, Irene Mitsiades. Loss of the Y chromosome as a candidate driver in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3133.
Abstract 3139: Pan-cancer splicing analysis reveals shared drivers of malignant transformation and survival
Authors: Bhattacharjee Anukana , Crowther Audrey , Li Guangyuan , Venkatasubramanian Meenakshi , Schnell Dan , Hay Stuart , Singh Preeti , Subramanian Krithika R. , Chetal Kashish , Chen Xiaoting , Kulkarni Aishwarya , Weirauch Matthew T. , Salomonis Nathan 
Published: April 2023

Abstract
Alternative splicing is one of the primary mechanisms used to achieve mRNA transcript and proteomic diversity in higher order eukaryotes. In cancer, altered mRNA splicing can lead to aberrant protein products that promote oncogenic transformation, metastasis and confer chemotherapy resistance, due to splicing factor mutation or mis-expression. We hypothesize that the role of splicing imbalance in cancer is grossly underestimated and is likely regulated by the same recurrent global disruptions observed across human cancers. To determine common and malignancy specific splicing subtypes across cancer we designed a novel integrated computational workflow that uses genome variant data from RNA-Seq in conjunction with fully unsupervised analyses (NMF and SVM) to identify novel patient splicing-defined subtypes (OncoSplice). Applied to 20 adult and pediatric cancers with large cohorts, we identified common-recurrent splicing subtypes associated with MYC-hyperactivation and TGF-beta signaling, lineage reprogramming, tumor infiltration and broad mutation impacts. Such recurrent and tumor specific subtypes were frequently associated with poor prognosis and novel dominantly regulated driving splicing events (e.g., transcription factors). Broad splicing subtypes were associated with circadian dysregulation, as determined from normal healthy tissues (GTEx) and in many cases were found to phenocopy well-described splicing mutation impacts or were associated with new RNA-binding proteins (RBPs) evidenced by orthogonal computational predictions. Splicing subtype associated RBPs were frequently undergo autoregulation, as further evidenced by CLIP-Seq and RBP knockdown. To enhance the RNA community’s ability to explore hundreds of known and novel splicing variation across cancers and healthy tissues, we provide an interactive online splicing explorer at oncosplice.org. Together, these data highlight previously unknown regulatory relationships and prognostic associations in cancer associated with broad and targeted splicing regulation.
Citation Format: Anukana Bhattacharjee, Audrey Crowther, Guangyuan Li, Meenakshi Venkatasubramanian, Dan Schnell, Stuart Hay, Preeti Singh, Krithika R. Subramanian, Kashish Chetal, Xiaoting Chen, Aishwarya Kulkarni, Matthew T. Weirauch, Nathan Salomonis. Pan-cancer splicing analysis reveals shared drivers of malignant transformation and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3139.