bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1450: Interactions of DNMTs genetic variants associated with breast cancer risk
Authors: Lin Hui-Yi , Su L. Joseph , Rogers Lora J. , Runnells Gail A. , Hsu Ping-Ching , Stahr Shelbie D. , Chiang Tung-Chin 
Published: June 2022

Abstract
Background: DNA methyltransferases (DNMTs) control DNA methylation and impact gene expression. Many studies have demonstrated that genetic variants in DNMT genes play a role in cancer development, including breast cancer. However, the impact of SNP-SNP interactions for DNMTs associated with breast cancer risk is unclear. The objective is to evaluate SNP-SNP interactions associated with breast cancer risk.
Methods: We selected 14 SNPs in 3 DNMT genes (DNMT1, DNMT3A, and DNMT3B) for the 4,195 women (1:2 match for breast cancer cases and controls), including 1,085 African Americans (AAs) and 3,110 European Americans (EAs) in the Arkansas Rural Community Health (ARCH) cohort. We included different inheritance models (dominant, recessive, and additive) for individual SNP effects, using logistic regressions with breast cancer status (yes/no) as the outcome. Two-way SNP-SNP interactions associated with breast cancer risk were analyzed using the SNP Interaction Pattern Identifier (SIPI) approach developed by our research team.
Results: Out of the 14 DNMTs SNPs, we found two SNPs (rs7605753 and rs10196635 in DNMT3A) were individually associated with breast cancer risk (p&lt;0.05) in EAs, however, none was statistically significant in AAs. Interestingly, we applied the SIPI approach, targeting SNP-SNP interactions,19 SNP-SNP interaction pairs for EAs, and 6 pairs for AAs associated with breast cancer risk. These promising SNP interaction pairs had an interaction p-value less than 0.05, far less than the p-values of the 2 constituent SNPs. Also, these promising SNP-SNP interaction pairs are different between races. For example, the EA women with the CC + AT/TT genotype in rs12991495 + rs10196635 (both in DNMT3A) had a higher risk of breast cancer risk than other genotype combinations (Odds ratio [OR]=2.2, p=0.011). On the other hand, the AA women with the TT+AA genotype in the SNP pair of rs2304429 (DNMT3A) + rs2290684 (DNMT1) tend to have a higher breast cancer risk than other genotype combinations in the same pair (OR=4.3, p=0.034). Notably, the individual effects of the two constituent SNPs are not significant (p=0.537 and 0.547).
Conclusion: Our findings support that the SNPs in DNMT genes play an essential role in breast cancer risk. SIPI is an excellent tool to evaluate SNP-SNP interactions, which can better predict breast cancer risk.
Citation Format: Hui-Yi Lin, L. Joseph Su, Lora J. Rogers, Gail A. Runnells, Ping-Ching Hsu, Shelbie D. Stahr, Tung-Chin Chiang. Interactions of DNMTs genetic variants associated with breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1450.
Abstract 1457: NELFE regulates chromatin accessibility to affect MYC induced transcription
Authors: Zhang Kai , Barry Anna , Lamm Ryan , Dang Hien 
Published: June 2022

Abstract
Liver cancer incidence rates have more than tripled in the last 40 years and is projected to increase more than 40% in the next decade. Although progress has been made, there is still limited therapeutic options. Due to the various etiological factors associated in HCC development and late stage in which it is diagnosed, the five-year survival rate is only 20%. Molecularly, more than 80% of HCC has an alteration in MYC signaling. Yet, MYC remains undruggable and studies over the recent years show that targeting proteins that regulate MYC is a promising approach in developing anti-cancer therapies. One such protein is the RNA binding protein (RBP) Negative Elongation Factor E (NELFE). We recently demonstrated for the first-time that NELFE recruits MYC via protein-protein interactions to the chromatin to control the expression of pro-survival genes. Consistent with the role of NELFE as a regulator of MYC in these cancers, we showed that patients with aberrant NELFE expression concurrently have active MYC signaling and poor outcome. These studies suggest that the NELFE/MYC interplay may be important for HCC maintenance. Thus, our hypothesis is that NELFE modulates the chromatin landscape to facilitate MYC-induced transcription to promote HCC. To investigate NELFE’s effect on MYC-induced transcription, we performed NELFE and MYC ChIP-sequencing and ATAC-sequencing analyses on CRISPR/Cas9-mediated NELFE knockout HCC cells. We found NELFE depletion resulted in significant reduction in nucleosomal accessibility and MYC binding to the chromatin near promoter-proximal regions. Although NELFE depletion alters the chromatin landscape, we found it rarely interacts with the chromatin, specifically within MYC bound regions, suggesting that the MYC/NELFE interaction is facilitated by a third protein. NELFE co-immunoprecipitation followed by mass spectrometry analyses identified the protein SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1 (SMARCB1) as a potential MYC cofactor that facilitates the NELFE/MYC interaction. Immunoblotting analyses show NELFE interacts with SMARCB1 and MYC and loss of NELFE significantly reduced SMARCB1/MYC interactions, indicating that NELFE facilitates chromatin accessibility through SMARCB1, which is required for MYC-induced transcription. Future studies include investigating SMARCB1’s oncogenic role in HCC through NELFE/MYC signaling.
Citation Format: Kai Zhang, Anna Barry, Ryan Lamm, Hien Dang. NELFE regulates chromatin accessibility to affect MYC induced transcription [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1457.
Abstract 1482: Efficient targeting of prostate cancer using ligand conjugated and chemically modified tumor suppressive miRNA
Authors: Abdelaal Ahmed M. , Kasireddy Sudarshan , Sohal Ikjot S. , Low Philip S. , Kasinski Andrea L. 
Published: June 2022

Abstract
MicroRNAs (miRNAs) inhibit the expression of genes through imperfect base pairing with target messenger RNAs (mRNAs), which allows a single miRNA the ability to regulate the expression of multiple genes, potentially acting as a multi-drug cocktail. In principle, tumor-suppressive miRNAs, such as miRNA-34a (miR-34a) are excellent anti-cancer agents; however, due to toxicity associated with currently used delivery vehicles and poor in vivo miRNA stability, the clinical application of miRNAs is thwarted. To overcome these challenges, we engineered two modifications to the miRNA. The first entails conjugating the miRNA to a ligand that promotes delivery specifically to cancer cells while the second involves using a fully chemically modified miRNA (FM-miR) to enhance miRNA stability. The ligand chosen for delivery, 2- [3-(1,3-dicarboxy propyl) ureido] pentanedioic acid (DUPA), is a high-affinity binding partner of the Prostate-Specific Membrane Antigen (PSMA), which is significantly upregulated on prostate cancer cells. We show that DUPA-miR-34a is specifically targeted to tumor cells overexpressing PSMA, is rapidly internalized by the cells, and induces target gene silencing. The binding and uptake of miR-34a by the tumor cells is dependent on conjugating the miRNA to DUPA. In vivo, DUPA-conjugates bind specifically to PSMA expressing prostate tumors with no significant uptake from normal organs or tumors with no PSMA expression. Additionally, Incorporation of the ionophore nigericin in the DUPA ligand enhances miR-34a silencing activity through facilitating its endosomal escape. However, since RNAs are inherently unstable a second modification was engineered to enhance the miRNA stability. Modifying miRNA through the inclusion of phosphorothioate linkages and 2′-fluoro and 2′-O-methyl modified ribose bases, enhances miRNA stability without compromising its activity. Fully modified miR-34a (FM-miR-34a) exhibits enhanced silencing activity of its target genes such as MET, and CD44 in comparison to partially modified miR-34a (PM-miR-34a). In addition, both PM-miR-34a and FM-miR-34a significantly inhibit cell proliferation in vitro, and the silencing of target genes requires the presence of argonaute 2 (AGO2) protein. We plan to identify the targeting differences between FM- and PM-miR-34a and will combine the DUPA ligand with FM-miR-34a to enhance both delivery and activity of miR-34a.
Citation Format: Ahmed M. Abdelaal, Sudarshan Kasireddy, Ikjot S. Sohal, Philip S. Low, Andrea L. Kasinski. Efficient targeting of prostate cancer using ligand conjugated and chemically modified tumor suppressive miRNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1482.
Abstract 1483: RNA interference seed-based approach to inhibit androgen signaling and induce prostate cancer cell death
Authors: Corbin Joshua M. , Ruiz-Echevarria Maria J. 
Published: June 2022

Abstract
The goal of this study is to identify RNA interference (RNAi) seed sequences that inhibit androgen signaling and induce toxicity in prostate cancer (PCa) cells. The high prevalence of acquired resistance to androgen deprivation therapy, as well as first and second generation androgen receptor (AR) antagonists, drives the development of lethal castration resistant prostate cancer (CRPC). As a result, PCa remains one of the leading causes of cancer related deaths in men. AR amplification, gain of function mutations and constitutively active splice isoforms of the AR, and the overexpression of AR coregulators, play considerable roles in promoting CRPC by sustaining AR activity in the presence of the low androgen environment and/or AR antagonists. The development of specific small molecule inhibitors of AR splice isoforms has been largely unsuccessful, and inhibitors of individual AR coregulators have not translated well into the clinic, likely due to their large number and functional redundancies. Therefore, novel therapeutic strategies for targeting androgen signaling in CRPC are necessary. Previous studies in our lab have demonstrated RNAi-mediated PCa cell death through seed region (nucleotides 2-8) complementarity of shRNA/siRNA guide strands to the 3’UTR of the AR and multiple AR coregulators and essential genes. In the current study, we used an unbiased novel seed-based shRNA screen to identify seed sequences that are toxic to different PCa cells, including CRPC cells expressing the clinically relevant constitutively active AR variant 7 (AR-V7). Common motifs were identified among toxic seed sequences, and the miRDB target prediction database was used to select those seeds that were predicted to target the AR and AR coregulators. Using RNA-seq analyses we confirmed that selected seed sequences inhibited global androgen signaling and identified potential direct targets known to be relevant to PCa. Conclusions: These studies have identified androgen signaling inhibitory sequences that have the potential to be used in RNAi-seed based therapies for PCa. The ability to inhibit the expression of the AR and multiple essential AR coregulators simultaneously with one agent, and the reduced likelihood of developed resistance, are considerable benefits of this approach.
Citation Format: Joshua M. Corbin, Maria J. Ruiz-Echevarria. RNA interference seed-based approach to inhibit androgen signaling and induce prostate cancer cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1483.
Abstract 1500: Exonuclease 1 recruitment in human DNA mismatch repair
Authors: Knicely Breanna 
Published: June 2022

Abstract
DNA repair is the process by which cells identify and correct mutations present within the genome. These correction mechanisms maintain genomic stability and prevent the development of cancer. The DNA mismatch repair (MMR) pathway identifies and corrects small insertions, deletions, and misincorporations that arise within the genome as a result of errors during DNA replication. The process by which MMR corrects these mispairs includes recognition of the mispair by the MutS complex, recruitment of the MutL complex to the mutation site, excision of the mispair, and gap filling by DNA polymerase. MMR is also critical for inducing apoptosis after chemically induced mispairs, such as those from alkylating agents. Exonuclease 1 is the protein responsible for the excision step of MMR. However, MMR can occur in the absence of Exo-1. Thus, MMR can be separated into two subpathways: Exo1-dependent MMR and Exo1-independent MMR. In Exo1-dependent MMR Exo-1 binds to both the MutS complex and MutL complex. The MutL interaction is facilitated by an MLH1 interaction peptide (MIP) box. We recently identified a Msh2 interaction peptide (SHIP) box in yeast Exo1. This project aims to understand how MIP and putative human SHIP box motifs influence human Exo1 recruitment to MMR processes. We have created mutations within the predicted binding domains of human Exo1. We observe changes in localization of Exo1-mutant proteins within the cell, suggesting that changes in the overall MMR process may be present. We also observe changes in MMR-mediated apoptotic response when a subset of Exo1-mutations are expressed in the presence of endogenous wildtype Exo1, indicating a potential for a dominant negative interaction. Our ongoing studies are expected to shed more light upon how the changes in these interactions may affect the human MMR process and overall genomic stability.
Citation Format: Breanna Knicely. Exonuclease 1 recruitment in human DNA mismatch repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1500.
Abstract 1503: Augmenting genomic instability in HPV head and neck cancer tumors through combination bromodomain and extra-terminal (BET) proteins inhibition and radiation treatments
Authors: Rao Aakarsha , Ni Zijian , Wang Albert , Suresh Dhruthi , Mohanty Chitrasen , Kendziorski Christina , Iyer Gopal 
Published: June 2022

Abstract
Integration of human papillomavirus (HPV)16 genomes into host head and neck squamous cell carcinoma (HNSCC) DNA is an essential driver for cancer progression. Currently, there are no treatment strategies based on HPV integration status. We postulate that a conceptual advance in the treatment of HPV HNSCC cancer can be formalized by targeting transcriptional co-regulator - bromodomain and extra-terminal (BET) proteins which mediate viral and host transcription. HPV maintenance in the host environment is dependent on BET protein-BRD4. An additional function of BET proteins in regulating transcription of tumor suppressors and DNA damage repair (DDR) genes. Given that patient populations have viral integrations into their genomes and its maintenance depends on cellular Brd4, displacing Brd4 through novel second-generation BET inhibitors can abrogate HPV transcription. Through chemical and knockdown studies of BET proteins in integrated viral HNSCC cells, we show viral oncogenes E6 and E7 are directly regulated by Brd4, reactivate tumor suppressors p53, release E2F1-Rb cell cycle brake to induce G1 cell cycle arrest, and significantly converge towards downregulation of DDR pathways in disrupted viral genomes. In contrast, non-disrupted viral genomes diverge from DDR pathways towards downregulation of interferon signaling pathways. As a result of the intrinsic genomic instability caused by the downregulation of components of the DDR machinery, the addition of external beam radiation further delayed DNA repair kinetics quantified through H2AX foci formation in cells harboring disrupted viral genomes. Taken together, targeting BET proteins is not a viable monotherapy but creates genomic instability, which, when combined with radiation, has the potential to eradicate HPV-associated tumors.
Citation Format: Aakarsha Rao, Zijian Ni, Albert Wang, Dhruthi Suresh, Chitrasen Mohanty, Christina Kendziorski, Gopal Iyer. Augmenting genomic instability in HPV head and neck cancer tumors through combination bromodomain and extra-terminal (BET) proteins inhibition and radiation treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1503.
Abstract 1506: APOBEC3A a causative agent in cancer-related chromosomal instability and STING driven metastasis
Authors: Woermann Sonja Maria , Zhang Amy , Thege Fredrik I. , Gates Chris , Harris Reuben S. , Ross Susan R. , Notta Faiyaz , Maitra Anirban , Rhim Andrew D. 
Published: June 2022

Abstract
Chromosomal instability (CIN), a hallmark of cancer, has been associated with a highly metastatic phenotype in numerous cancers. Mechanisms by which these genomic events occur during the lifespan of a neoplasm have yet to be fully delineated. In our study we identified a novel function for APOBEC3A (A3A), a primate-specific cytidine deaminase upregulated in multiple cancers including Pancreatic ductal adenocarcinoma (PDAC), in the initiation of CIN.We demonstrate that A3A is not routinely detected in non-diseased pancreata; however, expression was detected in the epithelial and stromal compartments from patients with chronic pancreatitis and in precursor lesions of PDAC and is further significantly increased in invasive neoplasia. Strikingly, we found that A3A expression but not A3A-induced mutagenesis, was associated with a significantly reduced overall survival in PDAC. By employing a variety of genetic tools, we identified a novel function for A3A in initiating CIN, underscoring its potential role in driving the observed early metastatic propensity in PDAC. Using a series of in vivo and in vitro models, we demonstrate that A3A-induced CIN leads to aggressive cancer, featuring enhanced, STING-dependent, distant organ seeding and metastatic growth. As a consequence of aberrant A3A function and CIN-mediated upregulation of STING, NfkB and Stat3 pathways were activated. More importantly, all these effects were independent of the deaminase domain, underscoring a novel role of A3A beyond its established canonical function. Remarkably, in a novel autochthonous murine model of PDA expressing human A3A, we identified numerous copy number changes, homologous to those altered in A3A overexpressing patient tumors, including deletions in DNA repair pathway genes. While we showed that A3A-expressing PDAC cells do not fully phenocopy a BRCA mutation-like phenotype, A3A-expressing PDAC cells are exceptionally sensitive to PARP inhibition and DNA cross linking agents, recapitulating a state of “chemical BRCAness”. The combined effect of deletions in these genes has yet to be ascertained, and we hypothesize that these losses further add to ongoing DNA damage overall in PDAC. In summary, our study shows, that A3A drives metastasis and specific deletions through a deaminase-independent initiation of CIN, with potential implications for targeted treatment strategies in pancreatic cancer.
Citation Format: Sonja Maria Woermann, Amy Zhang, Fredrik I. Thege, Chris Gates, Reuben S. Harris, Susan R. Ross, Faiyaz Notta, Anirban Maitra, Andrew D. Rhim. APOBEC3A a causative agent in cancer-related chromosomal instability and STING driven metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1506.
Abstract 1508: Chromatin accessibility of primary human cancers ties regional mutational processes with tissues of origin
Authors: Reimand Jüri , Ocsenas Oliver 
Published: June 2022

Abstract
Cancer genomes are shaped by mutational processes with complex spatial variation at multiple scales. However, the underlying mechanisms of this mutagenesis and its functional and genetic determinants remain poorly understood. Somatic regional mutagenesis is known to correlate with DNA replication timing and chromatin accessibility; however, these studies have used epigenetic information from common cell lines while the epigenomes of primary human cancers remain uncharacterized in this context.
Here we model megabase-scale mutation frequencies of single nucleotide variants (SNVs) in thousands of whole cancer genomes using hundreds of genome-wide profiles of chromatin accessibility and replication timing spanning primary cancer samples, normal tissues, and cell lines. Using a machine learning framework, we show that CA profiles of primary cancers, rather than those of normal cells, predict regional mutagenesis and single base substitution (SBS) signatures in most cancer types. Thus the majority of passenger mutations follow the epigenetic landscapes of transformed cells of matching cancer sites and tissues.
Mutational signatures associated with carcinogen exposure, as well as signatures of unknown origin, show the strongest associations with epigenomes while associations with endogenous signatures are weaker. In most cases, overall mutation burden and SBS signatures inversely correlate with chromatin accessibility, however certain signatures are instead enriched in chromatin-accessible elements.
Lastly, the genomic regions with excess mutations unexplained by the epigenetic profiles in our models likely represent a combination of localized mutagenesis and positive selection of functional oncogenic mutations. Our computational models highlight an enrichment of known driver mutations, point out novel intergenic regions with putative non-coding drivers, and indicate an over-representation of developmental and lineage-specific genes in these frequently mutated genomic regions.
These results characterize the complex interplay of mutational processes, genome function, and somatic evolution in cancer and its tissues of origin, and also outline strategies for distinguishing driver and passenger mutations.
Citation Format: Jüri Reimand, Oliver Ocsenas. Chromatin accessibility of primary human cancers ties regional mutational processes with tissues of origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1508.