bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3365: MAP3K10 mutation as a biomarker for predicting response to chemotherapy in gastric cancer patients
Authors: Kwon Chae Hwa , Lee Sun Jin , Choi Yuri , Park Do Youn 
Published: August 2018

Abstract
Gastric cancer is one of most common malignant tumors. Although chemotherapy can improve the survival of gastric cancer, the benefit is limited because most cancer cells eventually become irresponsive to chemotherapeutic drugs. To investigate mechanism of resistance to chemotherapy, we performed whole-exome sequencing (WES) on resistant tumor and paired normal samples from 14 patients received adjuvant chemotherapy. We found that 3 patients had novel somatic mutations in mitogen-activated protein kinase kinase kinase 10 (MAP3K10), an upstream kinase of mitogen activated protein kinase (MAPK). MAP3K10R304C, MAP3K10H211R, or MAP3K10A30E were detected each patient, respectively. The survival rate was higher and apoptosis rate was smaller in the cells expressing each MAP3K10 mutations compared with parental controls and cells expressing wild-type MAP3K10, when treated with cisplatin or 5-FU. Moreover, cells expressing each MAP3K10 mutations exhibited higher levels of phosphorylated MEK1/2 and p38MAPK at baseline and when treated with cisplatin or 5-FU than wild-type AGS or MKN45 cells or those expressing wild-type MAP3K10. In summary, MAP3K10R304C, MAP3K10H211R, and MAP3K10A30E MAP3K10 confer resistance to cisplatin or 5-FU via activation of MAPK pathway in gastric cancer cells. Thus, somatic MAP3K10 mutations could be a potential biomarker for predicting resistance to chemotherapy for gastric cancer patients
Citation Format: Chae Hwa Kwon, Sun Jin Lee, Yuri Choi, Do Youn Park. MAP3K10 mutation as a biomarker for predicting response to chemotherapy in gastric cancer patients [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 3365.
Abstract 3366: APOBEC3 family of cytidine deaminases in sensitizing triple-negative breast cancer cells to cisplatin and carboplatin
Authors: Conner Kayla L. , Shaik Asra N. , White Jordan , Lei Wen , Cote Michele L. , Patrick Steve M. 
Published: August 2018

Abstract
Cisplatin is a DNA damaging chemotherapeutic which forms interstrand crosslinks (ICL) and intrastrand adducts that induce replication fork collapse and lead to apoptosis. These adduct sites can be repaired through several repair pathways, the most important being nucleotide excision repair (NER). Cisplatin and carboplatin ICLs form a unique structure that forces cytosines flanking the adduct site to become extrahelical. Our lab has previously shown that base excision repair (BER) and mismatch repair (MMR) mediate sensitivity to cisplatin and carboplatin as a consequence of nonproductive processing of DNA flanking the ICL structure. The APOBEC3 (A3) protein family of cytidine deaminases have recently been implicated in cancer development and have potential to deaminate the extrahelical cytosines formed by cisplatin ICLs. Polβ knockdown MDA-MB-231 cells are resistant to cisplatin in vivo compared to wild-type cells (p&lt;0.001). Knockdown of APOBEC3 family members in MDA-MB-231 breast cancer cells results in a resistant phenotype to cisplatin and carboplatin treatment compared to the control. Utilizing CRISPR-Cas9 genome editing, we generated knockouts of A3 members. A3D knockdown in the APOBEC3C (A3C) knockout results in resistance to cisplatin compared to the control, suggesting that multiple A3 enzymes can deaminate the ICL induced extrahelical cytosine. APOBEC3A (A3A) knockdown in a cell line with high expression of A3A (SK-BR-3) shows no difference in cisplatin and carboplatin treatment, suggesting that A3A does not deaminate extrahelical cytosines. Overexpression of A3C or A3D in cell lines with low expression of A3 proteins (SK-BR-3) results in sensitivity to cisplatin. These results together suggest that A3C, A3D, and A3G can deaminate the ICL extrahelical cytosines, resulting in the activation of BER. The subsequent nucleotide misincorporation by Polβ followed by MMR protein binding would physically block NER proteins from repairing the ICL, therefore conferring sensitivity to cisplatin and carboplatin.
Citation Format: Kayla L. Conner, Asra N. Shaik, Jordan White, Wen Lei, Michele L. Cote, Steve M. Patrick. APOBEC3 family of cytidine deaminases in sensitizing triple-negative breast cancer cells to cisplatin and carboplatin [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 3366.
Abstract 3367: USP7 regulates CSB protein recovery after UV-induced DNA damage
Authors: Wei Shengcai 
Published: August 2018

Abstract
Cockayne syndrome group B (CSB) protein functions in transcription-coupled repair (TCR), a sub-pathway of nucleotide excision repair (NER). We previously demonstrated that ultraviolet radiation (UVR) induces a valosin-containing protein (VCP)/p97-dependent ubiquitin-mediated CSB degradation. In this study, we further revealed that CSB protein is ubiquitinated immediately after ultraviolet-light irradiation and undergoes proteasomal degradation. The recovery of CSB protein level is dependent on USP7. Disruption of USP7 function sensitizes CSB degradation to lower UVR doses. We further demonstrated USP7's interaction with CSB in vivo by immunoprecipitation and in vitro by GST pulldown assays. Interestingly, in vitro CSB strongly binds to TRAF domain, which also interacts with UV stimulated scaffold protein A (UVSSA). Additionally, USP7 also interacts with VCP/p97 using its TRAF domain and C-terminal in in vitro. Furthermore, VCP/p97 was demonstrated to associates with USP7 in vivo. These results suggest that USP7 rescues CSB from ubiquitin-mediated proteolysis after (VCP)/p97-mediated CSB extraction from chromatin, preventing the CSB-ubiquitin conjugates being presented to proteasome for degradation.
Citation Format: Shengcai Wei. USP7 regulates CSB protein recovery after UV-induced DNA damage [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 3367.
Abstract 3376: Early onset of chromosomal instability in breast preneoplasia detected by single-cell genomics
Authors: Fagan-Solis Katerina , Simpson Dennis A. , Martelotto Luciano , Reis-Filho Jorge S. , Petrini John H. , Gupta Gaorav P. 
Published: August 2018

Abstract
Chromosomal rearrangements and copy number aberrations are a major mechanism for driver gene alterations in breast cancer. However, the origins of chromosomal instability during breast tumorigenesis are poorly understood. We have recently shown that oncogene expression in normal mammary epithelial cells induces replication stress and a DNA damage response (DDR). The double-strand break sensor Mre11 is required for the oncogene-induced DDR, and suppression of Mre11 is sufficient to promote the development of Her2/Neu-driven breast cancer in a transgenic mouse model. Here we have applied single-cell genomics to primary mammary epithelial cells from this mouse model and demonstrate a profound effect of oncogene expression on chromosomal instability in preneoplastic cells, which is further augmented in Mre11-mutant cells. Her2/Neu-induced chromosomal breakpoints are highly enriched in the vicinity of large genes, suggesting a possible role for gene transcription and/or R-loops in the origin of oncogene-induced genomic fragility. Mre11 hypomorphism does not affect the number of chromosomal breakpoints but alters the genomic aberration signature to one that is over-represented by larger-size deletions. These findings indicate that chromosomal instability is an early event during Her2/Neu-initiated breast neoplasia. Furthermore, DDR perturbation—in the form of Mre11 hypomorphism—is not required for oncogene-induced genomic instability but rather alters the pattern of observed copy number aberrations and promotes the proliferative expansion of genomically unstable clones. Thus, single-cell genomics applied to murine models of breast preneoplasia reveals insights into the origins of chromosomal instability in breast cancer that may inform novel strategies to prognosticate or prevent the progression of high-risk premalignant breast lesions.
Citation Format: Katerina Fagan-Solis, Dennis A. Simpson, Luciano Martelotto, Jorge S. Reis-Filho, John H. Petrini, Gaorav P. Gupta. Early onset of chromosomal instability in breast preneoplasia detected by single-cell genomics [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 3376.
Abstract 338: A new investigational ATM Inhibitor, M3541, synergistically potentiates fractionated radiotherapy and chemotherapy in cancer cells and animal models
Authors: Zimmermann Astrid , Zenke Frank , Dahmen Heike , Sirrenberg Christian , Grombacher Thomas , Vassilev Lyubomir T. , Fuchss Thomas , Blaukat Andree 
Published: August 2018

Abstract
Physical or chemical DNA damaging agents are among the most widely used classes of cancer therapeutics today. Radiotherapy and topoisomerase inhibitors induce double strand breaks (DSB) considered most dangerous if left unrepaired because they can induce growth arrest, chromosomal abnormality and/or cell death. ATM is an essential kinase which orchestrates one of the two major pathways for repair of DSBs via the high fidelity homologous recombination (HR) mechanism. In addition, ATM acts as an upstream signaling kinase, regulating cell cycle checkpoint control in the response to DSB damage. Inhibitors of ATM kinase are expected to suppress DSB DNA repair, block checkpoint controls and enhance the therapeutic effect of radiation therapy and other DSB-inducing treatment modalities. We have developed a novel, highly potent and selective inhibitor of ATM, M3541, which modifies cellular response to DSB damage leading to potentiation of radiation therapy and DSB-inducing chemotherapy. Here, we present data from the preclinical evaluation of M3541 therapeutic potential in cellular and xenograft models of cancer. ATM inhibitor sensitized multiple tumor cell lines to ionizing radiation and a topoisomerase inhibitor in vitro. Oral administration of M3541 to nude mice bearing human tumor xenografts in a clinically relevant radiation regimen strongly enhanced the antitumor activity, leading to complete tumor regression. These activities resulted from inhibition of ATM kinase activity and modulation of its downstream effects in the xenograft tissues. M3541 is currently under clinical investigation in a Phase I trial.
Citation Format: Astrid Zimmermann, Frank Zenke, Heike Dahmen, Christian Sirrenberg, Thomas Grombacher, Lyubomir T. Vassilev, Thomas Fuchss, Andree Blaukat. A new investigational ATM Inhibitor, M3541, synergistically potentiates fractionated radiotherapy and chemotherapy in cancer cells and animal 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 338.
Abstract 3380: BRIP1/FANCJ is vital for efficient response to and repair of replication-associated DNA damage
Authors: Clark David W. , Mani Chinnadurai , Palle Komariah 
Published: August 2018

Abstract
BRCA1-Interacting Protein 1 (BRIP1), a DNA helicase and tumor suppressor also known as FANCJ, is implicated in breast and ovarian cancers as well as the genetic instability syndrome Fanconi anemia (FA) which predisposes patients to multiple neoplasms. This study investigates the role of FANCJ in repair of replication-associated DNA damage which can lead to DNA strand breaks, chromosomal instability, and tumorigenesis. FANCJ has long been known to function in repair of DNA crosslinks; however, its role in protecting cells from replication-associated DNA damage is less well known. We have shown that loss of FANCJ sensitizes cells to damage caused by compounds that block DNA replication, such as hydroxyurea (HU) and the topoisomerase I poison camptothecin (CPT). Loss of FANCJ disrupts the cell's response to replication-associated DNA damage by impairing Chk1 and Chk2 phosphorylation and stability and activation of multiple DNA repair proteins. FANCJ-deficient cells exposed to low levels of CPT failed to progress through S-phase indicating that FANCJ is important for intra-S phase DNA damage checkpoint and recovery from replication fork blocks. FANCJ depletion leads to a 90% decrease in homologous recombination repair in assays designed to measure repair of DNA double strand breaks as well as a loss of expression of repair-associated proteins and DNA repair foci in response to damage from HU and CPT. Loss of FANCJ impairs DNA replication and leads to accumulation of gross chromosomal aberrations. Importantly, some of the DNA damage response functions of FANCJ are independent of its helicase activity, as a helicase-deficient mutant is able to compensate for loss of FANCJ in activation and stability of FANCD2 and other HR proteins. Collectively our findings indicate a novel role for FANCJ as a key regulator of the DNA damage response to errors in DNA replication potentially leading to mutagenesis and tumorigenesis.
Citation Format: David W. Clark, Chinnadurai Mani, Komariah Palle. BRIP1/FANCJ is vital for efficient response to and repair of replication-associated DNA damage [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 3380.
Abstract 339: Heterozygous germline mutation in ABRAXAS causes BRCA1 mislocalization and DNA damage response defects
Authors: Winqvist Robert , Bose Muthiah , Sachsenweger Juliane , Laurila Niina , Parplys Ann Christin , Willmann Jonas , Eshraghi Leila , Dunlop Thomas W. , Groth Marco , Rapakko Katrin , Nieminen Pentti , Friedl Thomas W. , Heiserich Lisa , Meyer Felix , Tuppurainen Hanna , Devarajan Ganapathy Raman , Peltoketo Hellevi , Nevanlinna Heli , Pylkäs Katri , Borgmann Kerstin , Wiesmuller Lisa , Pospiech Helmut 
Published: August 2018

Abstract
Whilst heterozygous germline mutations in the ABRAXAS gene have been associated with hereditary breast cancer predisposition, their initial effect on promoting tumorigenesis at the cellular level has not been explored. Here, we demonstrate in patient-derived cells that the Finnish ABRAXAS founder mutation (c.1082G&gt;A, Arg361Gln), even in the heterozygous state leads to decreased BRCA1 protein levels as well as reduced nuclear localization and foci formation of BRCA1 and CtIP. This causes disturbances in basal BRCA1-A complex localization, which is reflected by a restraint in error-prone DNA double-strand break (DSB) repair pathway usage, attenuated DNA damage response, deregulated G2-M checkpoint control and apoptosis. Most importantly, mutation carrier cells display a change in their transcriptional profile, which we attribute to the reduced nuclear levels of BRCA1. The current study clearly demonstrates how the Finnish ABRAXAS founder mutation acts in a dominant-negative manner on BRCA1 to promote genome destabilisation in heterozygous carrier cells.
Citation Format: Robert Winqvist, Muthiah Bose, Juliane Sachsenweger, Niina Laurila, Ann Christin Parplys, Jonas Willmann, Leila Eshraghi, Thomas W. Dunlop, Marco Groth, Katrin Rapakko, Pentti Nieminen, Thomas W. Friedl, Lisa Heiserich, Felix Meyer, Hanna Tuppurainen, Ganapathy Raman Devarajan, Hellevi Peltoketo, Heli Nevanlinna, Katri Pylkäs, Kerstin Borgmann, Lisa Wiesmuller, Helmut Pospiech. Heterozygous germline mutation in ABRAXAS causes BRCA1 mislocalization and DNA damage response defects [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 339.
Abstract 3393: Characterizing recurrent high-grade serous ovarian cancer through whole-genome sequencing
Authors: Christie Elizabeth L. , Pattnaik Swetansu , Fereday Sian , Study Australian Ovarian Cancer , Thorne Heather , Bild Andrea , Bowtell David D. 
Published: August 2018

Abstract
Acquired drug resistance is the major obstacle in controlling high-grade serous ovarian cancer (HGSC) and leads to poor overall survival. Comparatively little massively parallel sequencing data exist from HGSC patients with recurrent disease who have been extensively treated with chemotherapy or newer targeted agents, such as anti-angiogenics or PARP inhibitors (PARPi). We previously identified four mechanisms of acquired resistance from whole-genome sequencing (WGS) of 23 HGSC patients with recurrent disease; a resistance mechanism of any kind was only identified in half of the patients. Since 2012, we have collected tumor samples from 16 HGSC patients through our rapid-autopsy program. On average, we collect 17 tumor sites per patient during the autopsy, and to date we have performed WGS on 28 autopsy samples from 8 patients. These data are allowing us to understand HGSC at end-stage, by examining the complete catalog of resistance mechanisms within an individual patient and reconstructing the natural history of HGSC. One acquired resistance mechanism we identified in HGSC involves transcriptional fusion of the drug efflux pump ABCB1 to an upstream gene that causes its overexpression. ABCB1 encodes the multidrug resistance transporter MDR1, also known as P-glycoprotein. Through WGS and targeted RNA sequencing on end-stage tumor samples as well as recurrent ascites samples, we identified multiple fusion partners to ABCB1, with more than 15% of recurrent HGSC patients harboring ABCB1 transcriptional fusions. A number of HGSC patients carry multiple ABCB1 fusions, demonstrating convergent evolution within patients and the strong selective advantage of ABCB1 overexpression by gene fusion. Extending our analysis to recurrent and autopsy samples from breast and prostate cancer patients also identified ABCB1 transcriptional fusions as a resistance mechanism in these cancers. Our findings suggest that ABCB1 transcriptional fusions are a common mechanism of acquired chemotherapy resistance in ovarian, breast and prostate cancer patients, and that characterizing end-stage disease is particularly informative for understanding resistance mechanisms.
Citation Format: Elizabeth L. Christie, Swetansu Pattnaik, Sian Fereday, Australian Ovarian Cancer Study, Heather Thorne, Andrea Bild, David D. Bowtell. Characterizing recurrent high-grade serous ovarian cancer through whole-genome sequencing [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 3393.
Abstract 3399: Comparative genomic analyses of osteosarcoma etiology reveal a chromosomal structural rationale for the increased incidence of osteosarcoma in dogs
Authors: Sarver Aaron L. , Mills Lauren , Temiz Nuri , Scott MIlcah , Sarver Anne , Spector Logan , Wang Jinhua , Breen Mathew , Subramanian Subbaya , Moriarity Branden , Modiano Jaime , Largaespada David 
Published: August 2018

Abstract
Risk of osteosarcoma is significantly higher in large and giant breed dogs than in any other animal, including humans. To identify the reason for this observation, we used a comparative genomic approach to identify aberrations responsible for osteosarcoma etiology in a Sleeping Beauty transposon-accelerated mouse model, in human patients, and in naturally occurring canine tumors, using RNA-Seq and exome paired tumor normal analyses. Fusions identified in Sleeping Beauty-mutagenized tumors revealed a role for Cdkn2a disruption in Trp53 signaling, and for numerous genes which cooperate with disrupted TrpP53 signaling, indicating the existence of many diverse routes to osteosarcoma tumor formation. Similarly, human tumors showed TP53 pathway disruption associated with a high level of diversity of additional driver mechanisms, supporting multiple independent routes to tumor formation. However, in the majority of canine tumors, observed TP53 pathway aberrations co-occurred with loss of both copies of the region containing the PTEN tumor suppressor. In human osteosarcoma, only heterozygous PTEN loss was observed, and in both humans and mice, PTEN aberration was observed in a much smaller percentage of the tumor population. We hypothesize that increased osteosarcoma incidence in dogs is partly due to a syntenic rearrangement of the peri-PTEN locus in the canine genome. The PTEN gene is part of a small synteny block that localized in the distal end of canine chromosome 26 (CFA 26) during evolution. We hypothesize that this location change creates a high risk of loss in the context of cytogenetic instability caused by disruption of TP53, thereby providing a structural genetic rational for the higher incidence of osteosarcoma in dogs. Consistent with these results and with the powerful nature of PTEN as a tumor suppressor, canine osteosarcomas with homozygous loss of PTEN are associated with worse outcomes than canine osteosarcomas with intact PTEN. These results suggest that engineering genomes to minimize cancer risk may be a realistic approach to the prevention of cancer.
Citation Format: Aaron L. Sarver, Lauren Mills, Nuri Temiz, MIlcah Scott, Anne Sarver, Logan Spector, Jinhua Wang, Mathew Breen, Subbaya Subramanian, Branden Moriarity, Jaime Modiano, David Largaespada. Comparative genomic analyses of osteosarcoma etiology reveal a chromosomal structural rationale for the increased incidence of osteosarcoma in dogs [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 3399.