bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3854: Inhibition of uracil DNA glycosylase (UDG) sensitizes cancer cells to thymidylate synthase inhibitors
Authors: Yan Yan , Condie Allison , Gerson Stanton 
Published: August 2015

Abstract
Thymidylate synthase (TS) is responsible for the de novo synthesis of thymine nucleotides that are used as building blocks for DNA synthesis. Two classes of therapeutic agents inhibit TS including fluropyrimidines (eg, 5-FU, 5-FdU) and antifolates (eg, pemetrexed), which lead to depletion of deoxythymidine triphosphate (dTTP) and expansion of deoxyuridine triphosphate (dUTP). Fluropyrimidines are also metabolized to 5-fluorouridine triphosphate (5FdUTP). As a result, both elevated dUTP and 5FdUTP are incorporated into DNA. Uracil DNA N-glycosylase (UDG or UNG) is the primary DNA repair enzyme to remove uracil and 5-FU bases from DNA and creates abasic (AP) sites, thus initiating base excision repair (BER) pathway. However, whether the cytotoxic effects of TS inhibitors are dependent on UDG activity still remains controversial. Previously, our lab has shown that in DLD1 colon cancer cells, knockout of UDG hypersensitized cells to pemetrexed treatment and the cell death was accompanied by remarkable S phase arrest and stalled replication fork. In this study, we examined the cytotoxicity of both pemetrexed and 5-FdU in SW480, HCT116, DLD1, and HEC1A cancer cell lines after performing stable UDG knockdown (KD) by shRNA. We hypothesized that loss of UDG would sensitize cancer cells to TS inhibitors treatment with accumulation of a large amount of uracil and 5-FU bases in DNA and ultimately lead to replication folk collapse. Results showed that reduced UDG protein and activity levels enhanced the cell killing effect, increased the sub-G1 populations, and delayed cell cycle recovery following TS inhibitors treatment. In response to 5-FdU treatment, cells with UDG shRNA were mainly arrested at late G1 and early S phase by 24 hours of treatment. After releasing cells in drug free medium, loss of UDG displayed delayed recovery from cell cycle arrest in comparison to shRNA scramble control cells. We have also detected a significant induction of the amount of AP sites after incubation of extracted DNA from UDG shRNA KD cells with purified UDG protein following 5-FdU treatment, indicating the accumulation of uracil and 5-FU in DNA as a consequence of 5-FdU treatment. Now, further studies are undergoing to determine the actual levels of uracil and 5-FU incorporation into DNA and the replication status after TS inhibitors treatment. These studies confirm that uracil and 5-FU incorporation due to loss of UDG accelerates stall of replication, collapse of the replication fork, and increased cytotoxicity of TS inhibitors.
Citation Format: Yan Yan, Allison Condie, Stanton Gerson. Inhibition of uracil DNA glycosylase (UDG) sensitizes cancer cells to thymidylate synthase inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3854. doi:10.1158/1538-7445.AM2015-3854
Abstract 3857: The polymorphisms of XRCC1 Arg194Trp and the XRCC1Arg399Gln affect the clinical features and the prognosis of MDS
Authors: Norjmaa Batchimeg , Saitoh Takayuki , Kasamatsu Tetsuhiro , Minato Yusuke , Sunaga Noriaki , Murakami Hirokazu 
Published: August 2015

Abstract
Background: X-ray repair cross-complementing group 1 (XRCC1) is involved an important role in base excision repair (BER) system of DNA repair. Polymorphism in DNA repair genes may be modified of DNA repair capacity. However, it is unclear that the polymorphisms of XRCC1alter the clinical features of MDS patients. Our study was performed to evaluate the effect of the XRCC1Arg194Trp and the XRCC1Arg399Gln with the susceptibility and clinical features of MDS.
Methods: We genotyped the polymorphisms by using polymerase chain reaction -restriction fragment-length polymorphism (PCR-RFLP) analysis in 119 patients with MDS [median 67.9 years, range 17.1-86.5 years; male/female 81/38; RCUD (n = 40), RARS (n = 6), RCMD (n = 21), MDS-U (n = 13), RAEB-1(n = 14), RAEB-2 (n = 12), others (n = 13)] and 202-health controls.
Results: In the allele and genotype frequencies of the XRCC1Arg194Trp and the XRCC1Arg399Gln were not statistically significant difference in patients and the controls. However, Arg/Arg genotypes of XRCC1 194 and the XRCC1 399 were significantly associated with lower Hb. In addition, XRCC1 399 non Arg/Arg genotype was significantly associated with previous history of radiotherapy and multiple cancers. Furthermore, XRCC1Arg194Trp non Arg/Arg genotype and XRCC1Arg399Gln Arg/Arg genotype were significantly associated with poor prognosis of MDS patients.
Conclusion: We found that the polymorphisms of XRCC1 may be affected the clinical features and the prognosis of MDS.
Citation Format: Batchimeg Norjmaa, Takayuki Saitoh, Tetsuhiro Kasamatsu, Yusuke Minato, Noriaki Sunaga, Hirokazu Murakami. The polymorphisms of XRCC1 Arg194Trp and the XRCC1Arg399Gln affect the clinical features and the prognosis of MDS. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3857. doi:10.1158/1538-7445.AM2015-3857
Abstract 3861: Prognostic impact of KRAS copy number amplification in esophagogastric junction adenocarcinoma
Authors: Nakamura Kenichi , Imamura Yu , Tokunaga Ryuma , Ohuchi Mayuko , Kiyozumi Yuki , Kosumi Keisuke , Izumi Daisuke , Harada Kazuto , Kurashige Junji , Karashima Ryuichi , Hiyoshi Yukiharu , Iwagami Shiro , Baba Yoshifumi , Sakamoto Yasuo , Miyamoto Yuji , Yoshida Naoya , Saeki Hiroshi , Oki Eiji , Maehara Yoshihiko , Baba Hideo 
Published: August 2015

Abstract
Background: The incidence of esophageal adenocarcinoma (EAC) or esophagogastric junction adenocarcinoma (EGJA) has been dramatically increasing. KRAS oncogenic alterations activate multiple pathways in various types of cancer. A recent comprehensive genetic study has reported that around 20% of EAC harbor KRAS copy number gain (Dulak AM et al, 2012, Nat Genet). However, the prognostic role KRAS amplification has not been well examined in EAC/EGJA.
Methods: DNA was extracted from formalin-fixed paraffin-embedded tissue of 145 EGJA (Siewert types I-III). KRAS copy number was detected by real-time quantitative PCR, and KRAS copy number gain was defined as KRAS/RNase P (as a reference) ratio ≥ 2.5. The impact of KRAS amplification was analyzed in relation to clinicopathological factors, and patient outcomes [disease free survival (DFS), and overall survival (OS)]. Multivariate cox proportional hazards model was performed adjusting clinicopathological factors.
Results: KRAS amplification was observed in 40 (33.1%) cases. KRAS amplification was significantly associated with the lymph node metastasis (P = 0.0145), and was significantly associated with poorer patient outcome (P = 0.0355 in DFS, and P = 0.0067 in OS). In multivariate analysis, KRAS amplification was an independent prognostic factor for OS [multivatiate hazard ratio (HR) = 2.53; 95% confidence interval (CI), 1.22-5.25, P = 0.014] and DFS [multivatiate hazard ratio (HR) = 1.94; 95% confidence interval (CI), 1.04-3.56, P = 0.0382].
Conclusions: KRAS copy number gain may be a useful prognostic marker in EGJA.
Citation Format: Kenichi Nakamura, Yu Imamura, Ryuma Tokunaga, Mayuko Ohuchi, Yuki Kiyozumi, Keisuke Kosumi, Daisuke Izumi, Kazuto Harada, Junji Kurashige, Ryuichi Karashima, Yukiharu Hiyoshi, Shiro Iwagami, Yoshifumi Baba, Yasuo Sakamoto, Yuji Miyamoto, Naoya Yoshida, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Hideo Baba. Prognostic impact of KRAS copy number amplification in esophagogastric junction adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3861. doi:10.1158/1538-7445.AM2015-3861
Abstract 3869: Exploration of mechanisms for chromothripsis by irradiation
Authors: Morishita Maki , Muramatsu Tomoki , Hayashi Shin , Hirai Momoki , Suto Yumiko , Konishi Teruaki , Moriyama Keiji , Inazawa Johji 
Published: August 2015

Abstract
Chromothripsis is the massive but highly localized chromosome rearrangements within a one-step catastrophic event rather than a series of subsequent and random alterations. Chromothripsis occurs commonly in various human cancers and it is thought to be associated with increasing malignancy and oncogenesis. However the causes and consequences of chromothripsis remain unclear. Therefore, to explore mechanisms of chromothripsis, we investigated whether chromothripsis was artificially induced by irradiation. We elicited DNA double-strand breaks in the oral cancer cell line HOC313, or its highly metastatic subline HOC313-LM by The Single Particle Irradiation system to Cell (SPICE), a focused vertical micro-beam system designed to irradiate the nuclei of adhesive cells. We established irradiated monoclonal sublines and analyzed the copy number variations (CNVs) and SNPs using SNP array. Chromosomal alterations, induced by irradiation including CNVs, were detected in some monoclonal sublines. Interestingly SNP array analysis showed that one subline named LM200-#25 had multiple chromosomal alterations which happened locally in chromosome 7. Moreover, we detected several chromosomal alterations such as t(12;7;11) translocation in LM200-#25 subline by Multi-Color FISH analysis. These results suggested that chromothripsis might be induced by irradiation in LM200-#25 subline.
Citation Format: Maki Morishita, Tomoki Muramatsu, Shin Hayashi, Momoki Hirai, Yumiko Suto, Teruaki Konishi, Keiji Moriyama, Johji Inazawa. Exploration of mechanisms for chromothripsis by irradiation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3869. doi:10.1158/1538-7445.AM2015-3869
Abstract 3873: Improving the effectiveness of chemotherapy by combining compounds that suppress drug-induced microsatellite instability
Authors: Chang Christina L. , Huang Li-Yan , Wu Chang-Lin , Chi Jhih-Ying 
Published: August 2015

Abstract
Many chemotherapeutic agents damage DNA and induce DNA damage response (DDR) signaling, resulting in growth arrest or apoptosis. DNA mismatch repair (MMR) system not only maintains genomic stability but also participates in DDR signaling. MMR deficiency leads to genetic hypermutability, manifested as microsatellite instability (MSI), and contributes to cancer pathogenesis and drug resistance. MSI has been linked to chemotherapy and therapy-related secondary cancer. Therefore, it is important to prevent drug-induced MSI to increase the effectiveness of chemotherapy while reducing cancer mortality. The purpose of this study is to characterize the MSI-inducing ability of individual chemotherapeutic agents and identify small compounds that suppress drug-induced MSI. In a human colorectal cancer cell model, all tested drugs individually induced the instability of reporter and endogenous microsatellites while reducing steady-state levels of certain MMR proteins. Relatively, oxaliplatin induced a higher MSI frequency than many tested drugs such as 5-FU. It is known that MMR-deficient tumors are resistant to 5-FU and not oxaliplatin. We then screened a commercially available library for small compounds that suppress oxaliplatin-induced MSI using a dual-fluorescent MSI reporter. We found that the majority of compounds were capable of reducing oxaliplatin-induced MSI. However, they also undesirably decreased the cytotoxicity of oxaliplatin. On the other hand, a small number of compounds such as I-6 and II-13 suppressed oxaliplatin-induced MSI with or without an improvement of drug cytotoxicity. Relative to oxaliplatin alone, co-treatment of 1 μM oxaliplatin with 6-10 μM compound II-13 decreased drug-induced MSI frequency by 45-70% without significantly affecting the cytotoxicity of oxaliplatin. Co-treatment of oxaliplatin with 4-10 μM compound I-6, however, decreased both drug-induced MSI and cell numbers by 50-78% in a dose-dependent manner. To our surprise, compounds such as II-13 suppressed MSI induced by oxaliplatin but not by 5-FU. In conclusion, individual drugs displayed different MSI-inducing abilities whereas MSI-suppressing compounds appear to be drug-specific. Further identification and validation of MSI-suppressing compounds specific for 5-FU or leucovorin, for example, would improve the effectiveness of combination chemotherapy such as FOLFOX.
Citation Format: Christina L. Chang, Li-Yan Huang, Chang-Lin Wu, Jhih-Ying Chi. Improving the effectiveness of chemotherapy by combining compounds that suppress drug-induced microsatellite instability. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3873. doi:10.1158/1538-7445.AM2015-3873
Abstract 3874: Mutational landscapes of oral tongue squamous cell carcinoma reveal recurrent mutations in genes of therapeutic and prognostic relevance
Authors: Vettore Andre L. , Ramnarayanan Kalpana , Ong Choon Kiat , Leong Hui Sun , Lim Weng Khong , Cutcutache Ioana , Mcpherson John R. , Zhang Shenli , Skanthakumar Thankshayeni , Tan Daniel SW , Teh Bin Tean , Rozen Steve , Tan Patrick , Iyer N Gopalakrishna 
Published: August 2015

Abstract
Carcinoma of the oral tongue (OTSCC) is the most common malignancy of the oral cavity, characterized by frequent recurrence and poor survival. The last three decades has witnessed a change in the OTSCC epidemiological profile, with increasing incidence in younger patients, females and never-smokers. This study aims to characterize the OTSCC genomic landscape and to determine factors that may delineate the genetic basis of this disease, inform prognosis and identify targets for therapeutic intervention. Seventy-eight Asian OTSCC cases were subjected to whole-exome and targeted deep sequencing. While the most common mutation seen was in TP53, the OTSCC genetic landscape differed from previously described cohorts of patients with head and neck squamous cell cancers: OTSCCs demonstrated frequent mutations in DST, FSIP2 and RNF213 while alterations in CDKN2A and NOTCH1 were significantly less frequent than previously reported. Despite a lack of previously-known NOTCH1 mutations, integrated analysis showed enrichments of alterations affecting Notch signaling, more commonly seen in women. Importantly, Notch pathway alterations were prognostic on uni- and multivariate analyses. Furthermore, a high proportion of OTSCCs presented with alterations in drug targetable genes and chromatin remodeling genes. Mutations in these groups were also prognostic, where patients harboring mutations in these actionable pathways more likely to succumb from recurrent disease compared to those who did not, suggesting that these patients should indeed be considered for treatment with targeted compounds in future trial designs. In conclusion, these findings define the mutational landscape of OTSCC, highlight the key role of the Notch signaling pathway in oral tongue tumorigenesis and uncover somatic mutations in therapeutically relevant genes which may represent candidate drug targets.
Citation Format: Andre L. Vettore, Kalpana Ramnarayanan, Choon Kiat Ong, Hui Sun Leong, Weng Khong Lim, Ioana Cutcutache, John R. Mcpherson, Shenli Zhang, Thankshayeni Skanthakumar, Daniel SW Tan, Bin Tean Teh, Steve Rozen, Patrick Tan, N Gopalakrishna Iyer. Mutational landscapes of oral tongue squamous cell carcinoma reveal recurrent mutations in genes of therapeutic and prognostic relevance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3874. doi:10.1158/1538-7445.AM2015-3874
Abstract 3877: The mutational burdens and evolutionary ages of early gastric cancers are comparable to those of advanced gastric cancers
Authors: Jung Seung-Hyun , Kim Min Sung , Choi Youn Jin , Kim Shinn Young , Shin Sun , Yoo Nam Jin , Chung Yeun-Jun , Lee Sug Hyung 
Published: August 2015

Abstract
Early gastric cancers (EGCs) precede advanced gastric cancers (AGCs), with a favourable prognosis compared to AGC. To understand the progression mechanism of EGC to AGC, it is required to disclose EGC and AGC genomes in mutational and evolutionary perspectives. We performed whole-exome sequencing and copy number profiling of nine microsatellite (MS)-unstable (MSI-H) (five EGCs and four AGCs) and eight MS-stable (MSS) gastric cancers (four EGCs and four AGCs). In the cancers, we observed well-known driver mutations (TP53, APC, PIK3CA, ARID1A, and KRAS) that were enriched in cancer-related pathways, including chromatin remodelling and tyrosine kinase activity. The MSI-H genomes harboured ten times more mutations, but were largely depleted of copy number alterations (CNAs) compared to the MSS cancers. Interestingly, EGC genomes showed a comparable level of mutations to AGC in terms of the number, sequence composition, and functional consequences (potential driver mutations and affected pathways) of mutations. Furthermore, the CNAs between EGC and AGC genomes were not significantly different in either MSI-H and MSS. Evolutionary analyses using somatic mutations and MSI as molecular clocks further identified that EGC genomes were as old as AGC genomes in both MSS and MSI-H cancers. Our results suggest that the genetic makeup for gastric cancer may already be achieved in EGC genomes and that the time required for transition to AGC may be relatively short. Also, the data suggest a possibility that the mutational profiles obtained from early biopsies may be useful in the clinical settings for the molecular diagnosis and therapeutics of gastric cancer patients.
Citation Format: Seung-Hyun Jung, Min Sung Kim, Youn Jin Choi, Shinn Young Kim, Sun Shin, Nam Jin Yoo, Yeun-Jun Chung, Sug Hyung Lee. The mutational burdens and evolutionary ages of early gastric cancers are comparable to those of advanced gastric cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3877. doi:10.1158/1538-7445.AM2015-3877
Abstract 3893: Whole-exome sequencing analysis of primary central nervous system lymphoma reveals recurrent MYD88 and PIM1 mutations
Authors: Nagane Motoo , Fukumura Kazutaka , Ueno Toshihide , Lee Jeunghun , Shishido-Hara Yukiko , Shirahata Mitsuaki , Mishima Kazuhiko , Ichimura Koichi , Mukasa Akitake , Narita Yoshitaka , Nishikawa Ryo , Mano Hiroyuki 
Published: August 2015

Abstract
Primary central nervous system lymphoma (PCNSL) is defined as diffuse large B-cell lymphoma (DLBCL) confined to the central nervous system. Although PCNSL cannot be histologically distinguished from extracerebral DLBCL, its prognosis is quite poor. To gain insights into the transforming mechanism of PCNSL, we conducted whole-exome sequencing for 44 PCNSL specimens.
Genomic DNA was extracted from tumors and their matched normal samples. Exome fragments were captured by using SureSelectXT Human All ExonV5+lncRNA, and subjected to deep sequencing with the HiSeq 2000 system.
There were 8 cases with germinal center B-cell-like (GCB) subtype and 34 cases with non-GCB subtype. Whole-exome sequencing of tumor and paired normal yielded sequencing data with a mean coverage of 156X and 80X, with 98% and 99% of the targeted bases covered by ≥20 independent reads, respectively. Of 17,832 somatic mutations identified in the PCNSL specimens, 11,611 (65%) were nonsynonymous single nucleotide variations. Predominant nucleotide substitution was a C&gt;T transition (57%) especially in the context of the sequence GCG. We also identified 798 insertions/deletions. Interestingly, MYD88 mutations were detected in 35 of 44 patients (79.5%), and PIM1 mutations were detected in 42 patients (95.5%). Also, a number of genetic aberrations were shown to activate the NF-κB pathway.
These results suggest that MYD88 and PIM1 mutations have important roles in the development of PCNSL and could be the therapeutic targets of this intractable disorder.
Citation Format: Motoo Nagane, Kazutaka Fukumura, Toshihide Ueno, Jeunghun Lee, Yukiko Shishido-Hara, Mitsuaki Shirahata, Kazuhiko Mishima, Koichi Ichimura, Akitake Mukasa, Yoshitaka Narita, Ryo Nishikawa, Hiroyuki Mano. Whole-exome sequencing analysis of primary central nervous system lymphoma reveals recurrent MYD88 and PIM1 mutations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3893. doi:10.1158/1538-7445.AM2015-3893
Abstract 3895: Genomic alterations modify ubiquitination pathways in pulmonary carcinoid tumors
Authors: Asiedu Michael K. , Thomas Charles L. , Dong Jie , Khadka Prasidda , Sun Zhifu , Kosari Farhad , Jen Jin , Molina Julian , Vasmatzis George , Aubry Marie Christine , Yang Ping , Wigle Dennis 
Published: August 2015

Abstract
Introduction: Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, and comprise 30% of all carcinoid malignancies. They are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors, and are characterized by neuroendocrine differentiation and the potential to metastasize.
Method: We characterized genomic alterations in pulmonary carcinoid tumors using whole genome and exome sequencing in addition to mRNA expression and SNP genotyping from specimens of normal lung, typical and atypical carcinoid, and SCLC.
Results: Analysis of the sequencing data identified novel mutations in the pulmonary neuroendocrine tumor spectrum, including KRAS, ABCA9, GALNT10, HSFX1, PTHLH, RANBP2, BRIP1, FXR1, BACE2, NCOR2, DGKI, HERC1, HERC5 and GLI3. Pathway analysis found 45% of the cases to harbor a mutation in genes that are involved in protein-protein interaction with ubiquitin c (UBC) and may therefore play a role in ubiquitin protein degradation pathway. We also identified genes differentially expressed in corresponding regions of copy number variation, 52 of which were linked to ubiquitination pathways in 88% of the samples genotyped. Genes amplified in 15 to 23% of the cases included ITM2A, MAOA, EGR2, HAGH, TSC22D3, NBEA, TCEAL2, and TSPYL2 whereas deleted regions in 15% of the cases implicated CFD, GDI1, IFITM1 and IFITM2.
Conclusion: These results suggest that in addition to previously identified pathways, dysregulation of the ubiquitin pathway may contribute to lung carcinoid tumorigenesis and could be exploited for therapeutic purposes.
Citation Format: Michael K. Asiedu, Charles L. Thomas, Jie Dong, Prasidda Khadka, Zhifu Sun, Farhad Kosari, Jin Jen, Julian Molina, George Vasmatzis, Marie Christine Aubry, Ping Yang, Dennis Wigle. Genomic alterations modify ubiquitination pathways in pulmonary carcinoid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3895. doi:10.1158/1538-7445.AM2015-3895