bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1411: Differential mismatch repair-dependent damage responses in subpopulations of cells from human intestinal organoids
Authors: Lin Bo , Yang Qingfen , Rath Abhijit , Heinen Christopher D. 
Published: July 2017

Abstract
Hereditary mutations in DNA mismatch repair (MMR) genes cause the cancer predisposition syndrome called Lynch syndrome. Patients predominantly develop colorectal cancer and some extracolonic cancers at a young age. The MMR pathway repairs mismatches created during DNA replication, but also can induce apoptosis and cell cycle arrest in response to certain DNA damaging agents as a protective mechanism to eliminate cells at risk of accumulating mutations. Our understanding of this MMR-directed DNA damage response has come primarily from studies in human cancer cell lines. We wished to examine the role of the MMR-dependent damage response in a model that may be more relevant to the human intestine. Therefore, we have created human intestinal organoids (HIOs) in vitro either by directing the differentiation of human embryonic stem cells (hESCs) or through culturing of adult intestinal tissue samples. We have used these HIOs to specifically study the MMR dependent damage response to DNA alkylation damage. We have found that whereas hESCs undergo rapid apoptosis in response to alkylation damage, the differentiated HIOs or those created from adult tissues undergo not only apoptosis, but also senescence and accelerated differentiation following damage. Using CRISPR-Cas9 gene editing in hESCs, we also created MMR-deficient HIOs that failed to respond to the drug indicating that these responses are MMR-dependent. We then determined that the cells undergoing apoptosis following DNA damage are most likely the intestinal stem cells suggesting that different cell types in the intestine have different MMR-dependent responses to damage. Together these results suggest that loss of MMR function in the intestinal crypts may provide a selective advantage particularly in an environment conducive with DNA damage that promotes tumorigenesis.
Note: This abstract was not presented at the meeting.
Citation Format: Bo Lin, Qingfen Yang, Abhijit Rath, Christopher D. Heinen. Differential mismatch repair-dependent damage responses in subpopulations of cells from human intestinal organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1411. doi:10.1158/1538-7445.AM2017-1411
Abstract 1419: Role of a novel Senataxin-associated nuclease in DNA repair
Authors: McCartney Heather , Macara Ian 
Published: July 2017

Abstract
Yeast two-hybrid analysis has identified a novel, uncharacterized Senataxin-interacting protein with 5’ exonuclease activity, and homology to the FEN1 nuclease domain. Senataxin is an RNA/DNA helicase that functions in resolving R loop structures which occur as a result of normal replication and transcription but can also persist resulting in genomic instability. We found that SAN1 (Senataxin-Associated Nuclease 1) is unable to cut dsDNA or bubbles, but is active against 5’ overhangs and against ssDNAs of greater than 15 nucleotides. SAN1 cleaves 3 or 8 nt fragments from the 5’ end of ssDNA and utilizes magnesium as a cofactor. As the definitive 5’ nuclease responsible for unhooking ICLs has yet to be identified we speculate that SAN1 might function in excising crosslinked nucleotides that result from interstrand crosslink (ICL) damage. We generated a SAN1 -/- HeLa cell line through CRISPR/Cas gene editing and found that SAN1 -/- cells are sensitized to ICL agents mitomycin-c and cisplatin. Interestingly, colony survival assays have shown that SAN1 does not appear to be epistatic of FANCD2, a key component of the classical pathway for resolving ICLs, the Fanconi Anemia pathway. Additionally, although the nuclease domain of SAN1 is homologous to the FEN1 family of structure-specific nucleases, SAN1 also possesses a unique and conserved C terminus of unknown function. Our goal is to understand the relationship between the structure and nuclease activity of SAN1 in DNA repair and how SAN1 relates to other known ICL-repair pathways. Understanding the components that regulate genome stability is crucial in understanding how cancer occurs and what protein targets will be the most advantageous to pursue in developing potential therapeutics. This study may also provide a better understanding of a novel factor in resistance to ICL-inducing chemotherapeutics such as cisplatin and MMC which are still widely used in the treatment of breast and ovarian cancers.
Citation Format: Heather McCartney, Ian Macara. Role of a novel Senataxin-associated nuclease in DNA repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1419. doi:10.1158/1538-7445.AM2017-1419
Abstract 142: Exploiting replicative vulnerabilities to counter incomplete responses to PI3K/Akt/mTOR inhibition
Authors: Chopra Sameer , Niepel Mario , Jenney Anne , Hafner Marc , Sorger Peter 
Published: July 2017

Abstract
While a broad range of cancers harbor mutations that dysregulate PI3K-Akt-mTOR signaling, most small molecule drugs targeting this pathway have failed to demonstrate efficacy for the treatment of solid tumors. In this study, we investigated the mechanisms that account for drug efficacy and failure in PI3K-pathway dysregulated triple negative breast cancer (TNBC) cell lines using a diverse collection of 25 PI3K-Akt-mTOR inhibitors. Drug response phenotypes and changes in signaling were quantified using time-lapse imaging and quantitative single cell immunofluorescence microscopy, respectively. We identified GSK2126458 and Torin2 as having superior potency and efficacy in PI3K-pathway dysregulated TNBC. Unlike other PI3K pathway inhibitors, whose ineffectiveness arises from insufficient induction of apoptosis and variable inhibition of cell cycle progression at G1/S, GSK2126458 and Torin2 each rapidly induce caspase 3/7 activity and durably inhibit the proliferation of surviving cells. While the effectiveness of GSK2126458 in vitro appears to arise from near-complete suppression of PI3K-Akt-mTOR signaling, this approach has already proved unachievable in clinical trials. An alternative therapeutic strategy was identified by characterizing the mechanism of action of Torin2, a tool compound that inhibits both mTOR kinase and the DNA damage response kinases ATR, ATM, and DNA-PK. Unlike all other PI3K-Akt-mTOR inhibitors studied, Torin2 counters incomplete drug block at G1/S by concomitant induction of intolerable replication stress in S phase cells. The unique cell cycle pharmacology of Torin2 is recreated by combining inhibitors of mTOR and ATR/Chk1 kinases presently undergoing evaluation in clinical trials. In the context of combination therapy, where cytotoxicity arises from targeting S phase vulnerabilities rather than from PI3K-Akt-mTOR inhibition in G1, submaximal doses of mTOR kinase inhibitors are sufficient and confer benefit by preventing the outgrowth of cells that survive fractional killing from ATR/Chk1 inhibition. These findings suggest a novel strategy for mitigating the failure of precision monotherapy and have implications for the treatment of tumors where genetic lesions in the PI3K pathway co-occur with replicative vulnerabilities.
Citation Format: Sameer Chopra, Mario Niepel, Anne Jenney, Marc Hafner, Peter Sorger. Exploiting replicative vulnerabilities to counter incomplete responses to PI3K/Akt/mTOR inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 142. doi:10.1158/1538-7445.AM2017-142
Abstract 1432: Precision lung cancer medicine based on information on cancer and the host genomes
Authors: Kohno Takashi , Shiraishi Kouya , Yoshida Kazushi , Saito Motonobu , Okada Yukinori 
Published: July 2017

Abstract
Aberrations of oncogene, such as EGFR mutation; and ALK, RET, and ROS1 fusions, function as a driver in the development of lung adenocarcinoma (LADC). They are a solid target of therapy using tyrosine kinase inhibitors, as represented by a high response rate of RET-fusion positive LADC to vandetanib (LURET study, Yoh et al., Lancet Resp Med, 2016). Our genome-wide sequencing study revealed that oncogene aberration positive LADCs carry less numbers of mutations in cancer-related genes than negative ones (Saito, Cancer Res, 2015), indicating a small mutation burden in the development of the formers. Consistently, a clinical trial of anti-PD-1 therapy indicated that EGFR-mutation positive cases do not benefit well from the therapy (Borghaei et al., N Engl J Med. 2015). LADC driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). We recently revealed that variations in HLA-class II loci underlie the risk of the disease, by conducting a genome-wide association study of 3,173 patients and 15,158 controls, combined with imputation of HLA alleles using a Japanese-specific panel (Shiraishi et al., Nature Comm, 2016). The result indicates that LADC develops in vivo through interaction between somatic mutations and germline variations that modulate immune reaction. Therefore, efficacy of immune checkpoint blockade targeting therapy might also be influenced by such germline variations. On the other hand, oncogene-negative LADCs show a high mutation burden associated with nonsynonymous mutations in chromatin remodeling and other cancer-related genes. Thus, these cases would respond well to immune checkpoint blockade targeting therapies. We would like to discuss here precision lung cancer medicine based on information on cancer and the host genomes.
Citation Format: Takashi Kohno, Kouya Shiraishi, Kazushi Yoshida, Motonobu Saito, Yukinori Okada. Precision lung cancer medicine based on information on cancer and the host genomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1432. doi:10.1158/1538-7445.AM2017-1432
Abstract 1438: The dynamics of genetic aberrations in Crohn's disease associated colorectal carcinogenesis
Authors: Hirsch Daniela D. , Wangsa Darawalee , Hu Yue , Zhu Jack , Petersen David , Edelman Daniel C. , Meltzer Paul S. , Tran Bao , Heselmeyer-Haddad Kerstin , Ried Thomas , Gaiser Timo 
Published: July 2017

Abstract
Crohn’s disease, a condition of chronic inflammation of the intestine, significantly increases the risk for the development of colorectal cancer (CRC). Sporadic CRCs are characterized by a specific pattern of genomic imbalances and a landscape of acquired gene mutations. In this study we aimed to compare CRCs that arise as a consequence of chronic inflammation in Crohn’s disease with sporadic CRCs.
We analyzed 26 Crohn’s disease associated CRCs, four matched dysplastic lesions, six matched inflamed mucosa samples, and two matched lymph node metastases using array comparative genomic hybridization, targeted sequencing (564 cancer related genes) and gene expression profiling. As a control, we used normal intestinal mucosa from the resection margin of these CRCs and 24 sporadic CRCs.
In general, CRCs that developed in patients with Crohn’s disease had a similar distribution of genomic imbalances compared to sporadic CRC. However, we identified distinct mutation signatures: in the Crohn's disease associated CRCs the most frequently mutated gene was TP53, which occurred in 65% of the samples. The second, third and fourth most frequently mutated genes were KRAS (27%), APC (23%) and PIK3CA (19%). In the control group of sporadically arising CRCs, the most commonly mutated gene was APC (75%), followed by KRAS (54%), TP53 (33%), SMAD3 (29%) and SMAD2 (25%). The genetic analyses of multiple lesions from individual patients revealed a high degree of intertumoral heterogeneity with diverse patterns of gene mutations and allowed the reconstruction of the sequence of genetic events during Crohn’s disease associated tumorigenesis. In contrast to sporadic colorectal carcinogenesis, TP53 mutations were observed as early and common events while APC mutations occurred rather late and were infrequent.
Our comprehensive molecular profiling of Crohn’s disease associated CRCs suggests that the genetic landscape of CRC is influenced by the activation of inflammation related pathways. Furthermore, our findings offer potential for establishing an early detection marker for dysplasia in patients with Crohn’s disease.
Citation Format: Daniela D. Hirsch, Darawalee Wangsa, Yue Hu, Jack Zhu, David Petersen, Daniel C. Edelman, Paul S. Meltzer, Bao Tran, Kerstin Heselmeyer-Haddad, Thomas Ried, Timo Gaiser. The dynamics of genetic aberrations in Crohn's disease associated colorectal carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1438. doi:10.1158/1538-7445.AM2017-1438
Abstract 1439: Genetic profiling of colitis-associated cancer indicates de novo carcinogenesis and the impact of chronic inflammation
Authors: Fujita Masashi , Matsubara Nagahide , Maejima Kazuhiro , Yamano Tomoki , Matsuda Ikuo , Hirota Seiichi , Ikeuchi Hiroki , Tomita Naohiro , Nakagawa Hidewaki 
Published: July 2017

Abstract
Background: Chronic inflammation is one of the major causes of carcinogenesis. Ulcerative colitis (UC) and Crohn’s disease (CD) increase the risk of colitis-associated cancer (CAC) development, and its biological and pathological characters are also distinct. However, the genetic mechanism of how chronic inflammation leads to CACs is still unclear.
Methods: We obtained frozen tumor tissues from 21 CAC patients and performed exome or whole-genome sequencing of the matched tumor-normal samples. We enumerated recurrently mutated genes and selected 43 genes among them for target capture. We then performed targeted resequencing of 84 FFPE specimens from CAC tissues. Totally, we made genomic profiles of 105 CACs.
Results: The most frequently mutated gene was TP53, whose mutation was found in 70 of 105 samples (67%), which is more prevalent in CACs than common colorectal cancers (CRCs). Somatic mutations of APC and KRAS were less prevalent (17 and 13 samples, respectively). Genes in the Wnt signaling pathway (APC, FBXW7, TCF7L2, and RNF43) were mutated in 31 samples, whereas those in the TGFβ pathway (TGFBR2, ACVR1B, SMAD2, SMAD4, LTBP4) were mutated in 25 samples. Mutational signature of CACs shows some differences from common CRCs.
Conclusion: Our results confirmed genetic differences for cancer development between CACs and common CRCs. Frequent TP53 mutations and less frequent APC mutations are consistent with the idea of “de novo” carcinogenesis than adenoma-carcinoma sequence. The association between the mutations and clinical information are also discussed.
Citation Format: Masashi Fujita, Nagahide Matsubara, Kazuhiro Maejima, Tomoki Yamano, Ikuo Matsuda, Seiichi Hirota, Hiroki Ikeuchi, Naohiro Tomita, Hidewaki Nakagawa. Genetic profiling of colitis-associated cancer indicates de novo carcinogenesis and the impact of chronic inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1439. doi:10.1158/1538-7445.AM2017-1439
Abstract 1440: Germline loss-of-function alleles in Finnish colorectal cancer patients
Authors: Tanskanen Tomas , Hänninen Ulrika , Cajuso Tatiana , Kondelin Johanna , Katainen Riku , Hamberg Jiri , Välimäki Niko , Pitkänen Esa , Palin Kimmo , Aaltonen Lauri A. 
Published: July 2017

Abstract
Colorectal cancer, a major cause of cancer deaths worldwide, is often preventable by screening and surveillance, especially in patients at increased risk; however, its heritability is incompletely understood, and studies in isolated populations such as Finland may be valuable for gene discovery. We analyzed whole-genome or whole-exome sequencing data in 322 Finnish colorectal cancer cases of unknown etiology and 928 population-matched controls. To enrich for susceptibility alleles, cases were selected on the basis of early-onset colorectal cancer (age at diagnosis &lt;50 years; 50/322, 16%), synchronous or metachronous colorectal cancer (30/322, 9.3%), familial colorectal cancer (134/322, 42%), personal history of noncolorectal cancer (93/322, 29%), or family history of at least two noncolorectal cancers (124/322, 39%). To increase the prior probability of pathogenicity of variants, the study was restricted to rare and low-frequency protein-coding loss-of-function variants (nonsense, frameshift, and essential splice site variants; allele frequency &lt;3%). Single-variant and gene-level associations were tested, and genes with loss-of-function variants exclusively in cases were pinpointed. An independent set comprising 1,257 cases and 2,638 controls were genotyped using SNP arrays, and genotype imputation provided additional data on 225 (8.5%) of the 2,654 initially discovered loss-of-function variants. Principal component analysis was applied to correct for population structure. In association analyses, with a statistical power of at least 80% for a range of moderate-to-high effect sizes and low allele frequencies (e.g., odds ratio of 3 and allele frequency of 0.5%) at p &lt;0.15, a total of 35 candidate colorectal cancer predisposition genes were identified, although none of them reached exome-wide significance. There were 21 genes with rare loss-of-function alleles in at least two cases but none of the sequenced controls. Whole-genome sequencing data from paired normal and tumor tissues were available in 243 cases, and potential second hits (wild-type allele losses or somatic point mutations) were found in 15 genes. These results may, through further analysis and replication, contribute to our knowledge of the genetic architecture and pathobiology of colorectal cancer susceptibility.
Citation Format: Tomas Tanskanen, Ulrika Hänninen, Tatiana Cajuso, Johanna Kondelin, Riku Katainen, Jiri Hamberg, Niko Välimäki, Esa Pitkänen, Kimmo Palin, Lauri A. Aaltonen. Germline loss-of-function alleles in Finnish colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1440. doi:10.1158/1538-7445.AM2017-1440
Abstract 1441: A comprehensive cis-eQTL analysis revealed target genes in breast cancer susceptibility loci identified in genome-wide association studies
Authors: Guo Xingyi , Lin Weiqiang , Cai Qiuyin , Shi Jiajun , Sun Yaqiong , Pan Xiao , Han Mi-Ryung , Wen Wanqing , Li Bingshan , Long Jirong , Chen Jianghua , Zheng Wei 
Published: July 2017

Abstract
Genome-wide association studies (GWAS) have identified approximately 107 common single nucleotide polymorphisms (index SNPs) for breast cancer risk. The target genes and underlying mechanisms for the large majority of the identified associations remain unknown. We conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using transcriptome data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (N = 1,981), The Cancer Genome Atlas (TCGA) (N = 458), and the Genotype-Tissue Expression (GTEx) project (N = 183). We identified a total of 58 genes including SSBP4 at Benjamini-Hochberg adjusted P &lt; 0.05 in at least one dataset and another gene, PAX9, at P &lt; 0.05 with consistent association directions in all three datasets. Using data from the Encyclopedia of DNA Elements (ENCODE), we selected functional SNPs and showed that some alternative alleles could significantly change promoter activities of their target genes compared to reference alleles using luciferase reporter assays. The effects of target gene expression for those alleles were in line with eQTL observations. In addition, we validated the genes SETD9 and SSBP4 using Sequenom allelotype technique from 235 adjacent normal breast tissues and observed the allelic-specific expression associated with their index SNPs. This study revealed novel biological mechanisms for associations of genetic susceptibility risk loci for breast cancer.
Citation Format: Xingyi Guo, Weiqiang Lin, Qiuyin Cai, Jiajun Shi, Yaqiong Sun, Xiao Pan, Mi-Ryung Han, Wanqing Wen, Bingshan Li, Jirong Long, Jianghua Chen, Wei Zheng. A comprehensive cis-eQTL analysis revealed target genes in breast cancer susceptibility loci identified in genome-wide association studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1441. doi:10.1158/1538-7445.AM2017-1441
Abstract 1445: Understanding the 8q24 colorectal cancer risk locus via CRISPR/Cas9 scarless genome editing
Authors: Coggins Nicole , Stultz Jacob , Segal David , Carvajal-Carmona Luis 
Published: July 2017

Abstract
Colorectal Cancer (CRC) is one of the leading causes of mortality in the US, being the third most common cancer among both men and women. While an exact cause of CRC has not yet been elucidated, the existence of a clear heritable genetic component has been established. With the recent surge of data from Genome-Wide Association Studies, a handful of CRC-associated loci have been identified, each containing numerous Single Nucleotide Polymorphisms (SNPs). We hypothesize that among the ~25 loci associated with increased risk for CRC, there are driver SNPs functioning to contribute to initiation or progression of CRC development. It is crucial, in order to enhance our understanding CRC tumorigenesis, to extract these functional variants from the pool of associated SNPs and validate their causative significance within the cell. To model these functional SNPs, we have developed a novel “scarless” isolation pipeline for selecting isogenic clones with the desired single-base edit without selection markers following CRISPR-Cas9 mediated HDR. With this pipeline, we have successfully modeled our first selected SNP, rs6983267, from the 8q24 risk locus in HCT-116 cells, producing the heterozygous genotype (G/T) from the parental homozygous risk (G/G) genotype. Rs6983267 is located within a known c-Myc enhancer and has been shown to exert risk-allele specific increase in enhancer activity. Oncogenic c-Myc is known to play a significant role in CRC pathogenesis. In line with previous studies, we observe a slight decrease in c-Myc expression in our heterozygous clones compared to wildtype homozygous risk. Moreover, we observe a preferential binding of the transcription factor in control of c-Myc transcriptional regulation, TCF7L2, to the risk allele over the reference allele while binding of proximal factors such as CTCF show no allelic preference. Interestingly, we also see significant changes in expression of target genes of the WNT signaling pathway. Dysregulation of WNT is a hallmark characteristic of CRC. These changes indicate there is indeed an effect of the risk allele of rs6983267 on overall WNT activity in CRC cells due to increased binding of transcription factor TCF7L2. This novel SNP editing pipeline provides a method to study precise effects of single base changes located anywhere in the genome. Utilizing it to model other risk SNPs will enable the enhancement of our current understanding of GWAS-identified risk loci in CRC pathogenesis at the molecular level.
Citation Format: Nicole Coggins, Jacob Stultz, David Segal, Luis Carvajal-Carmona. Understanding the 8q24 colorectal cancer risk locus via CRISPR/Cas9 scarless genome editing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1445. doi:10.1158/1538-7445.AM2017-1445