bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2740: High-throughput and sensitive quantification of circulating tumor DNA
Authors: Guan Yinghui , Mayba Oleg , Lu Shan , Sandmann Thomas , Choi Younjeong , Darbonne Walter , Leveque Vincent , Ryner Lisa , Humke Eric , Tam Nga W. , Sujathasarma Sundari , Cheung Anna , Bourgon Richard , Wang Yulei 
Published: July 2017

Abstract
Circulating tumor DNA (ctDNA) has a great potential to serve as non-invasive biomarkers for monitoring disease progression and treatment response. However, its broad clinical applications have been hindered by sensitivity, throughput and complexity of existing ctDNA detection methods. Here we report an adaptation of a multiplex PCR pre-amplification (PreAmp) into the microfluidic multiplex PCR (MMP-Seq) technology for high-throughput and sensitive quantitation of ctDNA. We have demonstrated that PreAmp MMP-Seq enabled sensitive (down to 0.6% allele frequency), reproducible (R2=0.97), accurate and quantitative mutation detection from as low as 1.6 ng DNA input. An Empirical Bayesian Model has been established to estimate background error rates for every base of amplicons in the ctDNA panel using data from 43 normal plasmas. 0.1-0.3% of median error rates were observed across all positions. 149 longitudinal plasma samples from 12 ovarian and 10 pancreatic cancer patients of PhI DMUC5754A anti-MUC16 ADC trials were then profiled using PreAmp MMP-Seq. 79% (11/14) driver mutations found in tissue samples were also identified in matching baseline plasma samples at frequencies well above estimated error rates. Moreover, we found that changes of corresponding ctDNA concentration in post-treatment plasma samples were correlated with changes in tumor burdens and circulating protein marker levels. In conclusion, the MMP-seq PreAmp workflow provides an inexpensive, reproducible and flexible solution for mutation detection in plasma DNA samples.
Citation Format: Yinghui Guan, Oleg Mayba, Shan Lu, Thomas Sandmann, Younjeong Choi, Walter Darbonne, Vincent Leveque, Lisa Ryner, Eric Humke, Nga W. Tam, Sundari Sujathasarma, Anna Cheung, Richard Bourgon, Yulei Wang. High-throughput and sensitive quantification of circulating tumor DNA [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 2740. doi:10.1158/1538-7445.AM2017-2740
Abstract 2742: Cross-platform comparison of four leading technologies for detecting EGFR mutations in circulating tumor DNA from plasma of patients with non-small cell lung carcinoma
Authors: Xu Ting , Kang Xiaozheng , You Xiaofang , Liang Dai , Tian Dequan , Yan Wanpu , Yang Yongbo , Xiong Hongchao , Liang Zhen , Zhao Grace Q. , Lin Shengrong , Chen Ke-Neng , Xu Guobing 
Published: July 2017

Abstract
Analysis of circulating tumor DNA (ctDNA) is emerging as a powerful tool for guiding targeted therapy and monitoring tumor evolution in patients with non-small cell lung cancer (NSCLC), particularly when fresh tissue biopsy is not available. This study compared the ability of four leading technology platforms to detect epidermal growth factor receptor (EGFR) mutations (L858R, exon 19 deletion, T790M and G719X) in ctDNA from NSCLC patients. The platforms included two amplification refractory mutation systems (cobas-ARMS and ADx-ARMS), a droplet digital polymerase chain reaction platform (ddPCR) and a next-generation sequencing platform (Firefly NGS). Fifteen EGFR mutations across twenty NSCLC patients were identified. We observed superior sensitivity and specificity of cobas-ARMS, ddPCR and Firefly NGS platforms, while ADx-ARMS was only suitable for the qualitative detection of EGFR mutations with allele frequency higher than 1% in plasma samples. We observed high concordance between the plasma and tissue EGFR mutational profiles for three driver mutations that are known targets of the first generation EGFR-TKI therapy (L858R, E19-dels, and G719X). Discrepancies between plasma and tissue EGFR mutational profiling could be attributed to spatial and temporal tumor heterogeneity. This pilot study illustrates the promise of ctDNA analysis in the context of treatment evaluation and drug resistance detection, and results will be validated in follow-up studies.
Citation Format: Ting Xu, Xiaozheng Kang, Xiaofang You, Dai Liang, Dequan Tian, Wanpu Yan, Yongbo Yang, Hongchao Xiong, Zhen Liang, Grace Q. Zhao, Shengrong Lin, Ke-Neng Chen, Guobing Xu. Cross-platform comparison of four leading technologies for detecting EGFR mutations in circulating tumor DNA from plasma of patients with non-small cell lung carcinoma [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 2742. doi:10.1158/1538-7445.AM2017-2742
Abstract 2747: Plasma DNA methylation marker and hepatocellular carcinoma risk prediction model for the general population
Authors: Wu Hui-Chen , Yang Hwai-I , Wang Qiao , Chen Chien-Jen , Santella Regina M. 
Published: July 2017

Abstract
Metastases in the later stages of hepatocellular carcinoma (HCC) cause the majority of deaths associated with the disease, making early detection crucial to patient survival. Risk models that assess HCC risk in the general population can be used for risk stratification for further HCC surveillance, however, none have been validated externally. Methylation of circulating DNA shows potential for noninvasive and early diagnosis of HCC. Most evidence, however, comes from cross-sectional studies raising concerns about temporality. We conducted a prospective case-control study nested within a community-based cohort. We measured methylation levels in of 6 genes (CDKN2A, RASSF1A, STEAP4, TBX2, VIM, and ZNF154) using pre-diagnostic plasma DNA from 237 HCC cases and 257 matched controls. We found TBX2 hypermethylation was associated with increased HCC risk, with ORs (95%CI) of 3.7 (1.9-7.2). The associations were mainly among high-risk subjects; among subjects infected with HBV/HCV, the OR (95%CI) of TBX2 methylation was 5.3 (2.2-12.7). Among subjects with high risk, the ORs (95%CIs) were 8.9 (1.0-73.9) for Wen-HCC score ≥16, 5.6 (2.1-14.6) for Hung-HCC score ≥15, and 7.2 (2.1-24.4) for Michikawa-HCC ≥8. Adding information on TBX2 methylation improved the accuracy of risk models for a high risk population, with the area under the curve (AUC) of 74% for TBX2 methylation and Wen-HCC score compared with 64% with Wen-HCC score alone. The AUCs were 63% for Hung-HCC score and TBX2 methylation, 53% for Hung-HCC score alone, 65% for Michikawa-HCC score and TBX2 methylation and 59% for Michikawa-HCC risk alone. Our findings suggest the potential increase in risk assessment discrimination and accuracy from incorporation of DNA methylation.
Citation Format: Hui-Chen Wu, Hwai-I Yang, Qiao Wang, Chien-Jen Chen, Regina M. Santella. Plasma DNA methylation marker and hepatocellular carcinoma risk prediction model for the general population [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 2747. doi:10.1158/1538-7445.AM2017-2747
Abstract 2748: Liquid biopsy using extracellular vesicular DNA for EGFR mutation testing in the patients with NSCLC
Authors: Hur Jae Young , Kim Hee Jung , Choi Chang-Min , Lee Jae Cheol , Lee Kye Young 
Published: July 2017

Abstract
Background Tumor-derived extracelluar vesicles (EV) have been proved to carry double-stranded DNA including oncogenic mutants and expected to be a novel biomarker in cancer detection. Liquid biopsy using cell-free (cf) DNA for EGFR mutation testing is being actively investigated. In this study, we investigated whether liquid biopsy using EV DNA is superior to cf DNA for EGFR mutation testing in the patients with NSCLC.
Methods EV was isolated using ultracentrifugation and confirmed by transmission electron microscopy and zetasizer in 20 plasma samples (all tissue-proven EGFR mutated) and 32 bronchoalveolar lavage fluid (BALF) samples (23 EGFR-mutated including 14 TKI-naïve and 9 TKI resistant, and 9 wild-type). EV and cf DNA was separately extracted from each samples and EGFR mutation testing was performed by peptide nucleic acid (PNA)-clamping method.
Results In 20 plasma samples, the concordance rate of EV DNA for tissue EGFR genotyping was 55% (11/20), while 30% (6/20) in cf DNA. In 32 BALF samples, however, the sensitivity, specificity and concordance rate of EV DNA for activating EGFR mutations was 100% (23/23), 100% (9/9), and 100% (32/32), while cf DNA showed 73.9% (17/23), 100% (9/9) and 81.3% (26/32), respectively. The kappa value (p-value) of EV DNA was 1.0 (&lt;0.001), while it was 0.714 (p,0.001) in the case of cf DNA. As for 9 re-biopsy cases for T790M detection in which only 3 patients (33%) was proved as positive T790M, BALF EV DNA identified 2 more T790M patients (total 5 among 9 patients, 56%) without non-matching with tissue typing, while BALF cf DNA found 1 more T790M positive patient with missing 1 tissue proven case (total 3 among 9 patients, 33%)
Conclusions Liquid biopsy using EV DNA is significantly superior to cf DNA in both plasma and BALF. A little low sensitivity in plasma EV DNA is supposed to be improved with much more sensitive method such as ddPCR or BEAMing. Liquid biopsy using BALF EV DNA showed almost 100% matching with tissue EGFR typing and seems to be highly promising for T790M detection. A large number of clinical trials should be prompted.
Citation Format: Jae Young Hur, Hee Jung Kim, Chang-Min Choi, Jae Cheol Lee, Kye Young Lee. Liquid biopsy using extracellular vesicular DNA for EGFR mutation testing in the patients with NSCLC [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 2748. doi:10.1158/1538-7445.AM2017-2748
Abstract 2759: Technical limitations of capture-based, targeted deep sequencing for the detection of somatic variations in cell-free DNA
Authors: Park Gahee 
Published: July 2017

Abstract
Despite widespread applications of capture-based targeted deep sequencing, its limitations on detecting circulating tumor DNA (ctDNA) have not been systematically elucidated. Here, we analyze and characterize parameters critically determining its detection limits; depth of coverage and background errors. The depth increase by using more cell-free DNA (cfDNA) was saturated at around ~3000x with ~50 ng of cfDNA primarily due to a deduplication artifact, which limited the detection sensitivity of the method. Next, characterizing background errors, we uncovered that a majority of errors were not derived from biological origins but technical artifacts, especially during sample preparation and library construction rather than sequencing. Thus, it is important to use an appropriate protocol for those steps minimizing background errors. Considering the depth of coverage and the background error rate, we estimated the detection limit of the method approximately to be 0.4% variant allele frequency at 95% confidence level. Applying the method to pancreatic cancer patients, we found that the levels of ctDNAs measured by cfDNA sequencing well correlated with clinical responses to therapy and/or disease progression, but biopsy-free profiling of somatic variants was limited by the moderate sensitivity of 72% and PPV of 74% at the variant level. Our results clarify technical limitations of targeted deep sequencing and provide a guideline for applying the technique to analyze cfDNA.
Citation Format: Gahee Park. Technical limitations of capture-based, targeted deep sequencing for the detection of somatic variations in cell-free DNA [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 2759. doi:10.1158/1538-7445.AM2017-2759
Abstract 276: Retrospective analysis of epidemiological variants of malignancies in Sokoto, Northwestern Nigeria
Authors: Sahabi Saddiku M. , Abdullahi Kabiru 
Published: July 2017

Abstract
Background: The burden of cancer in Nigeria is increasing. Information on incidence, prevalence, pattern, and high risk factors are essential for evaluation and cancer control. This report is a follow up from earlier previous report published in 2005 on cancers seen in Usmanu Danfodiyo University Teaching Hospital (UDUTH) Sokoto.
Objectives: The aim of this study is to determine epidemiological variants of all malignancies seen from 1 January 2006 to 31 December 2015.
Materials and Methods: This is a retrospective review of all malignancies seen at the Usmanu Danfodiyo University Teaching Hospital in Sokoto during the period 2006 to 2016. There was no restriction on gender or age groups. Mean, frequencies, percentages, and independent sample t-test were performed using SPSS version 21.0 for Windows. Significant level set at p &lt; 0.05.
Results: A total of 3933 cancer patients were seen during the ten-year period. There were more female malignancies (n=2260, 57.5%) compared to male malignancies (n=1673, 42.5%). The overall mean age (years) was 44.28, median age was 45.0, modal age was 50, and SD was 18.69; the age range was 1 to 99 years. Males (mean age 45.77, median age in male 50.0, modal age 60, and SD 21.03) were significantly older than females (mean age 43.18, median age 45.0, modal age 50, and SD 16.67). The adult malignancies account for 90.9% (n=3575) and childhood malignancies account for 9.1% (n=358). Overall, the ten most common malignancies were: breast 763 (19.4%), cervix 312 (7.9%), prostate 267 (6.8%), lymph node 248 (6.3%), skin 225 (5.7%), bladder 191 (4.9%), rectum 114 (2.9%), ovary 110 (2.8%), eye 97 (2.5%), soft tissue 95 (2.4%). In males, the ten most frequent malignancies were: prostate 267 (16.00%), bladder 160 (9.60%), skin 138 (8.20%), nasophraynx 87 (5.2%), lymph node 85 (5.10%), rectum 61 (3.60%), eye 55 (3.30%), salivary gland 38 (2.3%), larynx 37 (2.20%), and anal 37 (2.20%). In females, the ten most common malignancies were breast 731 (731%), cervix 302 (13.40%), lymph node 163 (7.20%), ovary 110 (4.90%), skin 87 (3.80%) endometrial 61 (2.70%), rectum 53 (2.30%), nasophraynx 45 (2.0%), soft tissue 43 (1.90%), and eye 42 (1.90%).
Conclusion: Our study concludes that malignancies of the breast, cervix, and prostate are the three most common in our environment. These malignancies tend to present at younger age (less than 50 years of age) compared to other developing countries. Therefore, public education and well developed screening programs are urgently needed to overcome this burden.
Citation Format: Saddiku M. Sahabi, Kabiru Abdullahi. Retrospective analysis of epidemiological variants of malignancies in Sokoto, Northwestern Nigeria [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 276. doi:10.1158/1538-7445.AM2017-276
Abstract 2780: High nuclear FTH1 protein expression predicts early disease recurrence for BRCA1/2 mutation carriers
Authors: Hollestelle Antoinette , Timmermans Mieke , Broeren-Foekens Renée , Jansen Anita Trapman - , Deurzen Carolien H. van , Umar Arzu , Martens John W. , Hooning Maartje 
Published: July 2017

Abstract
FTH1 is a 21kD subunit of the ferritin complex, which is involved in intracellular iron storage. In a previous study we found that FTH1 proteins can be located either in the cytoplasm or nucleus and, depending on its cellular localization, is associated with good or poor prognosis in triple negative breast cancer (TNBC). Furthermore, cytoplasmic localization of cFTH1 was associated with an increased anti-tumor (CD8+) T-cell / tumor-promoting (CD4+) T-cell ratio suggesting an immune modulatory role for FTH1. In the current study we have assessed the prognostic value of FTH1 expression for BRCA1/2 mutation carriers. FTH1 proteins were visualized by immunohistochemistry on a tissue microarray containing primary breast cancer specimens from 222 BRCA1/2 mutation carriers that were diagnosed between 1982 and 2008. Primary breast cancers from BRCA1 carriers were predominantly of the TNBC subtype, whereas primary breast cancers from BRCA2 mutation carriers were mainly ER-positive. The association between FTH1 expression and clinical outcome was evaluated by a Cox proportional hazards regression model using left truncation to adjust for study inclusion bias. The median follow-up time of the study was 9.2 years. High nuclear FTH1 (nFTH1), but not cytoplasmic FTH1 (cFTH1), was associated with decreased metastasis-free and disease-free survival as compared with low nFTH1 (multivariable HR=3.54, 95% CI=1.45-8.66, P=0.0056 adjusted for tumor size and nodal status; multivariable HR=2.71, 95% CI=1.49-4.92, P=0.0011 adjusted for tumor size). Neither nFTH1 nor cFTH1 were associated with breast cancer-specific or overall survival. This suggests that high nFTH1 expression in primary breast cancer predicts earlier disease recurrence for BRCA1/2 mutation carriers. Since we had observed that CD4+:CD8+ T-cell ratios were increased among TNBCs with high nFTH1, we hypothesize that nFTH1 promotes recruitment of immune suppressive CD4+/FOXP3+ regulatory T-cells in TNBC and BRCA1/2-associated tumors, suppressing CD4+/FOXP3- and CD8+ T-cell anti-tumor immunity.
Citation Format: Antoinette Hollestelle, Mieke Timmermans, Renée Broeren-Foekens, Anita Trapman - Jansen, Carolien H. van Deurzen, Arzu Umar, John W. Martens, Maartje Hooning. High nuclear FTH1 protein expression predicts early disease recurrence for BRCA1/2 mutation carriers [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 2780. doi:10.1158/1538-7445.AM2017-2780
Abstract 2784: Identifying biomarkers to predict cardiotoxicity of doxorubicin in individual patients
Authors: Zhao Liqun , Zhang Baolin 
Published: July 2017

Abstract
Doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. This study aims to identify biomarkers to predict potential cardiotoxicity before the onset of cardiac tissue damage and dysfunction in individual cancer patients. First, we established a human cellular system to model the cardiac toxicity of oncology drugs using human induced pluripotent stem cells-derived cardiomyocytes (iPS-CMs). We tested a panel of clinically used drugs including anthracyclines (doxorubicin, daunorubicin, epirubicin and idarubicin), 5-FU, Taxol, Trastuzumab, and tyrosine kinase inhibitors (sunitinb, imatinib, and sorafinib). These drugs displayed varying degrees of cytotoxicity in iPS-CMs which are generally consistent with their known cardiotoxicity patterns. Second, we found that doxorubicin selectively upregulated the expression of death receptors in iPS-CMs. As a result, the treated iPS-CMs underwent spontaneous apoptosis that was further enhanced in the presence of specific cytokines. Based on these findings, we hypothesize that the baseline levels of the predefined cytokines in blood could be predictive of cardiotoxicity associated with doxorubicin treatment in individual patients. We are currently investigating the relationships between the levels of the predefined cytokine signature in blood and cardiac events in patients who received doxorubicin or related anthracycline therapy.
Citation Format: Liqun Zhao, Baolin Zhang. Identifying biomarkers to predict cardiotoxicity of doxorubicin in individual 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 2784. doi:10.1158/1538-7445.AM2017-2784
Abstract 2790: PRC2 mediated repression of SMARCA2 predicts for EZH2 inhibitor activity in tumors with SWI/SNF mutations
Authors: Januario Thomas , Ye Xiaofen , Bainer Russell , Alicke Bruno , Solon Margaret , Haley Benjamin , Modrusan Zora , Gould Stephen , Koeppen Hartmut , Yauch Robert L. 
Published: July 2017

Abstract
A synthetic lethality caused by EZH2 inhibition in the context of SNF5 mutations is supported by both preclinical and recent clinical data, however the extent of the synthetic lethal relationship in the context of other SWI/SNF subunit mutations is not well understood. We determined that a subset of SMARCA4 mutant cancer models are sensitive to EZH2 inhibition. EZH2 inhibition resulted in a heterogenous phenotypic response characterized by senescence and/or apoptosis amongst models, and further lead to tumor growth inhibition in vivo. The differential sensitivity to EZH2 inhibition was not caused by a differential pharmacodynamic effect of the drug, nor differences in basal histone methylation or PRC2 subunit levels. However, expression of the SWI/SNF subunit, SMARCA2, delineated sensitivity amongst SMARCA4 mutant models tested. Expression of SMARCA2 further delineated sensitivity amongst other SWI/SNF mutant models tested, including SNF5 and ARID1A mutants. We determined that SMARCA2 is under PRC2 mediated suppression and the derepression of SMARCA2 was necessary for apoptosis, but not senescence, in response to EZH2 inhibition. SMARCA2 has been shown to be concurrently lost in a high percentage of SNF5 mutant malignant rhabdoid tumors and SMARCA4 mutant SCCOHT tumors, however we determined that ≈15% of SMARCA4 mutant NSCLCs concurrently lose SMARCA2. Our data supports monitoring SMARCA2 expression as a predictive biomarker for EZH2-targeted therapies that are currently being developed in the context of SWI/SNF mutant cancers.
Citation Format: Thomas Januario, Xiaofen Ye, Russell Bainer, Bruno Alicke, Margaret Solon, Benjamin Haley, Zora Modrusan, Stephen Gould, Hartmut Koeppen, Robert L. Yauch. PRC2 mediated repression of SMARCA2 predicts for EZH2 inhibitor activity in tumors with SWI/SNF mutations [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 2790. doi:10.1158/1538-7445.AM2017-2790