108 results on '"Skanderup, A."'
Search Results
2. PARP4 interacts with hnRNPM to regulate splicing during lung cancer progression
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Yi Fei Lee, Cheryl Zi Jin Phua, Ju Yuan, Bin Zhang, May Yin Lee, Srinivasaraghavan Kannan, Yui Hei Jasper Chiu, Casslynn Wei Qian Koh, Choon Kong Yap, Edwin Kok Hao Lim, Jianbin Chen, Yuhua Lim, Jane Jia Hui Lee, Anders Jacobsen Skanderup, Zhenxun Wang, Weiwei Zhai, Nguan Soon Tan, Chandra S. Verma, Yvonne Tay, Daniel Shao Weng Tan, and Wai Leong Tam
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Non-small-cell lung cancer ,Functional genomics ,Mechanisms of disease ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n = 302), we now functionally assess the mechanistic role of a novel driver, PARP4. Methods In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4’s interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations. Results PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4’s tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss. Conclusions PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex—unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis.
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- 2024
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3. A multimodal atlas of hepatocellular carcinoma reveals convergent evolutionary paths and ‘bad apple’ effect on clinical trajectory
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Chen, Jianbin, Kaya, Neslihan Arife, Zhang, Ying, Kendarsari, Raden Indah, Sekar, Karthik, Lee Chong, Shay, Seshachalam, Veerabrahma Pratap, Ling, Wen Huan, Jin Phua, Cheryl Zi, Lai, Hannah, Yang, Hechuan, Lu, Bingxin, Lim, Jia Qi, Ma, Siming, Chew, Sin Chi, Chua, Khi Pin, Santiago Alvarez, Jacob Josiah, Wu, Lingyan, Ooi, London, Yaw-Fui Chung, Alexander, Cheow, Peng Chung, Kam, Juinn Huar, Wei-Chieh Kow, Alfred, Ganpathi, Iyer Shridhar, Bunchaliew, Chairat, Thammasiri, Jidapa, Koh, Peng Soon, Bee-Lan Ong, Diana, Lim, Jasmine, de Villa, Vanessa H., Dela Cruz, Rouchelle D., Loh, Tracy Jiezhen, Wan, Wei Keat, Leow, Wei Qiang, Yang, Yi, Liu, Jin, Skanderup, Anders Jacobsen, Pang, Yin Huei, Ting Soon, Gwyneth Shook, Madhavan, Krishnakumar, Kiat-Hon Lim, Tony, Bonney, Glenn, Goh, Brian K.P., Chew, Valerie, Dan, Yock Young, Toh, Han Chong, Sik-Yin Foo, Roger, Tam, Wai Leong, Zhai, Weiwei, and Kah-Hoe Chow, Pierce
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- 2024
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4. Correction: Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer
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Lee, Ning-Yuan, Hum, Melissa, Zihara, Sabna, Wang, Lanying, Myint, Matthew K., Lim, Darren Wan-Teck, Toh, Chee-Keong, Skanderup, Anders, Samol, Jens, Tan, Min-Han, Ang, Peter, Lee, Soo-Chin, Tan, Eng-Huat, Lai, Gillianne G. Y., Tan, Daniel S. W., Yap, Yoon-Sim, and Lee, Ann S. G.
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- 2023
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5. Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer
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Lee, Ning-Yuan, Hum, Melissa, Zihara, Sabna, Wang, Lanying, Myint, Matthew K., Lim, Darren Wan-Teck, Toh, Chee-Keong, Skanderup, Anders, Samol, Jens, Tan, Min-Han, Ang, Peter, Lee, Soo-Chin, Tan, Eng-Huat, Lai, Gillianne G. Y., Tan, Daniel S. W., Yap, Yoon-Sim, and Lee, Ann S. G.
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- 2023
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6. PUREE: accurate pan-cancer tumor purity estimation from gene expression data
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Revkov, Egor, Kulshrestha, Tanmay, Sung, Ken Wing-Kin, and Skanderup, Anders Jacobsen
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- 2023
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7. Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer
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Ning-Yuan Lee, Melissa Hum, Sabna Zihara, Lanying Wang, Matthew K. Myint, Darren Wan-Teck Lim, Chee-Keong Toh, Anders Skanderup, Jens Samol, Min-Han Tan, Peter Ang, Soo-Chin Lee, Eng-Huat Tan, Gillianne G. Y. Lai, Daniel S. W. Tan, Yoon-Sim Yap, and Ann S. G. Lee
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Multiple primary cancers ,Breast cancer ,Lung cancer ,Whole-exome sequencing ,Germline variants ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Cancer predisposition is most often studied in the context of single cancers. However, inherited cancer predispositions can also give rise to multiple primary cancers. Yet, there is a paucity of studies on genetic predisposition in multiple primary cancers, especially those outside of well-defined cancer predisposition syndromes. This study aimed to identify germline variants associated with dual primary cancers of the breast and lung. Methods Exome sequencing was performed on germline DNA from 55 Singapore patients (52 [95%] never-smokers) with dual primaries in the breast and lung, confirmed by histopathology. Using two large control cohorts: the local SG10K_Health (n = 9770) and gnomAD non-cancer East Asians (n = 9626); and two additional local case cohorts of early-onset or familial breast cancer (n = 290), and lung cancer (n = 209), variants were assessed for pathogenicity in accordance with ACMG/AMP guidelines. In particular, comparisons were made with known pathogenic or likely pathogenic variants in the ClinVar database, pathogenicity predictions were obtained from in silico prediction software, and case–control association analyses were performed. Results Altogether, we identified 19 pathogenic or likely pathogenic variants from 16 genes, detected in 17 of 55 (31%) patients. Six of the 19 variants were identified using ClinVar, while 13 variants were classified pathogenic or likely pathogenic using ACMG/AMP guidelines. The 16 genes include well-known cancer predisposition genes such as BRCA2, TP53, and RAD51D; but also lesser known cancer genes EXT2, WWOX, GATA2, and GPC3. Most of these genes are involved in DNA damage repair, reaffirming the role of impaired DNA repair mechanisms in the development of multiple malignancies. These variants warrant further investigations in additional populations. Conclusions We have identified both known and novel variants significantly enriched in patients with primary breast and lung malignancies, expanding the body of known cancer predisposition variants for both breast and lung cancer. These variants are mostly from genes involved in DNA repair, affirming the role of impaired DNA repair in the predisposition and development of multiple cancers.
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- 2023
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8. Brief Report: Droplet Digital Polymerase Chain Reaction Versus Plasma Next-Generation Sequencing in Detecting Clearance of Plasma EGFR Mutations and Carcinoembryonic Antigen Levels as a Surrogate Measure
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Stephanie P.L. Saw, MRCP, Gek San Tan, MSc, Wei Chong Tan, MRCP, Aaron C. Tan, PhD, Gillianne G.Y. Lai, MRCP, Darren W.T. Lim, MRCP, Ravindran Kanesvaran, MRCP, Wan Ling Tan, MRCP, Sze Huey Tan, PhD, Kiat Hon Lim, FRCPA, Anders J. Skanderup, PhD, and Daniel S.W. Tan, PhD
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EGFR-mutated NSCLC ,ddPCR ,NGS ,CEA ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Introduction: To compare the performance of droplet digital polymerase chain reaction (ddPCR) and plasma next-generation sequencing (NGS) in detecting clearance of plasma EGFR (pEGFR) mutations. Methods: Patients with treatment-naive advanced EGFR-mutated lung cancer treated with first-line tyrosine kinase inhibitors (TKIs) were included. pEGFR were measured at baseline and first response assessment using ddPCR and NGS. Clearance of pEGFR was defined as undetectable levels after a positive baseline result. Results were correlated with time-to-treatment failure (TTF). In exploratory analysis, corresponding change in carcinoembryonic antigen (CEA) levels was evaluated. Results: Between January 1, 2020, and December 31, 2021, 27 patients were recruited. Ex19del comprised 74% (20 of 27) and L858R 26% (seven of 27). Osimertinib was used in 59% (16 of 27), dacomitinib 4% (one of 27), and gefitinib/erlotinib 37% (10 of 27). Sensitivity of ddPCR and NGS in detecting pEGFR mutation at baseline was 70% (19 of 27) and 78% (21 of 27), respectively (p = 0.16). All patients with detectable pEGFR by ddPCR were detected by NGS.At a median of 8 (range 3–24) weeks post-TKI initiation, clearance of pEGFR was achieved in 68% (13 of 19) and 71% (15 of 21) using ddPCR and NGS, respectively. Concordance between ddPCR and NGS was 79% (kappa = 0.513, p = 0.013). Clearance of pEGFR was associated with longer median TTF (not reached versus 6 months, p = 0.03) and median decrease in CEA levels by 70% from baseline.In another cohort of 124 patients, decrease in CEA levels by greater than 70% within 90 days of TKI initiation was associated with doubling of both TTF and overall survival. Conclusions: Plasma NGS trended toward higher sensitivity than ddPCR in detecting pEGFR, although both had similar concordance in detecting pEGFR clearance. Our results support using NGS at diagnosis and interchangeability of NGS and ddPCR for monitoring, whereas CEA could be explored as a surrogate for pEGFR clearance.
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- 2023
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9. Correction: Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer
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Ning-Yuan Lee, Melissa Hum, Sabna Zihara, Lanying Wang, Matthew K. Myint, Darren Wan-Teck Lim, Chee-Keong Toh, Anders Skanderup, Jens Samol, Min-Han Tan, Peter Ang, Soo-Chin Lee, Eng-Huat Tan, Gillianne G. Y. Lai, Daniel S. W. Tan, Yoon-Sim Yap, and Ann S. G. Lee
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Medicine ,Genetics ,QH426-470 - Published
- 2023
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10. PUREE: accurate pan-cancer tumor purity estimation from gene expression data
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Egor Revkov, Tanmay Kulshrestha, Ken Wing-Kin Sung, and Anders Jacobsen Skanderup
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Biology (General) ,QH301-705.5 - Abstract
Abstract Tumors are complex masses composed of malignant and non-malignant cells. Variation in tumor purity (proportion of cancer cells in a sample) can both confound integrative analysis and enable studies of tumor heterogeneity. Here we developed PUREE, which uses a weakly supervised learning approach to infer tumor purity from a tumor gene expression profile. PUREE was trained on gene expression data and genomic consensus purity estimates from 7864 solid tumor samples. PUREE predicted purity with high accuracy across distinct solid tumor types and generalized to tumor samples from unseen tumor types and cohorts. Gene features of PUREE were further validated using single-cell RNA-seq data from distinct tumor types. In a comprehensive benchmark, PUREE outperformed existing transcriptome-based purity estimation approaches. Overall, PUREE is a highly accurate and versatile method for estimating tumor purity and interrogating tumor heterogeneity from bulk tumor gene expression data, which can complement genomics-based approaches or be used in settings where genomic data is unavailable.
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- 2023
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11. PD-L1 score as a prognostic biomarker in asian early-stage epidermal growth factor receptor-mutated lung cancer
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Saw, Stephanie P.L., Ng, Win Pin, Zhou, Siqin, Lai, Gillianne G.Y., Tan, Aaron C., Ang, Mei-Kim, Lim, Wan-Teck, Kanesvaran, Ravindran, Ng, Quan Sing, Jain, Amit, Tan, Wan Ling, Rajasekaran, Tanujaa, Chan, Johan W.K., Teh, Yi Lin, Pang, Mengyuan, Yeo, Jia-Chi, Takano, Angela, Ong, Boon-Hean, Tan, Eng-Huat, Tan, Sze Huey, Skanderup, Anders J., and Tan, Daniel S.W.
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- 2023
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12. Single-cell and bulk transcriptome sequencing identifies two epithelial tumor cell states and refines the consensus molecular classification of colorectal cancer
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Joanito, Ignasius, Wirapati, Pratyaksha, Zhao, Nancy, Nawaz, Zahid, Yeo, Grace, Lee, Fiona, Eng, Christine L. P., Macalinao, Dominique Camat, Kahraman, Merve, Srinivasan, Harini, Lakshmanan, Vairavan, Verbandt, Sara, Tsantoulis, Petros, Gunn, Nicole, Venkatesh, Prasanna Nori, Poh, Zhong Wee, Nahar, Rahul, Oh, Hsueh Ling Janice, Loo, Jia Min, Chia, Shumei, Cheow, Lih Feng, Cheruba, Elsie, Wong, Michael Thomas, Kua, Lindsay, Chua, Clarinda, Nguyen, Andy, Golovan, Justin, Gan, Anna, Lim, Wan-Jun, Guo, Yu Amanda, Yap, Choon Kong, Tay, Brenda, Hong, Yourae, Chong, Dawn Qingqing, Chok, Aik-Yong, Park, Woong-Yang, Han, Shuting, Chang, Mei Huan, Seow-En, Isaac, Fu, Cherylin, Mathew, Ronnie, Toh, Ee-Lin, Hong, Lewis Z., Skanderup, Anders Jacobsen, DasGupta, Ramanuj, Ong, Chin-Ann Johnny, Lim, Kiat Hon, Tan, Emile K. W., Koo, Si-Lin, Leow, Wei Qiang, Tejpar, Sabine, Prabhakar, Shyam, and Tan, Iain Beehuat
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- 2022
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13. A Randomized Phase 2 Trial of Nivolumab Versus Nivolumab-Ipilimumab Combination in EGFR-Mutant NSCLC
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Lai, Gillianne G.Y., Yeo, Jia Chi, Jain, Amit, Zhou, Siqin, Pang, Mengyuan, Alvarez, Jacob J.S., Sim, Ngak Leng, Tan, Aaron C., Suteja, Lisda, Lim, Tze Wei, Guo, Yu Amanda, Shen, Meixin, Saw, Stephanie P.L., Rohatgi, Neha, Yeong, Joe P.S., Takano, Angela, Lim, Kiat Hon, Gogna, Apoorva, Too, Chow Wei, Da Zhuang, Kun, Tan, Wan Ling, Kanesvaran, Ravindran, Ng, Quan Sing, Ang, Mei Kim, Rajasekaran, Tanujaa, Wang, Lanying, Toh, Chee Keong, Lim, Wan-Teck, Tam, Wai Leong, Tan, Sze Huey, Skanderup, Anders M.J., Tan, Eng-Huat, and Tan, Daniel S.W.
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- 2022
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14. Accurate somatic variant detection using weakly supervised deep learning
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Kiran Krishnamachari, Dylan Lu, Alexander Swift-Scott, Anuar Yeraliyev, Kayla Lee, Weitai Huang, Sim Ngak Leng, and Anders Jacobsen Skanderup
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Science - Abstract
Deep learning could be applied to the challenge of somatic variant calling in cancer by making use of large-scale genomic data. Here, the authors develop VarNet, a weakly supervised deep learning model for somatic variant calling in cancer with robust performance across multiple cancer genomics datasets.
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- 2022
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15. Accurate somatic variant detection using weakly supervised deep learning
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Krishnamachari, Kiran, Lu, Dylan, Swift-Scott, Alexander, Yeraliyev, Anuar, Lee, Kayla, Huang, Weitai, Leng, Sim Ngak, and Skanderup, Anders Jacobsen
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- 2022
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16. Obtaining spatially resolved tumor purity maps using deep multiple instance learning in a pan-cancer study
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Oner, Mustafa Umit, Chen, Jianbin, Revkov, Egor, James, Anne, Heng, Seow Ye, Kaya, Arife Neslihan, Alvarez, Jacob Josiah Santiago, Takano, Angela, Cheng, Xin Min, Lim, Tony Kiat Hon, Tan, Daniel Shao Weng, Zhai, Weiwei, Skanderup, Anders Jacobsen, Sung, Wing-Kin, and Lee, Hwee Kuan
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- 2022
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17. A Randomized Phase 2 Trial of Nivolumab Versus Nivolumab-Ipilimumab Combination in EGFR-Mutant NSCLC
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Gillianne G.Y. Lai, MBBS, Jia Chi Yeo, PhD, Amit Jain, MBBS, PhD, Siqin Zhou, MSc, Mengyuan Pang, MSc, Jacob J.S. Alvarez, BSc, Ngak Leng Sim, BCS, Aaron C. Tan, MBBS, FRACP, PhD, Lisda Suteja, BSc, Tze Wei Lim, BSc, Yu Amanda Guo, PhD, Meixin Shen, PhD, Stephanie P.L. Saw, MBBS, Neha Rohatgi, BSc, Joe P.S. Yeong, MBBS, PhD, Angela Takano, MBBS, Kiat Hon Lim, MBBS, Apoorva Gogna, MBBS, Chow Wei Too, MBBS, Kun Da Zhuang, MBBS, Wan Ling Tan, MBBS, Ravindran Kanesvaran, MBBS, Quan Sing Ng, MBBS, Mei Kim Ang, MBBS, Tanujaa Rajasekaran, MBBS, Lanying Wang, MBBS, Chee Keong Toh, MBBS, Wan-Teck Lim, MBBS, Wai Leong Tam, PhD, Sze Huey Tan, PhD, Anders M.J. Skanderup, PhD, Eng-Huat Tan, MBBS, and Daniel S.W. Tan, BSc, MBBS, MRCP, PhD
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Lung cancer ,Epidermal growth factor receptor ,Immunotherapy ,Biomarkers ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Introduction: Although immune checkpoint inhibitors (ICIs) have dramatically improved outcomes for nononcogene-addicted NSCLC, monotherapy with programmed cell death protein-1 (PD1) inhibition has been associated with low efficacy in the EGFR-mutant setting. Given the potential for synergism with combination checkpoint blockade, we designed a trial to test the activity of combination nivolumab (N)-ipilimumab (NI) in EGFR-mutant NSCLC. Methods: This is a randomized phase 2 study (NCT03091491) of N versus NI combination in EGFR tyrosine kinase inhibitor (TKI)–resistant NSCLC, with crossover permitted on disease progression. The primary end point was the objective response rate, and the secondary end points included progression-free survival, overall survival, and safety of ICI after EGFR TKI. Results: Recruitment ceased owing to futility after 31 of 184 planned patients were treated. A total of 15 patients received N and 16 received NI combination. There were 16 patients (51.6%) who had programmed death-ligand (PDL1) 1 greater than or equal to 1%, and 15 (45.2%) harbored EGFR T790M. Five patients derived clinical benefits from ICI with one objective response (objective response rate 3.2%), and median progression-free survival was 1.22 months (95% confidence interval: 1.15–1.35) for the overall cohort. None of the four patients who crossed over achieved salvage response by NI. PDL1 and tumor mutational burden (TMB) were not able to predict ICI response. Rates of all grade immune-related adverse events were similar (80% versus 75%), with only two grade 3 events. Conclusions: Immune checkpoint inhibition is ineffective in EGFR TKI–resistant NSCLC. Whereas a small subgroup of EGFR-mutant NSCLC may be immunogenic and responsive to ICI, better biomarkers are needed to select appropriate patients.
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- 2022
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18. Integrative epigenomic and high-throughput functional enhancer profiling reveals determinants of enhancer heterogeneity in gastric cancer
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Taotao Sheng, Shamaine Wei Ting Ho, Wen Fong Ooi, Chang Xu, Manjie Xing, Nisha Padmanabhan, Kie Kyon Huang, Lijia Ma, Mohana Ray, Yu Amanda Guo, Ngak Leng Sim, Chukwuemeka George Anene-Nzelu, Mei Mei Chang, Milad Razavi-Mohseni, Michael A. Beer, Roger Sik Yin Foo, Raghav Sundar, Yiong Huak Chan, Angie Lay Keng Tan, Xuewen Ong, Anders Jacobsen Skanderup, Kevin P. White, Sudhakar Jha, and Patrick Tan
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Enhancer landscape ,Gastric cancer ,CapSTARR-seq ,Enhancer-promoter interactions ,Enhancer heterogeneity ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Enhancers are distal cis-regulatory elements required for cell-specific gene expression and cell fate determination. In cancer, enhancer variation has been proposed as a major cause of inter-patient heterogeneity—however, most predicted enhancer regions remain to be functionally tested. Methods We analyzed 132 epigenomic histone modification profiles of 18 primary gastric cancer (GC) samples, 18 normal gastric tissues, and 28 GC cell lines using Nano-ChIP-seq technology. We applied Capture-based Self-Transcribing Active Regulatory Region sequencing (CapSTARR-seq) to assess functional enhancer activity. An Activity-by-contact (ABC) model was employed to explore the effects of histone acetylation and CapSTARR-seq levels on enhancer-promoter interactions. Results We report a comprehensive catalog of 75,730 recurrent predicted enhancers, the majority of which are GC-associated in vivo (> 50,000) and associated with lower somatic mutation rates inferred by whole-genome sequencing. Applying CapSTARR-seq to the enhancer catalog, we observed significant correlations between CapSTARR-seq functional activity and H3K27ac/H3K4me1 levels. Super-enhancer regions exhibited increased CapSTARR-seq signals compared to regular enhancers, even when decoupled from native chromatin contexture. We show that combining histone modification and CapSTARR-seq functional enhancer data improves the prediction of enhancer-promoter interactions and pinpointing of germline single nucleotide polymorphisms (SNPs), somatic copy number alterations (SCNAs), and trans-acting TFs involved in GC expression. We identified cancer-relevant genes (ING1, ARL4C) whose expression between patients is influenced by enhancer differences in genomic copy number and germline SNPs, and HNF4α as a master trans-acting factor associated with GC enhancer heterogeneity. Conclusions Our results indicate that combining histone modification and functional assay data may provide a more accurate metric to assess enhancer activity than either platform individually, providing insights into the relative contribution of genetic (cis) and regulatory (trans) mechanisms to GC enhancer functional heterogeneity.
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- 2021
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19. Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer
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Shigeki Nanjo, Wei Wu, Niki Karachaliou, Collin M. Blakely, Junji Suzuki, Yu-Ting Chou, Siraj M. Ali, D. Lucas Kerr, Victor R. Olivas, Jonathan Shue, Julia Rotow, Manasi K. Mayekar, Franziska Haderk, Nilanjana Chatterjee, Anatoly Urisman, Jia Chi Yeo, Anders J. Skanderup, Aaron C. Tan, Wai Leong Tam, Oscar Arrieta, Kazuyoshi Hosomichi, Akihiro Nishiyama, Seiji Yano, Yuriy Kirichok, Daniel S.W. Tan, Rafael Rosell, Ross A Okimoto, and Trever G. Bivona
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Oncology ,Therapeutics ,Medicine - Abstract
Molecularly targeted cancer therapy has improved outcomes for patients with cancer with targetable oncoproteins, such as mutant EGFR in lung cancer. Yet, the long-term survival of these patients remains limited, because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations of EGFR often harbor additional co-occurring genetic alterations. This hypothesis remains untested for most genetic alterations that co-occur with mutant EGFR. Here, we report the functional impact of inactivating genetic alterations of the mRNA splicing factor RNA-binding motif 10 (RBM10) that co-occur with mutant EGFR. RBM10 deficiency decreased EGFR inhibitor efficacy in patient-derived EGFR-mutant tumor models. RBM10 modulated mRNA alternative splicing of the mitochondrial apoptotic regulator Bcl-x to regulate tumor cell apoptosis during treatment. Genetic inactivation of RBM10 diminished EGFR inhibitor–mediated apoptosis by decreasing the ratio of (proapoptotic) Bcl-xS to (antiapoptotic) Bcl-xL isoforms of Bcl-x. RBM10 deficiency was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Coinhibition of Bcl-xL and mutant EGFR overcame the resistance induced by RBM10 deficiency. This study sheds light on the role of co-occurring genetic alterations and on the effect of splicing factor deficiency on the modulation of sensitivity to targeted kinase inhibitor cancer therapy.
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- 2022
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20. The long non-coding RNA MIR31HG regulates the senescence associated secretory phenotype
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Marta Montes, Michal Lubas, Frederic S. Arendrup, Bettina Mentz, Neha Rohatgi, Sarunas Tumas, Lea M. Harder, Anders J. Skanderup, Jens S. Andersen, and Anders H. Lund
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Science - Abstract
Senescence-associated secretory phenotype (SASP) involves secretion of factors such as pro-inflammatory cytokines. Here the authors show that MIR31HG regulates the expression and secretion of a subset of SASP components that induce paracrine invasion, through interaction with YBX1 and induction of IL1A translation.
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- 2021
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21. Tissue-specific cell-free DNA degradation quantifies circulating tumor DNA burden
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Guanhua Zhu, Yu A. Guo, Danliang Ho, Polly Poon, Zhong Wee Poh, Pui Mun Wong, Anna Gan, Mei Mei Chang, Dimitrios Kleftogiannis, Yi Ting Lau, Brenda Tay, Wan Jun Lim, Clarinda Chua, Tira J. Tan, Si-Lin Koo, Dawn Q. Chong, Yoon Sim Yap, Iain Tan, Sarah Ng, and Anders J. Skanderup
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Science - Abstract
Circulating tumour DNA (ctDNA) represents a non-invasive option to monitor cancer progression. Here, the authors perform deep sequencing of plasma cell-free DNA, and find that nucleosome-dependent cfDNA degradation at 6 specific regulatory regions is predictive of ctDNA burden.
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- 2021
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22. The long non-coding RNA MIR31HG regulates the senescence associated secretory phenotype
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Montes, Marta, Lubas, Michal, Arendrup, Frederic S., Mentz, Bettina, Rohatgi, Neha, Tumas, Sarunas, Harder, Lea M., Skanderup, Anders J., Andersen, Jens S., and Lund, Anders H.
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- 2021
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23. Integrative epigenomic and high-throughput functional enhancer profiling reveals determinants of enhancer heterogeneity in gastric cancer
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Sheng, Taotao, Ho, Shamaine Wei Ting, Ooi, Wen Fong, Xu, Chang, Xing, Manjie, Padmanabhan, Nisha, Huang, Kie Kyon, Ma, Lijia, Ray, Mohana, Guo, Yu Amanda, Sim, Ngak Leng, Anene-Nzelu, Chukwuemeka George, Chang, Mei Mei, Razavi-Mohseni, Milad, Beer, Michael A., Foo, Roger Sik Yin, Sundar, Raghav, Chan, Yiong Huak, Tan, Angie Lay Keng, Ong, Xuewen, Skanderup, Anders Jacobsen, White, Kevin P., Jha, Sudhakar, and Tan, Patrick
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- 2021
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24. Tissue-specific cell-free DNA degradation quantifies circulating tumor DNA burden
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Zhu, Guanhua, Guo, Yu A., Ho, Danliang, Poon, Polly, Poh, Zhong Wee, Wong, Pui Mun, Gan, Anna, Chang, Mei Mei, Kleftogiannis, Dimitrios, Lau, Yi Ting, Tay, Brenda, Lim, Wan Jun, Chua, Clarinda, Tan, Tira J., Koo, Si-Lin, Chong, Dawn Q., Yap, Yoon Sim, Tan, Iain, Ng, Sarah, and Skanderup, Anders J.
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- 2021
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25. Genomic and epigenomic EBF1 alterations modulate TERT expression in gastric cancer
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Xing, Manjie, Ooi, Wen Fong, Tan, Jing, Qamra, Aditi, Lee, Po-Hsien, Li, Zhimei, Xu, Chang, Padmanabhan, Nisha, Lim, Jing Quan, Guo, Yu Amanda, Yao, Xiaosai, Amit, Mandoli, Ng, Ley Moy, Sheng, Taotao, Wang, Jing, Huang, Kie Kyon, Anene-Nzelu, Chukwuemeka George, Ho, Shamaine Wei Ting, Ray, Mohana, Ma, Lijia, Fazzi, Gregorio, Lim, Kevin Junliang, Wijaya, Giovani Claresta, Zhang, Shenli, Nandi, Tannistha, Yan, Tingdong, Chang, Mei Mei, Das, Kakoli, Isa, Zul Fazreen Adam, Wu, Jeanie, Poon, Polly Suk Yean, Lam, Yue Ning, Lin, Joyce Suling, Tay, Su Ting, Lee, Ming Hui, Tan, Angie Lay Keng, Ong, Xuewen, White, Kevin, Rozen, Steven George, Beer, Michael, Foo, Roger Sik Yin, Grabsch, Heike Irmgard, Skanderup, Anders Jacobsen, Li, Shang, Teh, Bin Tean, and Tan, Patrick
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Mortality -- Singapore ,Stomach cancer -- Health aspects -- Analysis ,Vorinostat -- Health aspects -- Analysis ,Cancer genetics -- Health aspects -- Analysis ,Cancer -- Analysis -- Health aspects ,Nivolumab -- Analysis -- Health aspects ,Transcription (Genetics) -- Analysis -- Health aspects ,Telomerase -- Health aspects -- Analysis ,Pembrolizumab -- Health aspects -- Analysis ,Health care industry - Abstract
Transcriptional reactivation of telomerase catalytic subunit (TERT) is a frequent hallmark of cancer, occurring in 90% of human malignancies. However, specific mechanisms driving TERT reactivation remain obscure for many tumor types and in particular gastric cancer (GC), a leading cause of global cancer mortality. Here, through comprehensive genomic and epigenomic analysis of primary GCs and GC cell lines, we identified the transcription factor early B cell factor 1 (EBF1) as a TERT transcriptional repressor and inactivation of EBF1 function as a major cause of TERT upregulation. Abolishment of EBF1 function occurs through 3 distinct (epi)genomic mechanisms. First, EBF1 is epigenetically silenced via DNA methyltransferase, polycomb-repressive complex 2 (PRC2), and histone deacetylase activity in GCs. Second, recurrent, somatic, and heterozygous EBF1 DNA-binding domain mutations result in the production of dominant-negative EBF1 isoforms. Third, more rarely, genomic deletions and rearrangements proximal to the TERT promoter remobilize or abolish EBF7-binding sites, derepressing TERT and leading to high TERT expression. EBF1 is also functionally required for various malignant phenotypes in vitro and in vivo, highlighting its importance for GC development. These results indicate that multimodal genomic and epigenomic alterations underpin TERT reactivation in GC, converging on transcriptional repressors such as EBF1., Introduction Gastric cancer (GC) is a leading cause of global cancer mortality (1), with a particularly high prevalence in East Asia. With the exception of Japan and South Korea, where [...]
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- 2020
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26. Clinical and Genomic Features of HER2 Exon 20 Insertion Mutations and Characterization of HER2 Expression by Immunohistochemistry in East Asian Non–Small-Cell Lung Cancer
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Tan, Aaron C., Saw, Stephanie P.L., Chen, Jianbin, Lai, Gillianne G.Y., Oo, Hlaing Nwe, Takano, Angela, Lau, Dawn P.X., Yeong, Joe P.S., Tan, Gek San, Lim, Kiat Hon, Skanderup, Anders J., Chan, Johan W.K., Teh, Yi Lin, Rajasekaran, Tanujaa, Jain, Amit, Tan, Wan Ling, Ng, Quan Sing, Kanesvaran, Ravindran, Lim, Wan-Teck, Ang, Mei-Kim, and Tan, Daniel S.W.
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- 2022
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27. Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer
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Nanjo, Shigeki, Wu, Wei, Karachaliou, Niki, Blakely, Collin M., Suzuki, Junji, Chou, Yu-Ting, Ali, Siraj M., Kerr, D. Lucas, Olivas, Victor R., Shue, Jonathan, Rotow, Julia, Mayekar, Manasi K., Haderk, Franziska, Chatterjee, Nilanjana, Urisman, Anatoly, Yeo, Jia Chi, Skanderup, Anders J., Tan, Aaron C., Tam, Wai Leong, Arrieta, Oscar, Hosomichi, Kazuyoshi, Nishiyama, Akihiro, Yano, Seiji, Kirichok, Yuriy, Tan, Daniel S.W., Rosell, Rafael, Okimoto, Ross A., and Bivona, Trever G.
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RNA splicing -- Health aspects ,Drug resistance -- Genetic aspects ,Lung cancer -- Genetic aspects -- Drug therapy ,Health care industry - Abstract
Molecularly targeted cancer therapy has improved outcomes for patients with cancer with targetable oncoproteins, such as mutant EGFR in lung cancer. Yet, the long-term survival of these patients remains limited, because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations of EGFR often harbor additional co-occurring genetic alterations. This hypothesis remains untested for most genetic alterations that co-occur with mutant EGFR. Here, we report the functional impact of inactivating genetic alterations of the mRNA splicing factor RNA-binding motif 10 (RBM10) that co-occur with mutant EGFR. RBM10 deficiency decreased EGFR inhibitor efficacy in patient-derived EGFR-mutant tumor models. RBM10 modulated mRNA alternative splicing of the mitochondrial apoptotic regulator Bcl-x to regulate tumor cell apoptosis during treatment. Genetic inactivation of RBM10 diminished EGFR inhibitor-mediated apoptosis by decreasing the ratio of (proapoptotic) Bcl-xS to (antiapoptotic) Bcl-xL isoforms of Bcl-x. RBM10 deficiency was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Coinhibition of Bcl-xL and mutant EGFR overcame the resistance induced by RBM10 deficiency. This study sheds light on the role of co-occurring genetic alterations and on the effect of splicing factor deficiency on the modulation of sensitivity to targeted kinase inhibitor cancer therapy., Introduction Lung cancer is the leading cause of cancer mortality among men and women, comprising almost 25% of all cancer deaths (1). There has been significant progress in the treatment [...]
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- 2022
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28. Cancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis
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Jeffrey Vedanayagam, Walid K. Chatila, Bülent Arman Aksoy, Sonali Majumdar, Anders Jacobsen Skanderup, Emek Demir, Nikolaus Schultz, Chris Sander, and Eric C. Lai
- Subjects
Science - Abstract
DICER is involved in the processing of miRNAs, where the RNase IIIa and IIIb domains are thought to cut the 3p and 5p hairpin arms, respectively. Here, in endometrial cancer, the authors identify an RNase IIIa mutation, which phenocopies mutations in the RNase IIIb domain.
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- 2019
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29. Corrigendum to ‘A chemical genetic screen identifies Aurora kinases as a therapeutic target in EGFR T790M negative, gefitinib-resistant head and neck squamous cell carcinoma (HNSCC)’
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Joo-Leng Low, Dawn Pingxi Lau, Xiaoqian Zhang, Xue-Lin Kwang, Neha Rohatgi, Jane Vin Chan, Fui-Teen Chong, Stephen Qi Rong Wong, Hui-Sun Leong, Matan Thangavelu Thangavelu, Shivaji Rikka, Anders Martin Jacobsen Skanderup, Daniel Shao Weng Tan, Giridharan Periyasamy, Judice Lie Yong Koh, N Gopalakrishna Iyer, and Ramanuj DasGupta
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Medicine ,Medicine (General) ,R5-920 - Published
- 2021
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30. A chemical genetic screen identifies Aurora kinases as a therapeutic target in EGFR T790M negative, gefitinib-resistant head and neck squamous cell carcinoma (HNSCC)
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Joo-Leng Low, Dawn Pingxi Lau, Xiaoqian Zhang, Xue-Lin Kwang, Neha Rohatgi, Jane Vin Chan, Fui-Teen Chong, Stephen Qi Rong Wong, Hui-Sun Leong, Matan Thangavelu Thangavelu, Shivaji Rikka, Anders Martin Jacobsen Skanderup, Daniel Shao Weng Tan, Giridharan Periyasamy, Judice Lie Yong Koh, N Gopalakrishna Iyer, and Ramanuj DasGupta
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Head and neck squamous cell carcinoma ,Gefitinib resistance ,Aurora kinase inhibition ,EGFR T790M negative ,Chemical genetics ,Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Overexpression of epidermal growth factor receptor (EGFR), and downstream pathway activation appears to be a common oncogenic driver in the majority of head and neck squamous cell cancers (HNSCCs); yet targeting EGFR for the treatment of HNSCC has met with limited success. Apart from the anti-EGFR antibody cetuximab, no small molecule EGFR/tyrosine kinase inhibitors (TKIs) have progressed to routine clinical use. The aim of this study was to determine factors contributing to the lack of response to TKIs and identify alternative therapeutic vulnerabilities. Methods: Genomic and transcriptomic sequencing, high-throughput compound screens, overexpression and siRNA knockdown, western blot, in vivo xenograft studies. Findings: We derived three pairs of isogenic gefitinib (TKI)-sensitive and resistant patient-derived HNSCC cell lines. Genomic sequencing of gefitinib-resistant cell lines identified a lack of activating and resistance-associated EGFR mutations. Instead, transcriptomic sequencing showed upregulated EMT gene signature in the gefitinib-resistant cells with a corresponding increase in their migratory phenotype. Additionally, the resistant cell displayed reduced growth rate. Surprisingly, while gefitinib-resistant cells were independent of EGFR for survival, they nonetheless displayed activation of downstream ERK and AKT signalling. High-throughput screening (HTS) of druggable, small molecule libraries revealed that the gefitinib-resistant cells were particularly sensitive to inhibitors of genes involved in cell cycle and mitosis, such as Aurora kinase inhibitors (AKIs), cyclin-dependent kinase (CDK) inhibitors, and microtubule inhibitors. Notably our results showed that in the EGFR inhibited state, Aurora kinases are essential for cell survival. Interpretation: Our study demonstrates that in the absence of activating EGFR mutations, HNSCCs may gain resistance to gefitinib through decreased cell proliferation, which makes them exceptionally vulnerable to cell-cycle inhibitors. Funding: Agency for Science, Technology, and Research (A*STAR), National Medical Research Council (NMRC), and the National Institutes of Health (NIH)/National Cancer Institute (NCI).
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- 2021
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31. MutSpot: detection of non-coding mutation hotspots in cancer genomes
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Guo, Yu Amanda, Chang, Mei Mei, and Skanderup, Anders Jacobsen
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- 2020
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32. Mutation hotspots at CTCF binding sites coupled to chromosomal instability in gastrointestinal cancers
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Yu Amanda Guo, Mei Mei Chang, Weitai Huang, Wen Fong Ooi, Manjie Xing, Patrick Tan, and Anders Jacobsen Skanderup
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Science - Abstract
The impact of non-coding somatic mutations in gastric cancer is unknown. Here, using whole genome sequencing data from 212 gastric tumors, the authors identify recurring mutations at specific CTCF binding sites that are common across gastrointestinal cancers and associated with chromosomal instability.
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- 2018
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33. Individualized Molecular Profiling for Allocation to Clinical Trials Singapore Study—An Asian Tertiary Cancer Center Experience
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Seet, Amanda O. L., Tan, Aaron C., Tan, Tira J., Ng, Matthew C. H., Tai, David W. M., Lam, Justina Y. C., Tan, Gek San, Gogna, Apoorva, Too, Chow Wei, Tan, Bien Soo, Takano, Angela, Lim, Alvin, Lim, Tse Hui, Lim, Soon Thye, Dent, Rebecca Alexandra, Ang, Mei Kim, Yap, Yoon-Sim, Tan, Iain B. H., Choo, Su Pin, Toh, Chee Keong, Lim, Elaine H., Farid, Mohamad, Skanderup, Anders Jacobsen, Iyer, N. Gopalakrishna, Lim, Wan Teck, Tan, Eng Huat, Lim, Tony K. H., and Tan, Daniel S. W.
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- 2021
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34. ΔNp63 Inhibits Oxidative Stress-Induced Cell Death, Including Ferroptosis, and Cooperates with the BCL-2 Family to Promote Clonogenic Survival
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Gary X. Wang, Ho-Chou Tu, Yiyu Dong, Anders Jacobsen Skanderup, Yufeng Wang, Shugaku Takeda, Yogesh Tengarai Ganesan, Song Han, Han Liu, James J. Hsieh, and Emily H. Cheng
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Biology (General) ,QH301-705.5 - Abstract
Summary: The BCL-2 family proteins are central regulators of apoptosis. However, cells deficient for BAX and BAK or overexpressing BCL-2 still succumb to oxidative stress upon DNA damage or matrix detachment. Here, we show that ΔNp63α overexpression protects cells from oxidative stress induced by oxidants, DNA damage, anoikis, or ferroptosis-inducing agents. Conversely, ΔNp63α deficiency increases oxidative stress. Mechanistically, ΔNp63α orchestrates redox homeostasis through transcriptional control of glutathione biogenesis, utilization, and regeneration. Analysis of a lung squamous cell carcinoma dataset from The Cancer Genome Atlas (TCGA) reveals that TP63 amplification/overexpression upregulates the glutathione metabolism pathway in primary human tumors. Strikingly, overexpression of ΔNp63α promotes clonogenic survival of p53−/−Bax−/−Bak−/− cells against DNA damage. Furthermore, co-expression of BCL-2 and ΔNp63α confers clonogenic survival against matrix detachment, disrupts the luminal clearance of mammary acini, and promotes cancer metastasis. Our findings highlight the need for a simultaneous blockade of apoptosis and oxidative stress to promote long-term cellular well-being. : Apoptosis-defective cells remain vulnerable to oxidative stress, which limits long-term survival. Wang et al. identify ΔNp63α as a central regulator of redox homeostasis through transcriptional control of a tightly coupled glutathione metabolic circuit. ΔNp63α alleviates oxidative stress and cooperates with the BCL-2 family to promote both long-term cellular well-being and cancer metastasis. Keywords: oxidative stress, ROS, apoptosis, necrosis, programmed necrotic death, TP63, BCL-2, ferroptosis, redox, glutathione metabolism
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- 2017
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35. Targeting the developmental origins of cancer
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Skanderup, Anders Jacobsen and DasGupta, Ramanuj
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- 2021
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36. Brief Report: Droplet Digital Polymerase Chain Reaction Versus Plasma Next-Generation Sequencing in Detecting Clearance of Plasma EGFR Mutations and Carcinoembryonic Antigen Levels as a Surrogate Measure
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Saw, Stephanie P.L., Tan, Gek San, Tan, Wei Chong, Tan, Aaron C., Lai, Gillianne G.Y., Lim, Darren W.T., Kanesvaran, Ravindran, Tan, Wan Ling, Tan, Sze Huey, Lim, Kiat Hon, Skanderup, Anders J., and Tan, Daniel S.W.
- Published
- 2023
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37. Cancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis
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Vedanayagam, Jeffrey, Chatila, Walid K., Aksoy, Bülent Arman, Majumdar, Sonali, Skanderup, Anders Jacobsen, Demir, Emek, Schultz, Nikolaus, Sander, Chris, and Lai, Eric C.
- Published
- 2019
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38. Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets
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Ying-Bei Chen, Jianing Xu, Anders Jacobsen Skanderup, Yiyu Dong, A. Rose Brannon, Lu Wang, Helen H. Won, Patricia I. Wang, Gouri J. Nanjangud, Achim A. Jungbluth, Wei Li, Virginia Ojeda, A. Ari Hakimi, Martin H. Voss, Nikolaus Schultz, Robert J. Motzer, Paul Russo, Emily H. Cheng, Filippo G. Giancotti, William Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, and James J. Hsieh
- Subjects
Science - Abstract
A subset of renal cell carcinomas have uncertain histology and are aggressive in nature. Here, the authors examine this group of unclassified renal cancers using genomics techniques and identify further subclasses of the tumours that have differing prognoses.
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- 2016
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39. Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in squamous cell carcinoma
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Tan, Daniel S W, Chong, Fui Teen, Leong, Hui Sun, Toh, Shen Yon, Lau, Dawn P, Kwang, Xue Lin, Zhang, Xiaoqian, Sundaram, Gopinath M, Tan, Gek San, Chang, Mei Mei, Chua, Boon Tin, Lim, Wan Teck, Tan, Eng Huat, Ang, Mei Kim, Lim, Tony K H, Sampath, Prabha, Chowbay, Balram, Skanderup, Anders J, DasGupta, Ramanuj, and Iyer, N Gopalakrishna
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Gene expression -- Health aspects ,Squamous cell carcinoma -- Genetic aspects -- Development and progression -- Care and treatment ,Biological sciences ,Health - Abstract
Targeting EGFR is a validated approach in the treatment of squamous-cell cancers (SCCs), although there are no established biomarkers for predicting response. We have identified a synonymous mutation in EGFR, c.2361G [greater than] A (encoding p.Gln787Gln), in two patients with head and neck SCC (HNSCC) who were exceptional responders to gefitinib, and we showed in patient-derived cultures that the A/A genotype was associated with greater sensitivity to tyrosine kinase inhibitors (TKIs) as compared to the G/A and G/G genotypes. Remarkably, single-copy G [greater than] A nucleotide editing in isogenic models conferred a 70-fold increase in sensitivity due to decreased stability of the EGFR-AS1 long noncoding RNA (lncRNA). In the appropriate context, sensitivity could be recapitulated through EGFR-AS1 knockdown in vitro and in vivo, whereas overexpression was sufficient to induce resistance to TKIs. Reduced EGFR-AS1 levels shifted splicing toward EGFR isoform D, leading to ligand-mediated pathway activation. In co-clinical trials involving patients and patient-derived xenograft (PDX) models, tumor shrinkage was most pronounced in the context of the A/A genotype for EGFR-Q787Q, low expression of EGFR-AS1 and high expression of EGFR isoform D. Our study reveals how a 'silent' mutation influences the levels of a lncRNA, resulting in noncanonical EGFR addiction, and delineates a new predictive biomarker suite for response to EGFR TKIs., Author(s): Daniel S W Tan (corresponding author) [1, 2, 3]; Fui Teen Chong [1]; Hui Sun Leong [1]; Shen Yon Toh [1]; Dawn P Lau [1]; Xue Lin Kwang [1]; [...]
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- 2017
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40. Obstructive sleep apnea and Fuhrman grade in patients with clear cell renal cell carcinoma treated surgically
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Vilaseca, Antoni, Nguyen, Daniel P., Vertosick, Emily A., Corradi, Renato B., Musquera, Mireia, Pérez, Meritxell, Fossati, Nicola, Sjoberg, Daniel D., Farré, Ramon, Almendros, Isaac, Montserrat, Josep M., Benfante, Nicole E., Hakimi, A. Ari, Skanderup, Anders J., Russo, Paul, Alcaraz, Antonio, and Touijer, Karim A.
- Published
- 2017
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41. Integrative epigenomic and high-throughput functional enhancer profiling reveals determinants of enhancer heterogeneity in gastric cancer
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Yiong-Huak Chan, Taotao Sheng, Chukwuemeka George Anene-Nzelu, Mohana Ray, Shamaine Wei Ting Ho, Roger Foo, Kie Kyon Huang, Wen Fong Ooi, Milad Razavi-Mohseni, Kevin P. White, Anders Jacobsen Skanderup, Ngak Leng Sim, Mei Mei Chang, Angie Lay Keng Tan, Sudhakar Jha, Patrick Tan, Nisha Padmanabhan, Chang Xu, Yu Amanda Guo, Manjie Xing, Lijia Ma, Raghav Sundar, Michael A. Beer, and Xuewen Ong
- Subjects
Epigenomics ,Enhancer landscape ,CapSTARR-seq ,Single-nucleotide polymorphism ,Computational biology ,QH426-470 ,Histones ,Germline mutation ,Stomach Neoplasms ,Cell Line, Tumor ,Genetics ,Humans ,natural sciences ,RNA-Seq ,Promoter Regions, Genetic ,Enhancer ,Molecular Biology ,Gene ,Genetics (clinical) ,Cell Proliferation ,Whole Genome Sequencing ,biology ,ADP-Ribosylation Factors ,Research ,Enhancer-promoter interactions ,Acetylation ,Genomics ,Oncogenes ,Chromatin ,Gene Expression Regulation, Neoplastic ,Enhancer Elements, Genetic ,Histone ,biology.protein ,Molecular Medicine ,Medicine ,Transcriptome ,Gastric cancer ,Inhibitor of Growth Protein 1 ,Enhancer heterogeneity - Abstract
Background Enhancers are distal cis-regulatory elements required for cell-specific gene expression and cell fate determination. In cancer, enhancer variation has been proposed as a major cause of inter-patient heterogeneity—however, most predicted enhancer regions remain to be functionally tested. Methods We analyzed 132 epigenomic histone modification profiles of 18 primary gastric cancer (GC) samples, 18 normal gastric tissues, and 28 GC cell lines using Nano-ChIP-seq technology. We applied Capture-based Self-Transcribing Active Regulatory Region sequencing (CapSTARR-seq) to assess functional enhancer activity. An Activity-by-contact (ABC) model was employed to explore the effects of histone acetylation and CapSTARR-seq levels on enhancer-promoter interactions. Results We report a comprehensive catalog of 75,730 recurrent predicted enhancers, the majority of which are GC-associated in vivo (> 50,000) and associated with lower somatic mutation rates inferred by whole-genome sequencing. Applying CapSTARR-seq to the enhancer catalog, we observed significant correlations between CapSTARR-seq functional activity and H3K27ac/H3K4me1 levels. Super-enhancer regions exhibited increased CapSTARR-seq signals compared to regular enhancers, even when decoupled from native chromatin contexture. We show that combining histone modification and CapSTARR-seq functional enhancer data improves the prediction of enhancer-promoter interactions and pinpointing of germline single nucleotide polymorphisms (SNPs), somatic copy number alterations (SCNAs), and trans-acting TFs involved in GC expression. We identified cancer-relevant genes (ING1, ARL4C) whose expression between patients is influenced by enhancer differences in genomic copy number and germline SNPs, and HNF4α as a master trans-acting factor associated with GC enhancer heterogeneity. Conclusions Our results indicate that combining histone modification and functional assay data may provide a more accurate metric to assess enhancer activity than either platform individually, providing insights into the relative contribution of genetic (cis) and regulatory (trans) mechanisms to GC enhancer functional heterogeneity.
- Published
- 2021
42. The long non-coding RNA MIR31HG regulates the senescence associated secretory phenotype
- Author
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Frederic S Arendrup, Jens S. Andersen, Marta Montes, Anders H. Lund, Sarunas Tumas, Lea M. Harder, Anders Jacobsen Skanderup, Neha Rohatgi, Bettina Mentz, and Michal Lubas
- Subjects
0301 basic medicine ,Translation ,Aging ,General Physics and Astronomy ,0302 clinical medicine ,Transcription (biology) ,Neoplasms ,Aging/genetics ,Phosphorylation ,Cellular Senescence ,Multidisciplinary ,Kinase ,Cell Transformation, Neoplastic/genetics ,Cyclin-Dependent Kinase Inhibitor p16/biosynthesis ,Translation (biology) ,Neoplasms/genetics ,Cell biology ,Gene Expression Regulation, Neoplastic ,Proto-Oncogene Proteins B-raf/metabolism ,Cell Transformation, Neoplastic ,Cellular Senescence/genetics ,030220 oncology & carcinogenesis ,RNA, Long Noncoding ,Proto-Oncogene Proteins B-raf ,Senescence ,Science ,Repressor ,Biology ,Ribosomal Protein S6 Kinases, 90-kDa ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Cell Proliferation/genetics ,03 medical and health sciences ,Paracrine signalling ,Humans ,Secretion ,RNA, Long Noncoding/genetics ,Cyclin-Dependent Kinase Inhibitor p16 ,Cell Proliferation ,fungi ,Oncogenes ,General Chemistry ,Gene Expression Regulation, Neoplastic/genetics ,030104 developmental biology ,Ribosomal Protein S6 Kinases, 90-kDa/metabolism ,Long non-coding RNAs ,Y-Box-Binding Protein 1 ,Y-Box-Binding Protein 1/metabolism - Abstract
Oncogene-induced senescence provides a barrier against malignant transformation. However, it can also promote cancer through the secretion of a plethora of factors released by senescent cells, called the senescence associated secretory phenotype (SASP). We have previously shown that in proliferating cells, nuclear lncRNA MIR31HG inhibits p16/CDKN2A expression through interaction with polycomb repressor complexes and that during BRAF-induced senescence, MIR31HG is overexpressed and translocates to the cytoplasm. Here, we show that MIR31HG regulates the expression and secretion of a subset of SASP components during BRAF-induced senescence. The SASP secreted from senescent cells depleted for MIR31HG fails to induce paracrine invasion without affecting the growth inhibitory effect. Mechanistically, MIR31HG interacts with YBX1 facilitating its phosphorylation at serine 102 (p-YBX1S102) by the kinase RSK. p-YBX1S102 induces IL1A translation which activates the transcription of the other SASP mRNAs. Our results suggest a dual role for MIR31HG in senescence depending on its localization and points to the lncRNA as a potential therapeutic target in the treatment of senescence-related pathologies., Senescence-associated secretory phenotype (SASP) involves secretion of factors such as pro-inflammatory cytokines. Here the authors show that MIR31HG regulates the expression and secretion of a subset of SASP components that induce paracrine invasion, through interaction with YBX1 and induction of IL1A translation.
- Published
- 2021
43. 1175P Universal circulating tumor DNA quantification using deep learning.
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Skanderup, A., Zhu, G., and Rahman, C.R.
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CIRCULATING tumor DNA , *DEEP learning - Published
- 2024
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44. Corrigendum to ‘A chemical genetic screen identifies Aurora kinases as a therapeutic target in EGFR T790M negative, gefitinib-resistant head and neck squamous cell carcinoma (HNSCC)’
- Author
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Low, Joo-Leng, Lau, Dawn Pingxi, Zhang, Xiaoqian, Kwang, Xue-Lin, Rohatgi, Neha, Chan, Jane Vin, Chong, Fui-Teen, Wong, Stephen Qi Rong, Leong, Hui-Sun, Thangavelu, Matan Thangavelu, Rikka, Shivaji, Skanderup, Anders Martin Jacobsen, Tan, Daniel Shao Weng, Periyasamy, Giridharan, Koh, Judice Lie Yong, Iyer, N Gopalakrishna, and DasGupta, Ramanuj
- Published
- 2021
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45. Cancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis
- Author
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Walid K. Chatila, Chris Sander, Bülent Arman Aksoy, Anders Jacobsen Skanderup, Eric C. Lai, Emek Demir, Sonali Majumdar, Jeffrey P. Vedanayagam, and Nikolaus Schultz
- Subjects
0301 basic medicine ,Ribonuclease III ,Small RNA ,RNase P ,Somatic cell ,Science ,General Physics and Astronomy ,02 engineering and technology ,Biology ,Cleavage (embryo) ,General Biochemistry, Genetics and Molecular Biology ,Article ,Gene regulatory networks ,DEAD-box RNA Helicases ,03 medical and health sciences ,Cancer genome ,Databases, Genetic ,Cancer genomics ,Humans ,lcsh:Science ,Derepression ,Genetics ,Phenocopy ,Multidisciplinary ,General Chemistry ,021001 nanoscience & nanotechnology ,3. Good health ,Endometrial Neoplasms ,MicroRNAs ,030104 developmental biology ,RNAi ,Mutation ,Female ,lcsh:Q ,0210 nano-technology ,MiRNA biogenesis - Abstract
Somatic mutations in the RNase IIIb domain of DICER1 arise in cancer and disrupt the cleavage of 5' pre-miRNA arms. Here, we characterize an unstudied, recurrent, mutation (S1344L) in the DICER1 RNase IIIa domain in tumors from The Cancer Genome Atlas (TCGA) project and MSK-IMPACT profiling. RNase IIIa/b hotspots are absent from most cancers, but are notably enriched in uterine cancers. Systematic analysis of TCGA small RNA datasets show that DICER1 RNase IIIa-S1344L tumors deplete 5p-miRNAs, analogous to RNase IIIb hotspot samples. Structural and evolutionary coupling analyses reveal constrained proximity of RNase IIIa-S1344 to the RNase IIIb catalytic site, rationalizing why mutation of this site phenocopies known hotspot alterations. Finally, examination of DICER1 hotspot endometrial tumors reveals derepression of specific miRNA target signatures. In summary, comprehensive analyses of DICER1 somatic mutations and small RNA data reveal a mechanistic aspect of pre-miRNA processing that manifests in specific cancer settings., DICER is involved in the processing of miRNAs, where the RNase IIIa and IIIb domains are thought to cut the 3p and 5p hairpin arms, respectively. Here, in endometrial cancer, the authors identify an RNase IIIa mutation, which phenocopies mutations in the RNase IIIb domain.
- Published
- 2019
46. A phase 1b study of OXIRI in pancreatic adenocarcinoma patients and its immunomodulatory effects.
- Author
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Ng, Matthew, Chen, Sylvia, Ong, Whee Sze, Balachander, Akhila, Seet, Amanda, Yeong, Joe, Sutiman, Natalia, Lim, Tony Kiat Hon, Lee, Bernett, Guo, Yu Amanda, Leong, Wai Fook, Lee, Sze Sing, Lam, Justina, Choo, Su Pin, Skanderup, Anders Jacobsen, Biswas, Subhra Kumar, Tai, David, and Chowbay, Balram
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and debilitating disease with limited therapeutic options. The aim of this clinical study was to evaluate the safety, efficacy and pharmacokinetics of a novel regimen comprised of metronomic oxaliplatin (O), chronomodulated capecitabine (X) and UGT1A1 genotype‐guided dosing of irinotecan (IRI) [OXIRI] as well as its immunomodulatory effects. Thirty‐six patients were enrolled into either dose‐escalation or expansion cohorts. In the dose escalation phase, capecitabine doses (2000, 2650, 3500 and 4500 mg/day) were administered at midnight on days 1 to 14 while oxaliplatin and irinotecan were intravenously infused at fixed doses of 50 and 75 mg/m2 respectively on days 1, 8 in a 21‐day cycle. The maximum tolerated dose of capecitabine was 2650 mg/day and the most common grade 3 adverse events were neutropenia (30.6%) and diarrhea (13.9%). No grade 4 toxicity was observed. UGT1A1‐genotype directed dosing resulted in similar exposure levels of irinotecan, SN‐38 and SN‐38G in all patients. Objective response rate was 22.2%. Median overall survival and progression‐free survival were 8.1 and 5.2 months, respectively. Exploratory immunoprofiling by flow cytometry and quantitative spatial localization analysis of infiltrated immune cells performed on biopsy and plasma samples revealed significant declines in CCL22, CCL2 and TNFα levels at end of first cycle and an active host immune response. Our study showed that OXIRI was well‐tolerated and exhibited good efficacy, with immunomodulatory effects. It may be considered as an alternative to FOLFIRINOX in patients intolerant to the latter. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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47. A chemical genetic screen identifies Aurora kinases as a therapeutic target in EGFR T790M negative, gefitinib-resistant head and neck squamous cell carcinoma (HNSCC)
- Author
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Neha Rohatgi, Hui-Sun Leong, Anders Jacobsen Skanderup, Stephen Qi Rong Wong, Giridharan Periyasamy, Matan Thangavelu Thangavelu, Judice Lie Yong Koh, Fui-Teen Chong, Xiaoqian Zhang, Ramanuj DasGupta, N. Gopalakrishna Iyer, Dawn Pingxi Lau, Daniel Shao Weng Tan, Jane Vin Chan, Xue-Lin Kwang, Joo-Leng Low, and Shivaji Rikka
- Subjects
0301 basic medicine ,lcsh:Medicine ,General Biochemistry, Genetics and Molecular Biology ,Chemical genetics ,03 medical and health sciences ,0302 clinical medicine ,Aurora kinase ,Gefitinib ,Cyclin-dependent kinase ,medicine ,Epidermal growth factor receptor ,lcsh:R5-920 ,Aurora kinase inhibition ,Gefitinib resistance ,biology ,Cetuximab ,Cell growth ,lcsh:R ,Head and neck squamous cell carcinoma ,EGFR T790M negative ,General Medicine ,medicine.disease ,Head and neck squamous-cell carcinoma ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,lcsh:Medicine (General) ,Tyrosine kinase ,medicine.drug ,Research Paper - Abstract
Background Overexpression of epidermal growth factor receptor (EGFR), and downstream pathway activation appears to be a common oncogenic driver in the majority of head and neck squamous cell cancers (HNSCCs); yet targeting EGFR for the treatment of HNSCC has met with limited success. Apart from the anti-EGFR antibody cetuximab, no small molecule EGFR/tyrosine kinase inhibitors (TKIs) have progressed to routine clinical use. The aim of this study was to determine factors contributing to the lack of response to TKIs and identify alternative therapeutic vulnerabilities. Methods Genomic and transcriptomic sequencing, high-throughput compound screens, overexpression and siRNA knockdown, western blot, in vivo xenograft studies. Findings We derived three pairs of isogenic gefitinib (TKI)-sensitive and resistant patient-derived HNSCC cell lines. Genomic sequencing of gefitinib-resistant cell lines identified a lack of activating and resistance-associated EGFR mutations. Instead, transcriptomic sequencing showed upregulated EMT gene signature in the gefitinib-resistant cells with a corresponding increase in their migratory phenotype. Additionally, the resistant cell displayed reduced growth rate. Surprisingly, while gefitinib-resistant cells were independent of EGFR for survival, they nonetheless displayed activation of downstream ERK and AKT signalling. High-throughput screening (HTS) of druggable, small molecule libraries revealed that the gefitinib-resistant cells were particularly sensitive to inhibitors of genes involved in cell cycle and mitosis, such as Aurora kinase inhibitors (AKIs), cyclin-dependent kinase (CDK) inhibitors, and microtubule inhibitors. Notably our results showed that in the EGFR inhibited state, Aurora kinases are essential for cell survival. Interpretation Our study demonstrates that in the absence of activating EGFR mutations, HNSCCs may gain resistance to gefitinib through decreased cell proliferation, which makes them exceptionally vulnerable to cell-cycle inhibitors. Funding Agency for Science, Technology, and Research (A*STAR), National Medical Research Council (NMRC), and the National Institutes of Health (NIH)/National Cancer Institute (NCI).
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- 2021
48. Data-driven inference of crosstalk in the tumor microenvironment
- Author
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Marjan Mojtabavi Naeini, Sundar Solai, Puay Hoon Tan, Balram Chowbay, Ramanuj DasGupta, Tin Trung Nguyen, Neha Rohatgi, Joe Yeong, Egor Revkov, Umesh Ghoshdastider, Anders Jacobsen Skanderup, Angeline Mei Lin Wong, and Jabed Iqbal
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Tumor microenvironment ,Crosstalk (biology) ,Stromal cell ,Receptor expression ,Cancer cell ,medicine ,Cancer research ,Biology ,Autocrine signalling ,Carcinogenesis ,medicine.disease_cause ,Immune checkpoint - Abstract
Signaling between cancer and nonmalignant (stromal) cells in the tumor microenvironment (TME) is key to tumorigenesis yet challenging to decipher from tumor transcriptomes. Here, we report an unbiased, data-driven approach to deconvolute bulk tumor transcriptomes and predict crosstalk between ligands and receptors on cancer and stromal cells in the TME of 20 solid tumor types. Our approach recovers known transcriptional hallmarks of cancer and stromal cells and is concordant with single-cell and immunohistochemistry data, underlining its robustness. Pan-cancer analysis reveals previously unrecognized features of cancer-stromal crosstalk. We find that autocrine cancer cell cross-talk varied between tissues but often converged on known cancer signaling pathways. In contrast, many stromal cross-talk interactions were highly conserved across tumor types. Interestingly, the immune checkpoint ligand PD-L1 was overexpressed in stromal rather than cancer cells across all tumor types. Moreover, we predicted and experimentally validated aberrant ligand and receptor expression in cancer cells of basal and luminal breast cancer, respectively. Collectively, our findings validate a data-driven method for tumor transcriptome deconvolution and establishes a new resource for hypothesis generation and downstream functional interrogation of the TME in tumorigenesis and disease progression.
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- 2019
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- View/download PDF
49. Genomic differences between black and white patients implicate a distinct immune response to papillary renal cell carcinoma
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Kathleen Kan, Anders Jacobsen Skanderup, Ketan K. Badani, Che-Kai Tsao, Matthew D. Galsky, John P. Sfakianos, David J. Paulucci, and A. Ari Hakimi
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0301 basic medicine ,Oncology ,Male ,medicine.medical_specialty ,immune system signaling ,medicine.medical_treatment ,papillary renal cell carcinoma ,Black People ,immune response ,White People ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Renal cell carcinoma ,Internal medicine ,Databases, Genetic ,Medicine ,Humans ,Gene Regulatory Networks ,Propensity Score ,Carcinoma, Renal Cell ,B cell receptor signaling pathway ,Aged ,Neoplasm Staging ,Oligonucleotide Array Sequence Analysis ,Hematology ,Papillary renal cell carcinomas ,business.industry ,Gene Expression Profiling ,Wnt signaling pathway ,Middle Aged ,medicine.disease ,targeted therapy ,Kidney Neoplasms ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunology ,Significance analysis of microarrays ,racial disparities ,Mutation ,Female ,business ,Research Paper - Abstract
// David J. Paulucci 1 , John P. Sfakianos 1 , Anders J. Skanderup 2 , Kathleen Kan 1 , Che-Kai Tsao 3 , Matthew D. Galsky 3 , A. Ari Hakimi 4 , Ketan K. Badani 1 1 Department of Urology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA 2 Computational Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA 3 Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA 4 Department of Surgery—Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA Correspondence to: Ketan K. Badani, email: Ketan.Badani@mountsinai.org Keywords: papillary renal cell carcinoma, racial disparities, immune system signaling, targeted therapy, immune response Received: May 03, 2016 Accepted: November 22, 2016 Published: December 23, 2016 ABSTRACT Significant disparities in survival, incidence and possibly response to current therapies exist between black and white patients with renal cell carcinoma (RCC). Recent genomic evidence to account for these disparities has been reported for clear cell RCC. However, racial disparities at the genomic level for papillary RCC (pRCC) which is a genetically distinct and less responsive histologic subtype of RCC have not been reported. Using The Cancer Genome Atlas (TCGA) data, the present study assessed gene-level expression, somatic mutation and pathway differences between 58 black and 58 white patients with pRCC propensity matched on age, gender and pathologic T stage. Distinct tumor biology with differential expression patterns were observed in black vs. white patients with pRCC. Specifically, significance analysis of microarrays was applied to TCGA gene expression data and identified 163 genes and 120 genes overexpressed in black and white patients, respectively (FDR q
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- 2016
50. MutSpot: detection of non-coding mutation hotspots in cancer genomes
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Yu Amanda Guo, Anders Jacobsen Skanderup, and Mei Mei Chang
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0301 basic medicine ,lcsh:QH426-470 ,Somatic cell ,lcsh:Medicine ,Feature selection ,Computational biology ,Biology ,Brief Communication ,Genome informatics ,medicine.disease_cause ,Genome ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Cancer genomics ,Genetics ,medicine ,Epigenetics ,Cluster analysis ,Molecular Biology ,Genetics (clinical) ,lcsh:R ,Cancer ,medicine.disease ,lcsh:Genetics ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation (genetic algorithm) ,Carcinogenesis - Abstract
SummaryRecurrence and clustering of somatic mutations (hotspots) in cancer genomes may indicate positive selection and involvement in tumorigenesis. MutSpot performs genome-wide inference of mutation hotspots in non-coding and regulatory DNA of cancer genomes. MutSpot performs feature selection across hundreds of epigenetic and sequence features followed by estimation of position and patient-specific background somatic mutation probabilities. MutSpot is user-friendly, works on a standard workstation, and scales to thousands of cancer genomes.Availability and implementationMutSpot is implemented as an R package and is available at https://github.com/skandlab/MutSpot/Supplementary informationSupplementary data are available at https://github.com/skandlab/MutSpot/
- Published
- 2019
- Full Text
- View/download PDF
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