Please use this identifier to cite or link to this item: https://doi.org/10.3389/fonc.2021.709525
Title: Integrated Genomic Profiling and Drug Screening of Patient-Derived Cultures Identifies Individualized Copy Number-Dependent Susceptibilities Involving PI3K Pathway and 17q Genes in Neuroblastoma
Authors: Wong, Rachel LY
Wong, Megan RE
Kuick, Chik Hong
Saffari, Seyed Ehsan 
Wong, Meng Kang 
Tan, Sheng Hui
Merchant, Khurshid 
Chang, Kenneth TE 
Thangavelu, Matan
Periyasamy, Giridharan
Chen, Zhi Xiong
Iyer, Prasad 
Tan, Enrica EK
Soh, Shui Yen 
Iyer, N Gopalakrishna 
Fan, Qiao 
Loh, Amos HP 
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
neuroblastoma
patient-derived culture
copy number variations (CNV)
Comprehensive genomic profiling (CGP)
PI3K
AKT pathway
CDK (cyclin-dependent kinase)
JAK-STAT cascade
SEGMENTAL CHROMOSOMAL ALTERATIONS
HUMAN TUMOR XENOGRAFTS
IN-VITRO
KINASE INHIBITOR
MYCN PROTEIN
CELL-LINE
CANCER
TARGET
MODELS
GROWTH
Issue Date: 14-Oct-2021
Publisher: FRONTIERS MEDIA SA
Citation: Wong, Rachel LY, Wong, Megan RE, Kuick, Chik Hong, Saffari, Seyed Ehsan, Wong, Meng Kang, Tan, Sheng Hui, Merchant, Khurshid, Chang, Kenneth TE, Thangavelu, Matan, Periyasamy, Giridharan, Chen, Zhi Xiong, Iyer, Prasad, Tan, Enrica EK, Soh, Shui Yen, Iyer, N Gopalakrishna, Fan, Qiao, Loh, Amos HP (2021-10-14). Integrated Genomic Profiling and Drug Screening of Patient-Derived Cultures Identifies Individualized Copy Number-Dependent Susceptibilities Involving PI3K Pathway and 17q Genes in Neuroblastoma. FRONTIERS IN ONCOLOGY 11. ScholarBank@NUS Repository. https://doi.org/10.3389/fonc.2021.709525
Abstract: Neuroblastoma is the commonest extracranial pediatric malignancy. With few recurrent single nucleotide variations (SNVs), mutation-based precision oncology approaches have limited utility, but its frequent and heterogenous copy number variations (CNVs) could represent genomic dependencies that may be exploited for personalized therapy. Patient-derived cell culture (PDC) models can facilitate rapid testing of multiple agents to determine such individualized drug-responses. Thus, to study the relationship between individual genomic aberrations and therapeutic susceptibilities, we integrated comprehensive genomic profiling of neuroblastoma tumors with drug screening of corresponding PDCs against 418 targeted inhibitors. We quantified the strength of association between copy number and cytotoxicity, and validated significantly correlated gene-drug pairs in public data and using machine learning models. Somatic mutations were infrequent (3.1 per case), but copy number losses in 1p (31%) and 11q (38%), and gains in 17q (69%) were prevalent. Critically, in-vitro cytotoxicity significantly correlated only with CNVs, but not SNVs. Among 1278 significantly correlated gene-drug pairs, copy number of GNA13 and DNA damage response genes CBL, DNMT3A, and PPM1D were most significantly correlated with cytotoxicity; the drugs most commonly associated with these genes were PI3K/mTOR inhibitor PIK-75, and CDK inhibitors P276-00, SNS-032, AT7519, flavopiridol and dinaciclib. Predictive Markov random field models constructed from CNVs alone recapitulated the true z-score-weighted associations, with the strongest gene-drug functional interactions in subnetworks involving PI3K and JAK-STAT pathways. Together, our data defined individualized dose-dependent relationships between copy number gains of PI3K and STAT family genes particularly on 17q and susceptibility to PI3K and cell cycle agents in neuroblastoma. Integration of genomic profiling and drug screening of patient-derived models of neuroblastoma can quantitatively define copy number-dependent sensitivities to targeted inhibitors, which can guide personalized therapy for such mutationally quiet cancers.
Source Title: FRONTIERS IN ONCOLOGY
URI: https://scholarbank.nus.edu.sg/handle/10635/218658
ISSN: 2234-943X
2234-943X
DOI: 10.3389/fonc.2021.709525
Appears in Collections:Staff Publications
Elements

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
Integrated Genomic Profiling and Drug Screening of Patient-Derived Cultures Identifies Individualized Copy Number-Dependent .pdf5.2 MBAdobe PDF

OPEN

NoneView/Download

Page view(s)

50
checked on Sep 29, 2022

Download(s)

3
checked on Sep 29, 2022

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.