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

Matan Thangavelu¹  Giridharan Periyasamy¹  Qiao Fan²  Seyed Ehsan Saffari²  Prasad Iyer³  Enrica E. K. Tan³  Shui Yen Soh³  Amos H. P. Loh⁴  Chik Hong Kuick⁵  Kenneth T. E. Chang⁵  Khurshid Merchant⁵  Zhi Xiong Chen⁶  N. Gopalakrishna Iyer⁷  Rachel L. Y. Wong⁸  Megan R. E. Wong⁹  Sheng Hui Tan⁹  Meng Kang Wong⁹ 

[1] Centre for High Throughput Phenomics (CHiP-GIS), Genome Institute of Singapore, Singapore, Singapore;Centre for Quantitative Medicine, Duke NUS Medical School, Singapore, Singapore;Department of Paediatric Subspecialties Haematology Oncology Service, KK Women’s and Children’s Hospital, Singapore, Singapore;Department of Paediatric Surgery, KK Women’s and Children’s Hospital, Singapore, Singapore;Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore, Singapore;Department of Physiology, National University of Singapore, Singapore, Singapore;Division of Medical Sciences, National Cancer Centre, Singapore, Singapore;Duke NUS Medical School, Singapore, Singapore;VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore, Singapore;

关键词: neuroblastoma;    patient-derived culture;    copy number variations (CNV);    Comprehensive genomic profiling (CGP);    PI3K - AKT pathway;    CDK (cyclin-dependent kinase);   

DOI  :  10.3389/fonc.2021.709525

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown