AUTHOR=Wong Rachel L. Y. , Wong Megan R. E. , Kuick Chik Hong , Saffari Seyed Ehsan , Wong Meng Kang , Tan Sheng Hui , Merchant Khurshid , Chang Kenneth T. E. , Thangavelu Matan , Periyasamy Giridharan , Chen Zhi Xiong , Iyer Prasad , Tan Enrica E. K. , Soh Shui Yen , Iyer N. Gopalakrishna , Fan Qiao , Loh Amos H. P. 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 JOURNAL=Frontiers in Oncology VOLUME=11 YEAR=2021 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.709525 DOI=10.3389/fonc.2021.709525 ISSN=2234-943X 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,