@article{d7213e465cf9429792c2cd9f883f766a,
title = "Integrative Bayesian Analysis Identifies Rhabdomyosarcoma Disease Genes",
abstract = "Identifying oncogenic drivers and tumor suppressors remains a challenge in many forms of cancer, including rhabdomyosarcoma. Anticipating gene expression alterations resulting from DNA copy-number variants to be particularly important, we developed a computational and experimental strategy incorporating a Bayesian algorithm and CRISPR/Cas9 “mini-pool” screen that enables both genome-scale assessment of disease genes and functional validation. The algorithm, called iExCN, identified 29 rhabdomyosarcoma drivers and suppressors enriched for cell-cycle and nucleic-acid-binding activities. Functional studies showed that many iExCN genes represent rhabdomyosarcoma line-specific or shared vulnerabilities. Complementary experiments addressed modes of action and demonstrated coordinated repression of multiple iExCN genes during skeletal muscle differentiation. Analysis of two separate cohorts revealed that the number of iExCN genes harboring copy-number alterations correlates with survival. Our findings highlight rhabdomyosarcoma as a cancer in which multiple drivers influence disease biology and demonstrate a generalizable capacity for iExCN to unmask disease genes in cancer.",
keywords = "Bayesian algorithm, CRISPR/Cas9, childhood cancer, integrative genomic analysis, oncogene, rhabdomyosarcoma, tumor suppressor gene",
author = "Lin Xu and Yanbin Zheng and Jing Liu and Dinesh Rakheja and Sydney Singleterry and Laetsch, {Theodore W} and Shern, {Jack F.} and Javed Khan and Triche, {Timothy J.} and Hawkins, {Douglas S.} and Amatruda, {James F} and Skapek, {Stephen X}",
note = "Funding Information: We are grateful to M. DePlaza, J. Singh, and other members of the Skapek laboratory for technical assistance and helpful comments, to P. Leavey (UTSW) for comments on the manuscript, and to C. Liu and J. Mendell (UTSW) for advice and early technical assistance with CRISPR/Cas9 targeting. We acknowledge support from the Hyundai Hope on Wheels Foundation, the Wipe Out Kids{\textquoteright} Cancer Foundation, the Children's Cancer Fund, and the Patrick and Beatrice Haggerty Foundation, all of which were secured with assistance from the Children's Health Children's Medical Center Foundation, and from the Andrew McDonough B+ Foundation. Collection of expression and copy-number data in the COG dataset was supported by grants from the National Cancer Institute (U10CA098543 and U10CA098413). Work in the Skapek laboratory was also aided by grants from the Cancer Prevention and Research Institute of Texas (RP120685-P2) and the UTSW Harold C. Simmons Comprehensive Cancer Center from the National Cancer Institute (CA142543). Funding Information: We are grateful to M. DePlaza, J. Singh, and other members of the Skapek laboratory for technical assistance and helpful comments, to P. Leavey (UTSW) for comments on the manuscript, and to C. Liu and J. Mendell (UTSW) for advice and early technical assistance with CRISPR/Cas9 targeting. We acknowledge support from the Hyundai Hope on Wheels Foundation, the Wipe Out Kids{\textquoteright} Cancer Foundation, the Children{\textquoteright}s Cancer Fund, and the Patrick and Beatrice Haggerty Foundation, all of which were secured with assistance from the Children{\textquoteright}s Health Children{\textquoteright}s Medical Center Foundation , and from the Andrew McDonough B+ Foundation . Collection of expression and copy-number data in the COG dataset was supported by grants from the National Cancer Institute ( U10CA098543 and U10CA098413 ). Work in the Skapek laboratory was also aided by grants from the Cancer Prevention and Research Institute of Texas ( RP120685-P2 ) and the UTSW Harold C. Simmons Comprehensive Cancer Center from the National Cancer Institute ( CA142543 ). Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = jul,
day = "3",
doi = "10.1016/j.celrep.2018.06.006",
language = "English (US)",
volume = "24",
pages = "238--251",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}