Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial
Year: 2022
Type: article
Abstract: ABSTRACT Background Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases. Methods We examined the genomic landscape of a patient cohort of LMs (n=30 cases) that underwent comprehensive genomic profiling (CGP) using a large-panel next generation sequencing (NGS) assay. Immunohistochemical analyses were completed in parallel. Results These LMs had low mutational burden with hotspot PIK3CA mutations and NRAS mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal lymphatic malformation harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable complete response to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial ( NCT03941782 ). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive in vitro to alpelisib in a concentration-dependent manner. Conclusions Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations. Funding R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953. Clinical trial number NCT03941782
Source: eLife
DOI: 10.7554/elife.74510
Authors: Montaser F. Shaheen, Julie Y. Tse, Ethan S. Sokol, Margaret Masterson, Pranshu Bansal, Ian Rabinowitz, Christy A. Tarleton, Andrey S. Dobroff, Tracey L. Smith, Thèrése J. Bocklage, Brian K. Mannakee, Ryan N. Gutenkunst, Joyce E. Bischoff, Scott A. Ness, Gregory M. Riedlinger, Roman Groisberg, Renata Pasqualini, Shridar Ganesan, Wadih Arap
Institutions: University of Arizona, University of Arizona Cancer Center, Foundation Medicine (United States), Rutgers, The State University of New Jersey, Rutgers Cancer Institute, University of New Mexico, UNM Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Rutgers New Jersey Medical School, University of Kentucky, Markey Cancer Center, Boston Children's Hospital, Harvard University
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
OpenAlex ID: W4283820964