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dc.contributor.authorShaheen, M.F.
dc.contributor.authorTse, J.Y.
dc.contributor.authorSokol, E.S.
dc.contributor.authorMasterson, M.
dc.contributor.authorBansal, P.
dc.contributor.authorRabinowitz, I.
dc.contributor.authorTarleton, C.A.
dc.contributor.authorDobroff, A.S.
dc.contributor.authorSmith, T.L.
dc.contributor.authorBocklage, T.J.
dc.contributor.authorMannakee, B.K.
dc.contributor.authorGutenkunst, R.N.
dc.contributor.authorBischoff, J.
dc.contributor.authorNess, S.A.
dc.contributor.authorRiedlinger, G.M.
dc.contributor.authorGroisberg, R.
dc.contributor.authorPasqualini, R.
dc.contributor.authorGanesan, S.
dc.contributor.authorArap, W.
dc.date.accessioned2022-08-01T20:17:51Z
dc.date.available2022-08-01T20:17:51Z
dc.date.issued2022
dc.identifier.citationShaheen, M. F., Tse, J. Y., Sokol, E. S., Masterson, M., Bansal, P., Rabinowitz, I., Tarleton, C. A., Dobroff, A. S., Smith, T. L., Bocklage, T. J., Mannakee, B. K., Gutenkunst, R. N., Bischoff, J., Ness, S. A., Riedlinger, G. M., Groisberg, R., Pasqualini, R., Ganesan, S., & Arap, W. (2022). Genomic landscape of lymphatic malformations: A case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial. ELife, 11.
dc.identifier.issn2050-084X
dc.identifier.pmid35787784
dc.identifier.doi10.7554/elife.74510
dc.identifier.urihttp://hdl.handle.net/10150/665484
dc.description.abstractBackground: 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 using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel. Results: These LMs had low mutational burden with hotspot PIK3CA mutations (n = 20) and NRAS (n = 5) 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 LM harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable radiologic complete response, as defined in RECIST1.1, to the PI3Kα inhibitor alpelisib within the context of a personal-ized 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 to alpelisib treatment in vitro, which was demonstrated by a concentration-dependent drop in measurable imped-ance, an assessment of cell status. Conclusions: Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations. © Shaheen, Tse et al.
dc.language.isoen
dc.publishereLife Sciences Publications Ltd
dc.rightsCopyright © Shaheen, Tse et al. This article is distributed under the terms of the Creative Commons Attribution License.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleGenomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial
dc.typeArticle
dc.typetext
dc.contributor.departmentUniversity of Arizona Cancer Center
dc.contributor.departmentDivision of Hematology/ Oncology, Department of Medicine, University of Arizona College of Medicine
dc.contributor.departmentDepartment of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona
dc.contributor.departmentDepartment of Molecular and Cellular Biology, College of Science, University of Arizona
dc.identifier.journaleLife
dc.description.noteOpen access journal
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
dc.eprint.versionFinal published version
dc.source.journaltitleeLife
refterms.dateFOA2022-08-01T20:17:51Z


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Copyright © Shaheen, Tse et al. This article is distributed under the terms of the Creative Commons Attribution License.
Except where otherwise noted, this item's license is described as Copyright © Shaheen, Tse et al. This article is distributed under the terms of the Creative Commons Attribution License.