Genomic profiling of solid tumors harboring BRD4-NUT and response to immune checkpoint inhibitors.

Autor:	Riess JW; UC Davis Comprehensive Cancer Center, Sacramento, CA, United States., Rahman S; EQRx Inc, Cambridge, MA, United States., Kian W; Legacy Heritage Oncology Center/Larry Norton Cancer Institute, Soroka Medical Center, Ben-Gurion University, Beer Sheva, Israel., Edgerly C; Foundation Medicine, Cambridge, MA, United States., Heilmann AM; Foundation Medicine, Cambridge, MA, United States., Madison R; Foundation Medicine, Cambridge, MA, United States., Ramkissoon SH; Foundation Medicine, Cambridge, MA, United States., Klaitman SS; Legacy Heritage Oncology Center/Larry Norton Cancer Institute, Soroka Medical Center, Ben-Gurion University, Beer Sheva, Israel., Chung JH; Foundation Medicine, Cambridge, MA, United States., Trabucco SE; Foundation Medicine, Cambridge, MA, United States., Jin DX; Foundation Medicine, Cambridge, MA, United States., Alexander BM; Foundation Medicine, Cambridge, MA, United States., Klempner SJ; Massachusetts General Hospital, Boston, MA, United States., Albacker LA; Foundation Medicine, Cambridge, MA, United States., Frampton GM; Foundation Medicine, Cambridge, MA, United States., Roisman LC; Legacy Heritage Oncology Center/Larry Norton Cancer Institute, Soroka Medical Center, Ben-Gurion University, Beer Sheva, Israel., Miller VA; Foundation Medicine, Cambridge, MA, United States., Ross JS; Foundation Medicine, Cambridge, MA, United States; SUNY Upstate Medical University., Schrock AB; Foundation Medicine, Cambridge, MA, United States., Gregg JP; UC Davis Comprehensive Cancer Center, Sacramento, CA, United States; Foundation Medicine, Cambridge, MA, United States., Peled N; Legacy Heritage Oncology Center/Larry Norton Cancer Institute, Soroka Medical Center, Ben-Gurion University, Beer Sheva, Israel., Sokol ES; Foundation Medicine, Cambridge, MA, United States., Ali SM; Foundation Medicine, Cambridge, MA, United States. Electronic address: smalimdphd@gmail.com.
Jazyk:	angličtina
Zdroj:	Translational oncology [Transl Oncol] 2021 Oct; Vol. 14 (10), pp. 101184. Date of Electronic Publication: 2021 Jul 29.
DOI:	10.1016/j.tranon.2021.101184
Abstrakt:	Background: The translocation t(15:19) produces the oncogenic BRD4-NUT fusion which is pathognomonic for NUT carcinoma (NC), which is a rare, but extremely aggressive solid tumor. Comprehensive genomic profiling (CGP) by hybrid-capture based next generation sequencing of 186+ genes of a cohort of advanced cancer cases with a variety of initial diagnoses harboring BRD4-NUT may shed further insight into the biology of these tumors and possible options for targeted treatment. Case Presentation: Thirty-one solid tumor cases harboring a BRD4-NUT translocation are described, with only 16% initially diagnosed as NC and the remainder carrying other diagnoses, most commonly NSCLCNOS (22%) and lung squamous cell carcinoma (NSCLC-SCC) (16%). The cohort was all microsatellite stable and harbored a low Tumor Mutational Burden (TMB, mean 1.7 mut/mb, range 0-4). In two index cases, patients treated with immune checkpoint inhibitors (ICPI) had unexpected partial or better responses of varying duration. Notably, four cases - including the two index cases - were negative for PD-L1 expression. Neo-antigen prediction for BRD4-NUT and then affinity modeling of the peptide-MHC (pMHC) complex for an assessable index case predicted very high affinity binding, both on a ranked (99.9%) and absolute (33 nM) basis. Conclusions: CGP identifies BRD4-NUT fusions in advanced solid tumors which carry a broad range of initial diagnoses and which should be re-diagnosed as NC per guidelines. A hypothesized mechanism underlying responses to ICPI in the low TMB, PD-L1 negative index cases is the predicted high affinity of the BRD4-NUT fusion peptide to MHC complexes. Further study of pMHC affinity and response to immune checkpoint inhibitors in patients with NC harboring BRD4-NUT is needed to validate this therapeutic hypothesis. (Copyright © 2021. Published by Elsevier Inc.)
Databáze:	MEDLINE
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