학술논문
Genomic profiling of solid tumors harboring BRD4-NUT and response to immune checkpoint inhibitors
Document Type
article
Author
Jonathan W. Riess; Shaila Rahman; Waleed Kian; Claire Edgerly; Andreas M. Heilmann; Russell Madison; Shakti H. Ramkissoon; Shai Shlomi Klaitman; Jon H. Chung; Sally E. Trabucco; Dexter X. Jin; Brian M. Alexander; Samuel J. Klempner; Lee A. Albacker; Garrett M. Frampton; Laila C. Roisman; Vincent A. Miller; Jeffrey S. Ross; Alexa B. Schrock; Jeffrey P. Gregg; Nir Peled; Ethan S. Sokol; Siraj M. Ali
Source
Translational Oncology, Vol 14, Iss 10, Pp 101184- (2021)
Subject
Language
English
ISSN
1936-5233
Abstract
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.