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

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. GreggNir Peled, Ethan S. Sokol, Siraj M. Ali

Research output: Contribution to journalArticlepeer-review

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 NSCLC–NOS (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.

Original languageEnglish (US)
Article number101184
JournalTranslational Oncology
Volume14
Issue number10
DOIs
StatePublished - Oct 2021

Keywords

  • BRD4
  • BRD4-NUT
  • Checkpoint inhibitor
  • NUT carcinoma
  • NUT midline carcinoma
  • PD-L1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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