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.

中文翻译：

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携带 BRD4-NUT 的实体瘤的基因组分析和对免疫检查点抑制剂的反应

背景

易位 t(15:19) 产生致癌 BRD4-NUT 融合，这是 NUT 癌 (NC) 的特征，这是一种罕见但极具侵袭性的实体瘤。综合基因组分析 (CGP) 通过基于杂交捕获的下一代测序，对一系列具有各种初始诊断的 BRD4-NUT 晚期癌症病例的 186 多个基因进行，可能会进一步深入了解这些肿瘤的生物学和靶向靶向治疗的可能选择。治疗。

案例展示

描述了 31 例携带 BRD4-NUT 易位的实体瘤病例，其中只有 16% 最初被诊断为 NC，其余的携带其他诊断，最常见的是 NSCLC NOS (22%) 和肺鳞状细胞癌 (NSCLC-SCC) (16 %）。该队列都是微卫星稳定的，并且具有较低的肿瘤突变负担（TMB，平均 1.7 mut/mb，范围 0-4）。在两个指标病例中，接受免疫检查点抑制剂 (ICPI) 治疗的患者出现了不同持续时间的意外部分或更好的反应。值得注意的是，包括两个指示病例在内的四个病例对 PD-L1 表达呈阴性。BRD4-NUT 的新抗原预测，然后是肽-MHC (pMHC) 复合物的亲和力建模，用于可评估的指标案例预测非常高的亲和力结合，无论是在排名 (99.9%) 还是绝对 (33 nM) 基础上。

结论

CGP 在晚期实体瘤中识别 BRD4-NUT 融合，这些融合具有广泛的初始诊断范围，并且应根据指南重新诊断为 NC。在低 TMB、PD-L1 阴性指数病例中对 ICPI 反应的一个假设机制是预测的 BRD4-NUT 融合肽对 MHC 复合物的高亲和力。需要对携带 BRD4-NUT 的 NC 患者的 pMHC 亲和力和对免疫检查点抑制剂的反应进行进一步研究，以验证这一治疗假设。