Abstract

Several aggressive pediatric cancers harbor alterations in SMARCB1, including rhabdoid tumors, epithelioid sarcoma, and chordoma. As tumor profiling has become more routine in clinical care, we investigated the relationship between SMARCB1 genetic variants identified by next-generation sequencing (NGS) and INI1 protein expression. Therapeutic approaches for INI1-deficient tumors are limited. Early reports suggest a potential role for immune checkpoint inhibition in these patients. Thus, we also investigated PD-L1 and CD8 expression in INI1-negative pediatric brain and solid tumors. We performed immunohistochemistry (IHC) for INI1 and immune markers (PD-L1, CD8, and CD163) and NGS on tumor samples from 43 pediatric patients who had tumors with INI1 loss on previous IHC or SMARCB1 genomic alterations on prior somatic sequencing. SMARCB1 two-copy deletions and inactivating mutations on NGS were associated with loss of INI1 protein expression. Single-copy deletion of SMARCB1 was not predictive of INI1 loss in tumor histologies not known to be INI1-deficient. In the 27 cases with INI1 loss and successful tumor sequencing, 24 (89%) had a SMARCB1 alteration detected. In addition, 47% (14/30) of the patients with INI1-negative tumors had a tumor specimen that was PD-L1 positive and 60% (18/30) had positive or rare CD8 staining. We report on 3 patients with INI1-negative tumors with evidence of disease control on immune checkpoint inhibitors. A significant proportion of the INI1-negative tumors express PD-L1, and PD-L1 positivity was associated with extracranial tumor site. These results suggest that clinical trials of immune checkpoint inhibitors are warranted in INI1-negative pediatric cancers.

Highlights

  • SMARCB1 two-copy deletions and inactivating mutations on next-generation sequencing (NGS) were associated with loss of INI1 protein expression

  • A significant proportion of the INI1-negative tumors express PD-L1, and PD-L1 positivity was associated with extracranial tumor site

  • These results suggest that clinical trials of immune checkpoint inhibitors are warranted in INI1-negative pediatric cancers

Read more

Summary

Introduction

Multiple aggressive pediatric cancers are characterized by alterations in SMARCB1, which is a core subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex [1]. Inactivation of the SMARCB1 gene and subsequent loss of INI1 protein expression is well described in several tumor types including rhabdoid tumors, epithelioid sarcoma, and chordoma [2,3,4,5,6,7,8]. These rare tumor diagnoses are associated with a dismal prognosis, in the relapsed or refractory setting, and few novel treatment options are available [9,10,11,12,13,14]. Differentiated chordomas with loss of INI1 expression are rare pediatric tumors, which have been reported more recently and are associated with a dismal prognosis [4, 19]

Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call