Genomic and immunologic characterization of INI1-deficient pediatric cancers

Suzanne J. Forrest, Alyaa Al-Ibraheemi, Duong Doan, Abigail Ward, Catherine M. Clinton, Juan Putra, R. Seth Pinches, Cigall Kadoch, Susan N. Chi, Steven G. du Bois, Patrick J. Leavey, Nicole R. Le Boeuf, Elizabeth Mullen, Natalie Collins, Alanna J. Church, Katherine A. Janeway

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)2882-2890
Number of pages9
JournalClinical Cancer Research
Issue number12
StatePublished - Jun 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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