In conclusion, we demonstrate that BRG1 immunohistochemistry is a useful second-line immunostain for the workup of undifferentiated, polyphenotypic or rhabdoid pediatric tumors that demonstrate retained expression of INI1.
With the widespread adoption of SMARCB1 immunohistochemistry, an increasing number of SMARCB1-deficient tumors outside of the MRT-AT/RT spectrum have been described.
These include gene fusions in vascular neoplasms (FOSB, CAMTA1 and TFE3), round cell sarcomas (BCOR, DUX4 and WT1), and fibroblastic/myofibroblastic tumors (STAT6, ALK and Pan-TRK); amplifications in well-differentiated and dedifferentiated liposarcomas (MDM2 and CDK4); and deletions in several aggressive neoplasms (SMARCB1 and SMARCA4).
Furthermore, using human ATRT cell lines, patient-derived cell culture, ex vivo patient-derived tumor, and orthotopic xenograft models, we show that MYC inhibition is a molecular vulnerability in SMARCB1-deleted tumors and that such inhibition effectively suppresses BMP and pluripotency-associated genomic programs, attenuates tumor cell self-renewal, promotes senescence, and inhibits ATRT tumor growth in vivo.
This unique entity is a candidate to be recognized and distinguished from other types of chordoma or SMARCB1-deficient tumors which are clinically important differential diagnoses that represent a challenging task for the pathologists.
Deficient INI1 protein expression by immunohistochemistry and homozygous loss of the SMARCB1 gene by chromosomal microarray analysis ultimately justified this tumor's designation as ES.
The concept that SNF5 is a coactivator for MYC, however, is at odds with its role as a tumor-suppressor, and with observations that loss of SNF5 leads to activation of MYC target genes.
Tumors in the 3 subsets with different FISH findings largely exhibited similar clinicopathologic features, however, homozygous SMARCB1 deletion was found to show a significant association with the solid growth pattern, whereas tumors dominated by reticular/cribriform growth were enriched for SMARCB1 translocation.
The spectrum of INI1-negative tumors includes a wide variety of neoplasms that occur over a wide age range, are variably aggressive, and have a variable rhabdoid component on histopathologic evaluation.
Notably, activation of an embryonic stem cell (ESC)-like signature confers a rhabdoid histology in SMARCB1-deficient NPLC-derived tumors and causes a poor prognosis.
All tumors were associated with normal or low serum alpha fetoprotein levels, and showed an absence of immunohistochemical staining of hepatocellular markers (Hep-par1, Arginase) and loss of INI1 staining.
Definite histological diagnosis of the extradural tumor was difficult; however, a metastatic lesion in the rib showed a proliferation of INI1/SMARCB1-negative spindle and rhabdoid cells, indicating the tumor was MRT.
Collectively, these findings highlight tumor suppressor role of SMARCB1 and illustrate SWI/SNF<sup>Δ</sup> function in maintaining an oncogenic gene expression program in AML.<b>Implications:</b> Loss of SMARCB1 in AML associates with SWI/SNF<sup>Δ</sup> nucleation, which in turn promotes Rac GTPase <i>GEF</i> expression, Rac activation, migration, and survival of AML cells, highlighting SWI/SNF<sup>Δ</sup> downstream signaling as important molecular regulator in AML.<i></i>.
Pathological examination demonstrated a dimorphic tumor containing a spindle-pleomorphic component reminiscent of PXA and a rhabdoid component with INI1 loss showing features of AT/RT.
The human tumor suppressor SMARCB1/INI1/SNF5/BAF47 (SNF5) is a core subunit of the multi-subunit ATP-dependent chromatin remodeling complex SWI/SNF, also known as Brahma/Brahma-related gene 1 (BRM/BRG1)-associated factor (BAF).
The most commonly mutated oncogenes included KRAS (19%), PIK3CA (16%), EGFR (5%), BRAF (3%) and KIT (3%); while the most frequently mutated tumor suppressor genes included TP53 (40%), SMARCB1 (12%), APC (8%), PTEN (6%) and SMAD4 (5%).