SMARCB1/INI1-deficient tumors of adulthood

The SMARCB1/INI1 gene was first discovered in the mid-1990s, and since then it has been revealed that loss of function mutations in this gene result in aggressive rhabdoid tumors. Recently, the term “rhabdoid tumor” has become synonymous with decreased SMARCB1/INI1 expression. When genetic aberrations in the SMARCB1/INI1 gene occur, the result can cause complete loss of expression, decreased expression, and mosaic expression. Although SMARCB1/INI1-deficient tumors are predominantly sarcomas, this is a diverse group of tumors with mixed phenotypes, which can often make the diagnosis challenging. Prognosis for these aggressive tumors is often poor. Moreover, refractory and relapsing progressive disease is common. As a result, accurate and timely diagnosis is imperative. Despite the SMARCB1/INI1 gene itself and its implications in tumorigenesis being discovered over two decades ago, there is a paucity of rhabdoid tumor cases reported in the literature that detail SMARCB1/INI1 expression. Much work remains if we hope to provide additional therapeutic strategies for patients with aggressive SMARCB1/INI1-deficient tumors.


History of the SMARCB1/INI1
Gene SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), also known as integrase interactor 1 (INI1), is a crucial component of a chromatin-remodeling protein complex. SMARCB1/INI1 was first identified in yeast in the late 1980s 1 . By 1994, its human homologue was isolated in fibroblast cells 2,3 . Subsequent molecular investigations showed this nuclear protein complex enhances DNA transcription by interactions with HIV-1 integrase 2 . Nuclear SMARCB1/INI1 exists ubiquitously in all normal cells, and acts as a tumor suppressor gene 4 . It was revealed in the early 2000s by studies in mice that biallelic knockout of the SMARCB1/INI1 gene resulted in early lethality 5 . Mice with heterozygous loss before birth, or who had later conditional single-allele knockout after birth, of SMARCB1/INI1 developed aggressive rhabdoid tumors 6-8 . Since its discovery, much work has revealed this chromatin-remodeling protein has crucial roles in multiple signaling pathways that function to suppress tumorigenesis and tumor growth 9 . Although these pathways are highly complex, the development and use of targeted anti-cancer therapies has practically become ubiquitous for nearly all solid tumors. Thus, continued investigations are needed if we hope to provide additional therapeutic strategies for patients with aggressive SMARCB1/INI1-deficient tumors 9 .
Interestingly, the genetic signatures of SMARCB1/INI1-deficient tumors are far from monotonous. Three distinct patterns of abnormal SMARCB1/INI1 gene expression have been identifiedreduced, complete loss, and mosaic 9 .

Epidemiology, clinical, prognosis
Complete loss of SMARCB1/INI1 expression has been linked to a number of pediatric and adult sarcomas ( Aside from SMARCB1/INI1-deficient tumors sharing an aberration in the same gene, the relationship between these malignancies remains unclear. Following diagnosis in any age or organ, nearly all SMARCB1/INI1-deficient malignancies characteristically follow an aggressive clinical pattern and prognosis is often poor (Table 1). Survival rates are often reportedly low, but they may not be accurate given low rates of incidence, and considerations for newer treatments. Also, survival can be highly dependent on surgical intervention and completeness of tumor resection, especially for chordomas. GIST are the most common sarcomas of the gastrointestinal (GI) tract. They commonly develop in the sixth decade of life and have no gender predominance 35 . Following the diagnosis of a GIST, survival rates are highly variable and depend on specific biologic characteristics of the tumor, the type of treatment, and the risk of post-treatment recurrence 36 .

Challenges in retrospective data collection for adult cases of SMARCB1/INI-deficient tumors
Recently, the term "rhabdoid tumor" has become synonymous with tumors that harbor loss of function mutations in the SMARCB1/ INI1 gene 56 . We reviewed the literature and found a paucity of cases reporting SMARCB1/INI1 genetic aberrations in adult patients with sarcomas. A total of 450 cases of rare sarcomas were found to be described in single case reports, case series, or systematic reviews published between the years 2000 -2020 ( We located 25 cases of adult SMARCB1/INI1-deficient sarcomas that were described in 18 reports (Table 3) 42,50,93-108 . Median age at the time of diagnosis was 36 years old. A male predominance was mildly observed (14 cases, 56%), which is consistent with other larger reviews. Presentation in the head and neck (e.g. brain, eye, nose, and scalp) occurred more frequently (6 cases, 24%). No descriptive data analysis was performed to determine if our observations were significant. The majority of reports were originally described as proximal epithelioid sarcoma, but overall these remained a morphologically diverse group of cases that also included rhabdoid and mixed phenotypes.

Treatment
Prior to, and still after, the discovery that SMARCB1/ INI1-deficient tumors contribute to the large majority of soft tissue sarcomas, systemic cytotoxic agents have been used to treat this diverse group of neoplasms. Doxorubicin and ifosfamide have remained the mainstay of first-line treatment for advanced disease for the last few decades. Currently, the most widely used regimen for soft tissue sarcomas is termed AIM, which includes Adriamycin (doxorubicin) plus ifosfamide and mesna [109][110][111] . Therapies such as these, and other cytotoxic agents, exhibit intermediate to improved anti-cancer activity, and prolong survival in metastatic soft tissue sarcoma (Table 4). However, refractory or progressive disease can occur. With the hopes of improving outcomes in patients who develop aggressive sarcomas, multiple new therapies are being introduced. Olaratumab, a monoclonal antibody that targets platelet-derived growth factor alpha and beta (PDGFRA/B), has been approved for first-line therapy in combination with doxorubicin due to improved progression and overall survival in sarcoma patients 112 . The use of tyrosine kinase-inhibitors (TKIs) has transformed the treatment of advanced GIST. Imatinib, a TKI, as monotherapy is now approved for upfront treatment of metastatic GIST due to improved side effect profiles and outcomes in these patients [113][114][115] . Given its mechanism of action, imatinib is also approved for first-line treatment of the fibrosarcomatous variant of dermatofibrosarcoma protuberans 116,117 .
Additional TKIs have recently been introduced, with clinical trial data showing promise for their use in sarcomas. Sunitinib and regorafenib significantly improve overall survival in imatinibresistant GIST patients 118 . Pazopanib, a TKI that targets angiogenesis by inhibiting vascular endothelial growth factor receptor, PDGFRA/B, and KIT proto-oncogene, has been shown to improve progression free survival in certain histologic types of sarcoma. This led to its approval for advanced, refractory non-lipomatous sarcoma 119,120 . Alveolar sarcomas appear to respond well to anti-angiogenetic sorafenib and cediranib 121,122 . In phase II studies tivozanib, which mechanism of action mimics pazopanib, exhibits promising anti-cancer activity in metastatic or nonresectable soft tissue sarcomas 123 .
Recently, much work studying the complex mechanisms involved in sarcoma tumorigenesis has revealed the potential for numerous new drug targets. Targeting the mammalian target of rapamycin (mTOR) signaling pathway by serine/threonine kinase inhibition has been widely studied. However, thus far either only equivocal or minor benefits have been shown with the administration of these agents 124 . In contrast, phase II trial data is reassuring for the future use of palbociclib, a cyclin-dependent kinase 4 and 6 inhibitor approved in breast cancer, for liposarcoma 125,126 .
Preliminary data from pre-clinical and phase I/II trials is encouraging for small molecule inhibitors, such as with Murine double minute 2 (MDM2)-antagonists, histone deacetylase inhibitors, and histone methylation inhibitors 124 . A possible breakthrough in small molecular inhibition is represented by the recent discovery of a specific methyltransferase termed Enhancer of zeste homolog 2 (EZH2) is upregulated in SMARCB1/ INI1-deficient tumors 127 . Given the defining characteristic of SMARCB1/INI1 deficiency in the nearly all soft tissue sarcomas, tazemetostat has emerged as an intriguing compound for its direct inhibition of histone-lysine N-methyltransferase EZH2 127,138 . Another new agent that hopes to improve outcomes for patients with these rare and aggressive SMARCB1/ INI1-deficient rhabdoid sarcomas comes from the proteasome inhibitor drug class. Ixazomib selectively targets proteasomes involved in protein anabolism and cellular apoptosis, whose activity is directly enhanced by the transcription factor MYC in SMARCB1/INI1-deficient states. Currently, ixazomib plus gemcitabine and doxorubicin is being studied in the phase II trial setting for renal medullary carcinoma 139,140 .

Data availability
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