SMARCA4 inactivation defines a subset of undifferentiated uterine sarcomas with rhabdoid and small cell features and germline mutation association

Lin, Douglas I.; Allen, Justin; Hecht, Jonathan L.; Killian, Jonathan Keith; Ngo, Nhu; Edgerly, Claire; Severson, Eric Allan; Ali, Siraj M.; Erlich, Rachel; Ramkissoon, Shakti; Vergilio, Jo‐Anne; Ross, Jeffrey S.; Elvin, Julia A.

doi:10.1038/s41379-019-0303-z

Cited by 57 publications

(64 citation statements)

References 37 publications

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“…SMARCA4 expression is absent in these tumours . While EMA, CAM5.2 and CD10 may be focally positive, pan‐cytokeratin, claudin 4, desmin, SMA, H‐caldesmon, ER and PR are largely negative, and DNA mismatch repair protein expression is retained .…”

Section: Uusmentioning

confidence: 91%

“…Loss of SMARCA4 expression through truncating mutations or deep deletions of the SWI/SNF‐related, matrix‐associated, actin‐dependent regulator of chromatin, subfamily A, member 4 ( SMARCA4 ) gene have recently been detected in a subset of UUS . These tumours share overlapping clinicopathological and genetic features with other SMARCA4‐deficient cancers, such as ovarian small cell carcinoma of hypercalcaemic type, atypical teratoid/rhabdoid tumours and thoracic sarcomas .…”

Section: Uusmentioning

confidence: 99%

“…Vaguely nested architecture, spindled morphology, focal myxoid matrix and entrapped endometrioid glands may be seen. Extensive lymphovascular invasion, necrosis and infiltrative growth are common …”

Section: Uusmentioning

confidence: 99%

“…SMARCA4‐deficient UUS mainly occur in premenopausal women with a median age of 48 (range = 25–70) years and are clinically aggressive . In one study, all five died of disease at 1, 4, 7, 9 and 43 months after initial presentation .…”

Section: Uusmentioning

confidence: 99%

“…Loss of SMARCA4 expression through truncating mutations or deep deletions of the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) gene have recently been detected in a subset of UUS. 33,34 These tumours share overlapping clinicopathological and genetic features with other SMARCA4-deficient cancers, such as ovarian small cell carcinoma of hypercalcaemic type, atypical teratoid/rhabdoid tumours and thoracic sarcomas. [35][36][37] SMARCA4-deficient UUS are large bulky masses involving the endomyometrium that are composed of sheets of large discohesive and uniformly atypical epithelioid cells with eccentric round to oval nuclei, vesicular chromatin, prominent nucleoli and scant to abundant eosinophilic cytoplasm.…”

Section: Uusmentioning

confidence: 99%

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Uterine mesenchymal tumours: recent advances

Boroujeni

Chiang

2019

Histopathology

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Almost all uterine mesenchymal tumours have been historically classified as either smooth muscle or endometrial stromal neoplasms. Recent application of molecular techniques has identified numerous lesions with distinctive genetic abnormalities and clinicopathological characteristics. Newly discovered uterine sarcoma subtypes include high‐grade endometrial stromal sarcomas with BCOR genetic abnormalities, fibrosarcoma‐like uterine sarcomas with NTRK rearrangements and COL1A–PDGFRB fusions, as well as undifferentiated uterine sarcomas with SMARCA4 mutations. Novel PLAG1 and PGR fusions have been identified in subsets of myxoid and epithelioid leiomyosarcomas. Some uterine tumours resembling ovarian sex‐cord tumour harbour GREB1 and ESR1 rearrangements. Histological and immunophenotypical features as well as underlying genetic abnormalities defining these lesions are discussed.

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Section: Uusmentioning

confidence: 91%

Section: Uusmentioning

confidence: 99%

Section: Uusmentioning

confidence: 99%

Section: Uusmentioning

confidence: 99%

Section: Uusmentioning

confidence: 99%

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Uterine mesenchymal tumours: recent advances

Boroujeni

Chiang

2019

Histopathology

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The variability of SMARCA4‐related Coffin–Siris syndrome: Do nonsense candidate variants add to milder phenotypes?

Liu

Ahrens‐Nicklas

Baker

et al. 2020

American J of Med Genetics Pt A

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SMARCA4 encodes a central ATPase subunit in the BRG1‐/BRM‐associated factors (BAF) or polybromo‐associated BAF (PBAF) complex in humans, which is responsible in part for chromatin remodeling and transcriptional regulation. Variants in this and other genes encoding BAF/PBAF complexes have been implicated in Coffin–Siris Syndrome, a multiple congenital anomaly syndrome classically characterized by learning and developmental differences, coarse facial features, hypertrichosis, and underdevelopment of the fifth digits/nails of the hands and feet. Individuals with SMARCA4 variants have been previously reported and appear to display a variable phenotype. We describe here a cohort of 15 unrelated individuals with SMARCA4 variants from the Coffin–Siris syndrome/BAF pathway disorders registry who further display variability in severity and degrees of learning impairment and health issues. Within this cohort, we also report two individuals with novel nonsense variants who appear to have a phenotype of milder learning/behavioral differences and no organ‐system involvement.

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SWI/SNF‐deficiency defines highly aggressive undifferentiated endometrial carcinoma

Tessier‐Cloutier

Coatham

Carey

et al. 2020

The Journal of Pathology CR

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Dedifferentiated/undifferentiated endometrial carcinoma (DDEC/UEC) is an endometrial cancer characterized by the presence of histologically undifferentiated carcinoma. Genomic inactivation of core switch/sucrose nonfermentable (SWI/SNF) complex proteins was recently identified in approximately two‐thirds of DDEC/UEC. The aim of this study was to delineate the clinical behavior of SWI/SNF‐deficient DDEC/UEC in comparison to SWI/SNF‐intact DDEC/UEC. The study cohort consisted of 56 SWI/SNF‐deficient DDEC/UEC (2 POLE‐mutated), which showed either SMARCA4 (BRG1) loss, ARID1A/1B co‐loss, or SMARCB1 (INI1) loss in the undifferentiated tumor, and 26 SWI/SNF‐intact DDEC/UEC (4 POLE‐mutated). The average age at diagnosis was 61 years for patients with SWI/SNF‐deficient tumors and 64 years for SWI/SNF‐intact tumors. Mismatch repair (MMR) protein deficiency was seen in 66% of SWI/SNF‐deficient and 50% of SWI/SNF‐intact tumors. At initial presentation, 55% of patients with SWI/SNF‐deficient tumors had extrauterine disease spread in contrast to 38% of patients with SWI/SNF‐intact tumors. The 2‐year disease specific survival (DSS) for stages I and II disease was 65% for SWI/SNF deficient tumors relative to 100% for SWI/SNF‐intact tumors (p = 0.042). For patients with stages III and IV disease, the median survival was 4 months for SWI/SNF‐deficient tumors compared to 36 months for SWI/SNF‐intact tumors (p = 0.0003). All six patients with POLE‐mutated tumors, including one with stage IV SWI/SNF‐deficient tumor were alive with no evidence of disease. Among the patients with advanced stage SWI/SNF‐deficient tumors, 68% (21 of 31) received adjuvant or neoadjuvant chemotherapy (platinum/taxane‐based) and all except the patient with a POLE‐mutated tumor (20 of 21) experienced disease progression either during chemotherapy or within 4 months after its completion. These findings show that core SWI/SNF‐deficiency defines a highly aggressive group of undifferentiated cancer characterized by rapid disease progression that is refractory to conventional platinum/taxane‐based chemotherapy. This underscores the importance of accurate clinical recognition of this aggressive tumor and the need to consider alternative systemic therapy for these tumors.

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SMARCA4 inactivation defines a subset of undifferentiated uterine sarcomas with rhabdoid and small cell features and germline mutation association

Cited by 57 publications

References 37 publications

Uterine mesenchymal tumours: recent advances

Uterine mesenchymal tumours: recent advances

The variability of SMARCA4‐related Coffin–Siris syndrome: Do nonsense candidate variants add to milder phenotypes?

SWI/SNF‐deficiency defines highly aggressive undifferentiated endometrial carcinoma

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