Bengul Gokbayrak

Prognostic values of molecular subtypes and SWI/SNF protein expression in de‐differentiated/undifferentiated endometrial carcinoma

AimsClassification and risk stratification of endometrial carcinoma (EC) has transitioned from histopathological features to molecular classification, e.g. the ProMisE classifier, identifying four prognostic subtypes: POLE mutant (POLEmut) with almost no recurrence or disease‐specific death events, mismatch repair deficient (MMRd) and no specific molecular profile (NSMP), with intermediate outcome and p53 abnormal (p53abn) with poor outcomes. However, the applicability of molecular classification is unclear in rare but aggressive histotypes of EC, e.g. de‐differentiated and undifferentiated endometrial cancers (DD/UDEC). Here, we aim to assembled a cohort of DD/UDEC from a single institution and analysed the prognostic significance of ProMisE molecular subtypes and the expression of SWItch/sucrose non‐fermentable (SWI/SNF) chromatin remodelling complex members, previously implicated in the pathogenesis of DD/UDEC.Methods and resultsWe accrued 88 DD/UDEC cases, assessed POLE status by Sanger sequencing and performed immunohistochemistry for p53, mismatch repair and SWI/SNF proteins on the tissue microarrays assembled. Assignment of molecular subtypes was possible in 80 tumours; POLE sequencing failed in the remaining eight cases. There were 12 (15%) POLEmut, 44 (55%) MMRd, 14 (17.5%) p53abn and 10 (12.5%) NSMP DD/UDEC. POLEmut DD/UDECs had excellent outcomes, but the other three molecular subtypes all had poor outcomes, with no significant differences among them. The loss of one or more SWI/SNF proteins [AT‐rich interactive domain‐containing protein 1A (ARID1A), ARID1B, SWI/SNF‐related, matrix‐associated, actin‐dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), SMARCA2], observed in 66% (55 of 83) cases, was not of prognostic significance.ConclusionsThese results indicate that all molecular subtypes of DD/UDEC except POLEmut behave in an aggressive fashion. Further study is needed to determine whether these molecular alterations can be targeted with adjuvant therapy, in order to improve outcomes of patients with DD/UDEC.

Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in dedifferentiated endometrial carcinomas

The mammalian (m)SWI/SNF family of chromatin remodelers govern cell type-specific chromatin accessibility and gene expression and assemble as three distinct complexes: canonical BRG1-associated or BRM-associated factor (cBAF), poly(bromo)-associated BAF (PBAF) and noncanonical BAF (ncBAF). ARID1A and ARID1B are paralog subunits that specifically nucleate the assembly of cBAF complexes and are frequently co-mutated in highly aggressive dedifferentiated or undifferentiated endometrial carcinomas (DDEC/UECs). Here in cellular models and primary human tumors, we find that ARID1A and/or ARID1B (ARID1A/B) deficiency-mediated cBAF loss results in increased ncBAF and PBAF biochemical abundance and chromatin-level functions to maintain the DDEC oncogenic state. Furthermore, treatment with clinical-grade SMARCA4 and/or SMARCA2 ATPase inhibitors markedly attenuates DDEC cell proliferation and tumor growth in vivo and synergizes with carboplatin-based chemotherapy to extend survival. These findings reveal the oncogenic contributions of shifted mSWI/SNF family complex stoichiometry and resulting gene-regulatory dysregulation and suggest therapeutic utility of mSWI/SNF small molecule inhibitors in DDEC/UECs and other cBAF-disrupted cancer types.