SWI/SNF Complex Mutations in Gynecologic Cancers: Molecular Mechanisms and Models

Abstract

The SWI/SNF (mating type SWItch/Sucrose NonFermentable) chromatin remodeling complexes interact with histones and transcription factors to modulate chromatin structure and control gene expression. These evolutionarily conserved multisubunit protein complexes are involved in regulating many biological functions, such as differentiation and cell proliferation. Genomic studies have revealed frequent mutations of genes encoding multiple subunits of the SWI/SNF complexes in a wide spectrum of cancer types, including gynecologic cancers. These SWI/SNF mutations occur at different stages of tumor development and are restricted to unique histologic types of gynecologic cancers. Thus, SWI/SNF mutations have to function in the appropriate tissue and cell context to promote gynecologic cancer initiation and progression. In this review, we summarize the current knowledge of SWI/SNF mutations in the development of gynecologic cancers to provide insights into both molecular pathogenesis and possible treatment implications for these diseases.

Keywords: ARID1A; DDEC; SCCOHT; SMARCA4; SWI/SNF; clear cell carcinoma of the ovary; dedifferentiated endometrial carcinoma; small cell carcinoma of the ovary hypercalcemic type.

Figure 1.. Scheme of three classes of SWI/SNF complex.

For each class, there are distinct SWI/SNF complexes containing unique combination of mutually exclusive subunits of several components.

Figure 2.. SWI/SNF mutations and protein loss in gynecologic cancers.

Specific mutations of the SWI/SNF complex were indicated for each gynecologic cancer described. Representative H&E and IHC staining of relevant SWI/SNF subunits were shown.

Figure 3.. A hypothetic model of SCCOHT development.

SCCOHT may arise from progenitor cells of the ovary that hold the potential to undergo differentiation into neuronal lineages, in which SMARCA4 inactivation causes hyperactivation of polycomb repressive complex 2 (PRC2), reduces chromosomal accessibility of the promoters and/or enhancers of genes that promote differentiation, and drive the development of poorly differentiated cancer. Alternatively, SMARCA4 loss in sympathetic neurons of the ovary may alter the chromosomal structure, unleash the suppression of genes required for maintaining cell stemness (i.e. EZH2) and thereby drive cellular dedifferentiation and malignant transformation. SCCOHT is characterized by SMARCA4/A2 dual deficiency SCCOHT expresses abundant EZH2 and neuroepithelium markers SMARCA4 re-expression leads to growth suppression and differentiation into neuron-like cells SMARCA4 re-expression increased chromatin accessibility and H3K27Ac at active promoter/enhancer regions SCCOHT cells depend on the catalytic activity of PRC2 complex; EZH2 inhibitors and HDAC inhibitors displayed robust pre-clinical activity in SCCOHT; combination of two inhibitors have great synergistic effects SMARCA4 is genetic inactivated and SMARCA2 is epigenetically silenced in SCCOHT The neuroepithelium in immature teratoma is a putative cell of origin of SCCOHT development Re-expression of SMARCA4 increases the accessibility of nucleosome and promotes differentiation EZH2 and HDAC inhibitors suppress the growth of SCCOHT cells in vitro and in vivo

Figure 4.. A hypothetic model of ENOC and CCOC development.

Endometrial epithelial progenitor cells can differentiate into ciliated cells or secretory cells in normal endometrium or typical endometriosis. The local ovarian microenvironment of each patient, which holds distinct differentiation pressure, may determine the differentiation of ARID1A-deficient biopotential premalignant progenitor cells of endometriotic cysts and together with accumulated additional mutations to drive their malignant transformation towards either ENOC or CCOC. Such CCOC development pressure may include exposure to excessive hormones.

Figure 5.. A hypothetic model of the development of the dedifferentiated carcinoma of endometrium and ovary.

Accumulation of genetic alternations, including ARID1A inactivating mutations, in endometrial epithelial progenitor cells drive their malignant transformation and development of either endometrioid or clear cell carcinoma. Subsequent loss of additional SWI/SNF components, such as ARID1B (in the presence of ARID1A loss), SMARCA4 or SMARCB1 in endometrioid carcinoma, but not clear cell carcinoma, leads to complete inactivation of SWI/SNF complexes and development of dedifferentiated carcinoma, possibly through stalling the differentiation of cancer initiating cells.