Epigenetic Divergence Distinguishes Molecularly and Histologically Distinct Subtypes of Small Cell Carcinoma of the Ovary Hypercalcemic Type.
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Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and highly aggressive malignancy defined by inactivation of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, specifically SMARCA4. It predominantly affects adolescent and young women, with poor survival despite radical surgery and multi-agent chemotherapy. Novel targeted agents have emerged with variable success. Here, we show that DNA methylation profiling stratifies SCCOHT (n= 63) into two distinct clusters with different morphologies: SCCOHT-1 exhibits typical features, including small cells and follicle-like spaces, while SCCOHT-2 exhibits large cells and rhabdoid morphology. Despite these differences, both clusters showed low copy number variation burden, reinforcing SWI/SNF deficiency as the central oncogenic driver. Differential methylation analysis revealed CpG island hypermethylation and open sea hypomethylation in SCCOHT-2, consistent with reprogramming of promoter and enhancer compartments. These epigenetic states were mirrored by distinct chromatin regulator signatures, differentiation programs, and calcium-regulatory networks. Immunohistochemistry further delineated the subtypes: WT1 was negative in SCCOHT-2, whereas it was diffusely expressed in SCCOHT-1. Keratins and cyclin D1 showed the opposite profile and were absent in SCCOHT-1. p16 was abnormal in both clusters: it was diffusely expressed in SCCOHT-2 and absent in SCCOHT-1. Clinically, both subtypes presented at a young age and were aggressive; however, hypercalcemia was restricted to SCCOHT-1. These findings establish SCCOHT heterogeneity despite uniform SWI/SNF ATPase loss, with implications for lineage specification and therapeutic stratification.