Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4

Abstract

Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is an extremely rare, aggressive cancer affecting children and young women. We identified germline and somatic inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT cases in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors but in only 0.4% (2/485) of other primary ovarian tumors. These data implicate SMARCA4 in SCCOHT oncogenesis.

Figure 1

Inactivating germline and somatic SMARCA4 mutations identified in SCCOHT. (a) Schematic of the SMARCA4 protein showing the location of the alterations identified in SCCOHT germline and tumor DNA samples. QLQ, Gln, Leu, Gln motif; HSA, helicase/SANT-associated domain; BRK, brahma and kismet domain; DEXDc, DEAD-like helicase superfamily domain; HELICc, helicase superfamily C-terminal domain; Bromo, bromodomain. (b) SMARCA4 immunohistochemistry analysis. Representative images of SMARCA4-negative SCCOHT tumors. Only two tumor cases showed positive nuclear staining for SMARCA4 (SCCO-018 shown). 200× magnification; scale bars, 100 μm. Immunohistochemistry of A549 cells for SMARCA4 and SMARCB1 was used for negative and antibody specificity controls, respectively. 400× magnification; scale bars, 50 μm. (c) SMARCA4 protein expression in representative cell lines from five major ovarian carcinoma subtypes (small cell, BIN-67; high-grade serous, OVSAYO; clear cell, TOV21G; endometrioid, A2780; low-grade serous, VOA1312), immortalized granulosa cells (SVOG) and an adult granulosa cell tumor cell line (KGN). Lung (A549) and gastric (GP202) carcinoma cell lines were included as negative and positive SMARCA4 expression controls, respectively.