Ovarian small cell carcinoma of hypercalcemic type – evidence of germline origin and smarca4 gene inactivation. a pilot study

Abstract

Ovarian tumors from two patients, compatible by histological and immunohistochemical criteria with small cell carcinoma of hypercalcemic type (SCCHT) (WT1+, EMA dispersed+, synaptophysin+ or dispersed+), were extensively sampled in order to find clues to their histogenesis. Subsequently, small foci of immature teratoma were found in both of them (in 1/122 and in 3/80 tumor sections). In one case, microfoci of yolk sac tumor were also present within the teratoma area as well as in the background of the small cell tumor population -in the primary tumor and in omental metastasis. We found a resemblance of the microscopic patterns of SCCHT and atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system, and this prompted us to evaluate INI-1 and SMARCA4 immunohistochemical expression, because their alternative loss is regarded as a molecular hallmark of AT/RT. INI-1 expression was retained, while that of SMARCA4 was lost. We therefore analyzed tumor DNA by PCR amplification and sequencing for mutations in the SMARCA4 gene (NG_011556.1), which were identified in both tumors (c.2184_2206del; nonsense c.3277C>T -both in one tumor; nonsense c.3760G>T in another tumor). These data suggest that SCCHT is most likely an embryonal tumor originating from immature teratoma and related to malignant rhabdoid tumor. Further analyses are necessary to determine whether the tumors diagnosed as SCCHT constitute a homogeneous group or represent more than one entity.

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

“…Stringent variant-calling methods were used to identify single-base substitutions and indels (see the Online Methods and Supplementary Table 2 for a list of the variants identified in each tumor). SMARCA4 , a gene previously implicated in SCCOHT 7 , was the only recurrently mutated gene, bearing inactivating mutations in six of nine tumors and in BIN-67 cells (Table 1). Two tumors harbored two mutations each in SMARCA4 , suggesting biallelic inactivation.…”

Pattern of SMARCB1 (INI1) and SMARCA4 (BRG1) in poorly differentiated endometrioid adenocarcinoma of the uterus: analysis of a series with emphasis on a novel SMARCA4-deficient dedifferentiated rhabdoid variant

“…Furthermore, the recently observed clustering of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT; [8]) in families with malignant rhabdoid tumors suggests a link between SCCOHT and the SWI/SNF pathway [9,10]. This observation is strengthened by the fact that some of the SCCOHT cases display frank rhabdoid phenotype (so-called large cell variant [11]).…”

Loss of SMARCA4 Expression Is Both Sensitive and Specific for the Diagnosis of Small Cell Carcinoma of Ovary, Hypercalcemic Type

“…1, 2 Several recent studies have reported a high frequency of inactivating, predominantly nonsense, splice-site or frameshift SMARCA4 (also known as BRG1 ) mutations in these tumors, which lead to loss of protein expression. 3–6 No other recurrent mutations were detected in SCCOHT in these studies. 4 …”