title: Concomitant loss of SMARCA2 and SMARCA4 expression in small cell carcinoma of the ovary, hypercalcemic type.
abstract: Small cell carcinoma of the ovary, hypercalcemic type is an aggressive tumor generally affecting young women with limited treatment options. Mutations in SMARCA4, a catalytic subunit of the SWI/SNF chromatin remodeling complex, have recently been identified in nearly all small cell carcinoma of the ovary, hypercalcemic type cases and represent a signature molecular feature for this disease. Additional biological dependencies associated with small cell carcinoma of the ovary, hypercalcemic type have not been identified. SMARCA2, another catalytic subunit of the SWI/SNF complex mutually exclusive with SMARCA4, is thought to be post-translationally silenced in various cancer types. We analyzed 10 archival small cell carcinoma of the ovary, hypercalcemic type cases for SMARCA2 protein expression by immunohistochemistry and found that SMARCA2 expression was lost in all but one case. None of the 50 other tumors that primarily or secondarily involved the ovary demonstrated concomitant loss of SMARCA2 and SMARCA4. Deep sequencing revealed that this loss of SMARCA2 expression is not the result of mutational inactivation. In addition, we established a small cell carcinoma of the ovary, hypercalcemic type patient-derived xenograft and confirmed the loss of SMARCA2 in this in vitro model. This patient-derived xenograft model, established from a recurrent tumor, also had unexpected mutational features for this disease, including functional mutations in TP53 and POLE. Taken together, our data suggest that concomitant loss of SMARCA2 and SMARCA4 is another hallmark of small cell carcinoma of the ovary, hypercalcemic type-a finding that offers new opportunities for therapeutic interventions.
authors.affiliation: Department of Surgery, Gynecology Research Laboratory, Gynecology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Petar
authors.initials: P
authors.lastname: Jelinic
authors.affiliation: Department of Surgery, Gynecology Research Laboratory, Gynecology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Brooke A
authors.initials: BA
authors.lastname: Schlappe
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Niamh
authors.initials: N
authors.lastname: Conlon
authors.affiliation: Department of Surgery, Gynecology Research Laboratory, Gynecology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Tseng
authors.affiliation: Department of Surgery, Gynecology Research Laboratory, Gynecology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Narciso
authors.initials: N
authors.lastname: Olvera
authors.affiliation: Department of Surgery, Gynecology Research Laboratory, Gynecology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Fanny
authors.initials: F
authors.lastname: Dao
authors.affiliation: Department of Surgery, Gynecology Research Laboratory, Gynecology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Mueller
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Yaser
authors.initials: Y
authors.lastname: Hussein
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Soslow
authors.affiliation: Department of Surgery, Gynecology Research Laboratory, Gynecology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Douglas A
authors.identifier: http://orcid.org/0000-0003-1038-8232
authors.initials: DA
authors.lastname: Levine
mesh_terms: D000328:Adult; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010053:Ovary / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D009687:Nuclear Proteins; C084011:SMARCA2 protein, human; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases