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Concomitant loss of SMARCA2 and SMARCA4 expression in small cell carcinoma of the ovary, hypercalcemic type.

Jelinic P, Schlappe BA, Conlon N, Tseng J, Olvera N, Dao F, Mueller JJ, Hussein Y, Soslow RA, Levine DA - Mod. Pathol. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Gynecology Research Laboratory, Gynecology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Immunohistochemistry for SMARCA2 and SMARCA4 in formalin-fixed paraffin-embedded small cell carcinoma of the ovary, hypercalcemic type cases. (a) SMARCA2 staining of the original small cell carcinoma of the ovary, hypercalcemic type cases previously described and stained for SMARCA4. Note the strong staining of stromal cell nuclei as internal control. (b) SMARCA2 and SMARCA4 staining for two new small cell carcinoma of the ovary, hypercalcemic type cases.
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fig1: Immunohistochemistry for SMARCA2 and SMARCA4 in formalin-fixed paraffin-embedded small cell carcinoma of the ovary, hypercalcemic type cases. (a) SMARCA2 staining of the original small cell carcinoma of the ovary, hypercalcemic type cases previously described and stained for SMARCA4. Note the strong staining of stromal cell nuclei as internal control. (b) SMARCA2 and SMARCA4 staining for two new small cell carcinoma of the ovary, hypercalcemic type cases.

Mentions: Analysis of SMARCA2 expression by immunohistochemistry in small cell carcinoma of the ovary, hypercalcemic type cases revealed loss of SMARCA2 expression in 9 (90%) of 10 archival cases (Figure 1,Table 1). For the three cases with available frozen tissue, we also confirmed the loss of SMARCA2 protein expression by immunoblotting (Figure 2a). To investigate whether this loss of expression was owing to mutations in the SMARCA2 gene, we performed deep sequencing of the coding region and splice sites of SMARCA2. No SMARCA2 mutations were identified, suggesting that the loss of protein expression is non-mutational.


Concomitant loss of SMARCA2 and SMARCA4 expression in small cell carcinoma of the ovary, hypercalcemic type.

Jelinic P, Schlappe BA, Conlon N, Tseng J, Olvera N, Dao F, Mueller JJ, Hussein Y, Soslow RA, Levine DA - Mod. Pathol. (2015)

Immunohistochemistry for SMARCA2 and SMARCA4 in formalin-fixed paraffin-embedded small cell carcinoma of the ovary, hypercalcemic type cases. (a) SMARCA2 staining of the original small cell carcinoma of the ovary, hypercalcemic type cases previously described and stained for SMARCA4. Note the strong staining of stromal cell nuclei as internal control. (b) SMARCA2 and SMARCA4 staining for two new small cell carcinoma of the ovary, hypercalcemic type cases.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4697871&req=5

fig1: Immunohistochemistry for SMARCA2 and SMARCA4 in formalin-fixed paraffin-embedded small cell carcinoma of the ovary, hypercalcemic type cases. (a) SMARCA2 staining of the original small cell carcinoma of the ovary, hypercalcemic type cases previously described and stained for SMARCA4. Note the strong staining of stromal cell nuclei as internal control. (b) SMARCA2 and SMARCA4 staining for two new small cell carcinoma of the ovary, hypercalcemic type cases.
Mentions: Analysis of SMARCA2 expression by immunohistochemistry in small cell carcinoma of the ovary, hypercalcemic type cases revealed loss of SMARCA2 expression in 9 (90%) of 10 archival cases (Figure 1,Table 1). For the three cases with available frozen tissue, we also confirmed the loss of SMARCA2 protein expression by immunoblotting (Figure 2a). To investigate whether this loss of expression was owing to mutations in the SMARCA2 gene, we performed deep sequencing of the coding region and splice sites of SMARCA2. No SMARCA2 mutations were identified, suggesting that the loss of protein expression is non-mutational.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Gynecology Research Laboratory, Gynecology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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.

No MeSH data available.


Related in: MedlinePlus