Limits...
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

Assessment of the small cell carcinoma of the ovary, hypercalcemic type patient-derived xenograft case 113. (a) Hematoxylin and eosin staining shows histopathological features of the explanted small cell carcinoma of the ovary, hypercalcemic type. (b) Sequence analyses of SMARCA4, POLE and TP53. Top panels: next-generation sequence coverage demonstrating identified variants. Bottom panels: validation by Sanger sequencing. (c) TP53 immunohistochemical staining. High-grade serous ovarian carcinoma was used as a positive control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4697871&req=5

fig3: Assessment of the small cell carcinoma of the ovary, hypercalcemic type patient-derived xenograft case 113. (a) Hematoxylin and eosin staining shows histopathological features of the explanted small cell carcinoma of the ovary, hypercalcemic type. (b) Sequence analyses of SMARCA4, POLE and TP53. Top panels: next-generation sequence coverage demonstrating identified variants. Bottom panels: validation by Sanger sequencing. (c) TP53 immunohistochemical staining. High-grade serous ovarian carcinoma was used as a positive control.

Mentions: We previously reported SMARCA4 mutations in 9 of the 10 archival small cell carcinoma of the ovary, hypercalcemic type cases included in this study.2 Here, we also report the loss of SMARCA4 expression in two new cases: 113 and 114 (Figure 1b). Case 113 was a patient-derived xenograft obtained in the setting of recurrent small cell carcinoma of the ovary, hypercalcemic type. The xenograft tumor was grown in the peritoneum of SCID mice, as previously described, before being explanted and analyzed for mutations and protein expression.12 The tumor demonstrated characteristic features of small cell carcinoma of the ovary, hypercalcemic type, including a combination of small neoplastic and larger rhabdoid cells (Figure 3a). Case 114 was from a 27-year-old woman with newly diagnosed small cell carcinoma of the ovary, hypercalcemic type. These cases were deep-sequenced using the MSK-IMPACT assay, and Sanger sequencing confirmed the results. Biallelic SMARCA4 mutations, the small cell carcinoma of the ovary, hypercalcemic type molecular signature feature, were present in both cases (Figure 3b and Supplementary Figure S1). Immunohistochemistry staining confirmed the loss of SMARCA4 expression.


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)

Assessment of the small cell carcinoma of the ovary, hypercalcemic type patient-derived xenograft case 113. (a) Hematoxylin and eosin staining shows histopathological features of the explanted small cell carcinoma of the ovary, hypercalcemic type. (b) Sequence analyses of SMARCA4, POLE and TP53. Top panels: next-generation sequence coverage demonstrating identified variants. Bottom panels: validation by Sanger sequencing. (c) TP53 immunohistochemical staining. High-grade serous ovarian carcinoma was used as a positive control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Assessment of the small cell carcinoma of the ovary, hypercalcemic type patient-derived xenograft case 113. (a) Hematoxylin and eosin staining shows histopathological features of the explanted small cell carcinoma of the ovary, hypercalcemic type. (b) Sequence analyses of SMARCA4, POLE and TP53. Top panels: next-generation sequence coverage demonstrating identified variants. Bottom panels: validation by Sanger sequencing. (c) TP53 immunohistochemical staining. High-grade serous ovarian carcinoma was used as a positive control.
Mentions: We previously reported SMARCA4 mutations in 9 of the 10 archival small cell carcinoma of the ovary, hypercalcemic type cases included in this study.2 Here, we also report the loss of SMARCA4 expression in two new cases: 113 and 114 (Figure 1b). Case 113 was a patient-derived xenograft obtained in the setting of recurrent small cell carcinoma of the ovary, hypercalcemic type. The xenograft tumor was grown in the peritoneum of SCID mice, as previously described, before being explanted and analyzed for mutations and protein expression.12 The tumor demonstrated characteristic features of small cell carcinoma of the ovary, hypercalcemic type, including a combination of small neoplastic and larger rhabdoid cells (Figure 3a). Case 114 was from a 27-year-old woman with newly diagnosed small cell carcinoma of the ovary, hypercalcemic type. These cases were deep-sequenced using the MSK-IMPACT assay, and Sanger sequencing confirmed the results. Biallelic SMARCA4 mutations, the small cell carcinoma of the ovary, hypercalcemic type molecular signature feature, were present in both cases (Figure 3b and Supplementary Figure S1). Immunohistochemistry staining confirmed the loss of SMARCA4 expression.

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