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Abbas Agaimy - One of the best experts on this subject based on the ideXlab platform.

  • undifferentiated large cell rhabdoid carcinoma presenting in the intestines of patients with concurrent or recent non small cell lung cancer nsclc clinicopathologic and molecular analysis of 14 cases indicates an unusual pattern of dedifferentiated metastases
    Virchows Archiv, 2021
    Co-Authors: Abbas Agaimy, Ondrej Daum, Michal Michal, Arndt Hartmann, Mona W Schmidt, Robert Stoehr, Gregory Y Lauwers
    Abstract:

    Undifferentiated carcinoma metastatic to the bowel is uncommon in surgical pathology practice and might be confused with primary gastrointestinal carcinoma, melanoma, lymphoma, and others. We present 14 cases of uni- (n = 9) or multifocal (n = 5) undifferentiated large cell/rhabdoid carcinoma presenting in the bowel of patients with concurrent (n = 9) or recent (diagnosed 1 to 25 months earlier; median, 4) non-small cell lung cancer (NSCLC). Patients were 6 females and 8 males, aged 52 to 85 years. Primary NSCLC was verified histologically in 10 cases and by imaging in 4. The undifferentiated histology was present in the lung biopsy in 4/10 patients (as sole pattern in 3 and combined with adenocarcinoma in 1) and was limited to the intestinal metastases in the remainder. PDL1 was strongly expressed in 7/9 cases (CPS: 41 to 100). Loss of at least one SWI/SNF subunit was detected in 7/13 cases (54%). SMARCA2 loss (n = 6) was most frequent and was combined with SMARCA4 loss in one case. PBRM1 loss was observed in one tumor. Successful molecular testing of 11 cases revealed BRAF mutations in 4 (3 were non-V600E variants), KRAS mutations in 3, and wildtype in 4. None had EGFR mutations. Analysis of 4 paired samples revealed concordant KRAS (2) and BRAF (1) mutations or wildtype (1). Our study indicates that undifferentiated carcinoma within the intestines of patients with concurrent/recent NSCLC represents dedifferentiated metastasis from the NSCLC. Recognition of this unusual presentation is cardinal to avoid misdiagnosis with inappropriate therapeutic and prognostic implications.

  • SWI/SNF-deficient undifferentiated/rhabdoid carcinoma of the gallbladder carrying a POLE mutation in a 30-year-old woman: a case report
    'Springer Science and Business Media LLC', 2021
    Co-Authors: Tiemo S. Gerber, Abbas Agaimy, Arndt Hartmann, Michael Habekost, Wilfried Roth, Albrecht Stenzinger, Peter Schirmacher, Beate K. Straub
    Abstract:

    Abstract Background Undifferentiated carcinoma of the biliary tract are highly aggressive malignancies. In other organs, a subgroup of undifferentiated carcinoma related to SWI/SNF complex–deficiency have been described. Case presentation A 30-year-old woman presented with rising inflammatory markers (C-reactive protein (CRP)). Ultrasound examination revealed a large tumor of the liver. A computed tomography scan was performed and was primarily interpreted as a tumor-forming liver abscess, possibly caused by gallbladder perforation. Subsequent liver segment resection was performed. Microscopic examination showed an undifferentiated carcinoma with rhabdoid morphology and prominent inflammatory infiltrate in the gallbladder base. With SWI/SNF immunohistochemistry, intact expression of SMARCB1, SMARCA4, ARID1A, but loss of SMARCA2 and PBRM1 was detected. Next-generation-sequencing detected KRAS, PBRM1 and ARID1B mutations, a deleterious splice-site mutation in the POLE-gene and a mutation in the TP53-gene. Conclusions We were able to demonstrate loss of SMARCA2 expression and mutations characteristic of an SWI/SNF-deficient carcinoma in a tumor derived from the gallbladder. This is the first reported case of an undifferentiated carcinoma with rhabdoid features in the gallbladder carrying a POLE mutation and SWI/SNF-deficiency of PBRM1 and SMARCA2

  • swi snf protein and claudin 4 expression in anaplastic carcinomas arising in mucinous tumors of the ovary and retroperitoneum
    Histopathology, 2020
    Co-Authors: Kristine M Chaudet, Abbas Agaimy, Melinda F Lerwill, Robert H Young, Mari Minokenudson, Glenn W Mccluggage, Esther Oliva
    Abstract:

    AIMS: Anaplastic carcinoma arising in a mucinous tumor of the ovary and rarely in the retroperitoneum is an uncommon neoplasm with three morphologic patterns; rhabdoid, sarcomatoid and pleomorphic. We investigated expression of switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex components and claudin-4 expression. METHODS AND RESULTS: 22 ovarian and 3 retroperitoneal mucinous tumors were investigated using antibodies against SMARCB1, SMARCA4, SMARCA2, ARID1A and claudin-4. Loss of nuclear staining for any SWI/SNF protein was observed in the anaplastic component of 9 of 25 (36%), with retained expression within the mucinous component of all tumors. Five (56%) showed loss of more than one protein, with dual loss of SMARCA4 and SMARCA2 in two, loss of SMARCA2 and ARID1A in two, and loss of SMARCB1 and SMARCA2 in one. Retained expression of claudin-4 was seen in 39% of the anaplastic carcinomas and within the mucinous component of all tumors. Rhabdoid morphology was associated with poor prognosis (stage III or IV disease (6/6, 100% vs 4/14, 29%; p=0.0108) and death from disease (3/4, 75% vs 1/13, 8%; p=0.0223)). Although loss of a SWI/SNF protein was not significantly associated with death from disease (3/5, 60% vs 1/12, 8%; p=0.0525), it showed a trend in correlation with poor prognosis and was often noted in tumors with rhabdoid morphology within this small cohort. CONCLUSIONS: Our report adds to the growing list of female genital tract malignancies with loss of SWI/SNF proteins, underlining their broad differential diagnosis and the importance of careful, context-dependent interpretation of SWI/SNF protein loss.

  • swi snf protein and claudin 4 expression in anaplastic carcinomas arising in mucinous tumours of the ovary and retroperitoneum
    Histopathology, 2020
    Co-Authors: Kristine M Chaudet, Abbas Agaimy, Melinda F Lerwill, Robert H Young, Mari Minokenudson, Glenn W Mccluggage, Marina Kem, Esther Oliva
    Abstract:

    Aims Anaplastic carcinoma arising in a mucinous tumour of the ovary and rarely in the retroperitoneum is an uncommon neoplasm with three morphological patterns; rhabdoid, sarcomatoid and pleomorphic. We investigated expression of switch/sucrose non-fermentable (SWI/SNF) chromatin remodelling complex components and claudin-4 expression. Methods and results Twenty-two ovarian and three retroperitoneal mucinous tumours were investigated using antibodies against SMARCB1, SMARCA4, SMARCA2, ARID1A and claudin-4. Loss of nuclear staining for any SWI/SNF protein was observed in the anaplastic component of nine of 25 (36%), with retained expression within the mucinous component of all tumours. Five (56%) showed loss of more than one protein, with dual loss of SMARCA4 and SMARCA2 in two, loss of SMARCA2 and ARID1A in two and loss of SMARCB1 and SMARCA2 in one. Retained expression of claudin-4 was seen in 39% of the anaplastic carcinomas and within the mucinous component of all tumours. Rhabdoid morphology was associated with poor prognosis [stages III or IV disease (six of six, 100% versus four of 14, 29%; P = 0.0108] and death from disease (three of four, 75% versus one of 13, 8%; P = 0.0223). Although loss of a SWI/SNF protein was not significantly associated with death from disease (three of five, 60% versus one of 12, 8%; P = 0.0525), it showed a trend in correlation with poor prognosis and was often noted in tumours with rhabdoid morphology within this small cohort. Conclusions Our report adds to the growing list of female genital tract malignancies with loss of SWI/SNF proteins, underlining their broad differential diagnosis and the importance of careful, context-dependent interpretation of SWI/SNF protein loss.

  • swi snf protein expression status in fumarate hydratase deficient renal cell carcinoma immunohistochemical analysis of 32 tumors from 28 patients
    Human Pathology, 2018
    Co-Authors: Abbas Agaimy, Mahul B Amin, Anthony J Gill, Bernt Popp, Andre Reis, Daniel M Berney, Cristina Magigalluzzi, Mathilde Sibony, Steven C Smith, Saul Suster
    Abstract:

    Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive RCC type, originally described in the setting of hereditary leiomyomatosis and RCC syndrome, which is defined by germline FH gene inactivation. Inactivation of components of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex is involved in renal medullary carcinoma (SMARCB1/INI1 loss), clear cell RCC (PBRM1 loss), and subsets of dedifferentiated RCC of clear cell, chromophobe, and papillary types (loss of different SWI/SNF components). FH-RCC and SWI/SNF-deficient RCC share anaplastic nuclear features and highly aggressive course. We analyzed 32 FH-RCCs from 28 patients using 7 commercially available SWI/SNF antibodies (SMARCB1/INI1, SMARCA2, SMARCA4, SMARCC1, SMARCC2, PBRM1, and ARID1A). Variable loss of SMARCB1, ARID1A, and SMARCC1 was observed in 1 of 31, 2 of 31, and 1 of 29 evaluable cases, respectively; 3 of these 4 SWI/SNF-deficient tumors had confirmed FH mutations. No correlation of SWI/SNF loss with solid or sarcomatoid features was observed. Two tumors with SMARCB1 and ARID1A deficiency had available SWI/SNF molecular data; both lacked SMARCB1 and ARID1A mutations. The remaining 5 SWI/SNF components were intact in all cases. Especially PBRM1 seems not to be involved in the pathogenesis or progression of FH-RCC. Our data showed that a subset of FH-RCC (12%) have a variable loss of SWI/SNF complex subunits, likely as secondary genetic events. This should not be confused with SWI/SNF-deficient RCC of other types. Evaluation of FH and SWI/SNF together with comprehensive molecular genetic profiling is needed to explore possible prognostic implications of FH/SWI-SNF double deficiency and to better understand the somatic mutation landscape in high-grade RCC.

William P D Hendricks - One of the best experts on this subject based on the ideXlab platform.

  • abstract lb 058 gb 3103 an epigenetic immunomodulator shows potent antitumor activity against tumors harboring dual loss of smarca4 SMARCA2 atpases
    Immunology, 2019
    Co-Authors: Tong Wang, Jessica D Lang, William P D Hendricks, Paul Gonzales, Kari Kotlarczyk, Myungja Lee, Erin Bossert, Courtney Devore, Haiyong Han, Jeffrey M. Trent
    Abstract:

    Dual loss of SMARCA4/SMARCA2 ATPases of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex has been reported in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and other tumors. Loss of SMARCA4 is the result of inactivating mutations, and the loss of SMARCA2 results from the absence of mRNA expression. Restoration of either SMARCA4 or SMARCA2 can inhibit the growth of these cancers. We have evaluated the activity of a novel, structurally rigid, and potent, Class I/IIb HDAC inhibitor, GB-3103, against human SCCOHT and other cells lines deficient in SWI/SNF complex. GB-3103 shows potent anti-proliferative activities with low nM IC50 values against human SCCOHT lines BIN67 (51nM), COV434 (35nM) and SCCOHT-1 (293nM), and SWI/SNF-deficient rhabdoid and lung tumor lines A204 (95nM), A427 (174nM), G401 (138 nM), G402 (71nM), H522 (102nM). Treatment of human BIN67 SCCOHT cell line for 72h with GB-3103 revealed potent concentration- and time-dependent induction of SMARCA2 expression at both mRNA and protein levels. Treatment of mice bearing G401 human malignant rhabdoid tumor xenografts with GB-3103 at 5 mg/kg, QD resulted in 70% tumor growth inhibition (TGI) compared to vehicle control (P Citation Format: Tong Wang, Paul Gonzales, Kari Kotlarczyk, Myung-Ja Lee, Erin Bossert, Courtney Devore, Haiyong Han, Jessica Lang, William Hendricks, Jeffrey Trent, Stephen Gately. GB-3103, an epigenetic immunomodulator, shows potent antitumor activity against tumors harboring dual loss of SMARCA4/SMARCA2 ATPases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-058.

  • histone deacetylase inhibitors synergize with catalytic inhibitors of ezh2 to exhibit antitumor activity in small cell carcinoma of the ovary hypercalcemic type
    Molecular Cancer Therapeutics, 2018
    Co-Authors: Yemin Wang, Jessica D Lang, William P D Hendricks, Krystal A Orlando, Shary Yuting Chen, Shane Colborne, Galen Lambert, Chae Young Shin, Nancy Dos Santos, Marcel B Bally
    Abstract:

    Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but extremely lethal malignancy that mainly impacts young women. SCCOHT is characterized by a diploid genome with loss of SMARCA4 and lack of SMARCA2 expression, two mutually exclusive ATPases of the SWI/SNF chromatin-remodeling complex. We and others have identified the histone methyltransferase EZH2 as a promising therapeutic target for SCCOHT, suggesting that SCCOHT cells depend on the alternation of epigenetic pathways for survival. In this study, we found that SCCOHT cells were more sensitive to pan-HDAC inhibitors compared with other ovarian cancer lines or immortalized cell lines tested. Pan-HDAC inhibitors, such as quisinostat, reversed the expression of a group of proteins that were deregulated in SCCOHT cells due to SMARCA4 loss, leading to growth arrest, apoptosis, and differentiation in vitro and suppressed tumor growth of xenografted tumors of SCCOHT cells. Moreover, combined treatment of HDAC inhibitors and EZH2 inhibitors at sublethal doses synergistically induced histone H3K27 acetylation and target gene expression, leading to rapid induction of apoptosis and growth suppression of SCCOHT cells and xenografted tumors. Therefore, our preclinical study highlighted the therapeutic potential of combined treatment of HDAC inhibitors with EZH2 catalytic inhibitors to treat SCCOHT.

  • abstract 3673 targeting the epigenome of small cell hypercalcemic carcinoma of the ovary hypercalcemic type sccoht
    Cancer Research, 2018
    Co-Authors: Yemin Wang, Jessica D Lang, William P D Hendricks, Krystal A Orlando, Anthony N. Karnezis, Shary Yuting Chen, Shane Colborne, Gregg B Morin, Bernard E Weissman, Jeffrey M. Trent
    Abstract:

    Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare and poorly differentiated cancer that impacts young women with an average 2-year survival of less than 35%. We and others have discovered the inactivating mutations of SMARCA4 as the only consistent genetic alternation in SCCOHT genomes. SMARCA4 is the ATPase of the SWI/SNF chromatin-remodeling complex, which modulates chromatin accessibility to regulate transcription and plays critical roles in many biologic processes such as cell cycle control, apoptosis, and differentiation. SCCOHT also lacks the expression of SMARCA2, the alternative ATPase in the complex, contrasting the requirement of SMARCA2 for survival of most SMARCA4-deficient cancer cells. This suggest that the complete loss of chromatin-remodeling activity may rewire the epigenome and create opportunities for synthetic lethal targeting. A rational epigenetic drug screen identified EZH2 inhibitors and HDAC inhibitors as promising therapeutic agents in SCCOHT cells. We confirm that catalytic inhibition of EZH2 selectively suppressed the growth of SCCOHT cells in vitro and in xenograft models through activation of apoptosis and differentiation. Pan-HDAC inhibitors also displayed a more robust anticancer effect in SCCOHT cells than other in other ovarian cancer cell lines. Furthermore, combined treatment of EZH2 inhibitors and pan-HDAC inhibitors increased the global acetylation level at histone H3K27 site and synergistically suppressed the growth of SCCOHT cell lines and xenografts through robust induction of apoptosis. Although EZH2 or HDAC inhibitor treatment led to re-expression of SMARCA2, depletion of SMARCA2 had only minimal effect on drug response. Proteomic analysis identified key signaling pathways underlying the efficacy of epigenetic therapy that are under investigation. Therefore, inactivation of SWI/SNF chromatin remodeling complex may drive SCCOHT development through PRC2-dependent rewiring of the epigenome. Targeting these oncogenic events can be the feasible strategies for treatment of SCCOHT that warrant clinical investigation. Citation Format: Yemin Wang, Shary Yu-ting Chen, Shane Colborne, Krystal Orlando, Jessica Lang, Anthony Karnezis, William Hendricks, Gregg Morin, Bernard Weissman, Jeffrey Trent, David Huntsman. Targeting the epigenome of small cell hypercalcemic carcinoma of the ovary, hypercalcemic type (SCCOHT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3673.

  • ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type sccoht through multikinase inhibition
    Clinical Cancer Research, 2018
    Co-Authors: Jessica D Lang, William P D Hendricks, Krystal A Orlando, Patrick Pirrotte, Elizabeth A Raupach, Chris Sereduk, Pilar Ramos, Jeffrey Kiefer, Ritin Sharma, Nanyun Tang
    Abstract:

    Purpose: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT. Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two patient-derived xenograft (PDX) models and one cell-line xenograft model of SCCOHT. Results: The receptor tyrosine kinase (RTK) family was enriched in siRNA screen hits, with FGFRs and PDGFRs being overlapping hits between drug and siRNA screens. Of multiple potent drug classes in SCCOHT cell lines, RTK inhibitors were only one of two classes with selectivity in SCCOHT relative to three SWI/SNF wild-type ovarian cancer cell lines. We further identified ponatinib as the most effective clinically approved RTK inhibitor. Reexpression of SMARCA4 was shown to confer a 1.7-fold increase in resistance to ponatinib. Subsequent proteomic assessment of ponatinib target modulation in SCCOHT cell models confirmed inhibition of nine known ponatinib target kinases alongside 77 noncanonical ponatinib targets in SCCOHT. Finally, ponatinib delayed tumor doubling time 4-fold in SCCOHT-1 xenografts while reducing final tumor volumes in SCCOHT PDX models by 58.6% and 42.5%. Conclusions: Ponatinib is an effective agent for SMARCA4-mutant SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted. Clin Cancer Res; 24(8); 1932–43. ©2018 AACR.

  • ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type sccoht through multi kinase inhibition
    bioRxiv, 2017
    Co-Authors: Jessica D Lang, William P D Hendricks, Patrick Pirrotte, Elizabeth A Raupach, Chris Sereduk, Pilar Ramos, Ritin Sharma, Holly Yin, Jeff Kiefer, Nanyun Tang
    Abstract:

    Purpose: Subunits of the SWI/SNF chromatin-remodeling complex are tumor suppressors inactivated in ~20% of all cancers. Yet, few targeted treatments for SWI/SNF-mutant cancers exist. Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits, SMARCA4 and SMARCA2. Given poor two-year survival rates for these women, a great need exists for effective targeted therapies. Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches comprehensively profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two PDX models and one cell line xenograft model of SCCOHT. Results: FGFRs and PDGFRs were overlapping hits between screens and the receptor tyrosine kinase (RTK) family was enriched in the siRNA screen hits. Evaluation of eleven RTK inhibitors in three SCCOHT cell lines identified ponatinib, an inhibitor of multiple RTKs, as the most effective clinically approved agent. Proteomics approaches confirmed inhibition of known targets of ponatinib and more than 20 non-canonical ponatinib targets. Ponatinib also delayed tumor doubling time 4-fold in SCCOHT-1 xenografts and reducing final tumor volumes in two SCCOHT patient-derived xenograft (PDX) models by 58.6% and 42.5%. Conclusion: Ponatinib is an effective agent for SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted.

Jessica D Lang - One of the best experts on this subject based on the ideXlab platform.

  • abstract lb 058 gb 3103 an epigenetic immunomodulator shows potent antitumor activity against tumors harboring dual loss of smarca4 SMARCA2 atpases
    Immunology, 2019
    Co-Authors: Tong Wang, Jessica D Lang, William P D Hendricks, Paul Gonzales, Kari Kotlarczyk, Myungja Lee, Erin Bossert, Courtney Devore, Haiyong Han, Jeffrey M. Trent
    Abstract:

    Dual loss of SMARCA4/SMARCA2 ATPases of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex has been reported in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and other tumors. Loss of SMARCA4 is the result of inactivating mutations, and the loss of SMARCA2 results from the absence of mRNA expression. Restoration of either SMARCA4 or SMARCA2 can inhibit the growth of these cancers. We have evaluated the activity of a novel, structurally rigid, and potent, Class I/IIb HDAC inhibitor, GB-3103, against human SCCOHT and other cells lines deficient in SWI/SNF complex. GB-3103 shows potent anti-proliferative activities with low nM IC50 values against human SCCOHT lines BIN67 (51nM), COV434 (35nM) and SCCOHT-1 (293nM), and SWI/SNF-deficient rhabdoid and lung tumor lines A204 (95nM), A427 (174nM), G401 (138 nM), G402 (71nM), H522 (102nM). Treatment of human BIN67 SCCOHT cell line for 72h with GB-3103 revealed potent concentration- and time-dependent induction of SMARCA2 expression at both mRNA and protein levels. Treatment of mice bearing G401 human malignant rhabdoid tumor xenografts with GB-3103 at 5 mg/kg, QD resulted in 70% tumor growth inhibition (TGI) compared to vehicle control (P Citation Format: Tong Wang, Paul Gonzales, Kari Kotlarczyk, Myung-Ja Lee, Erin Bossert, Courtney Devore, Haiyong Han, Jessica Lang, William Hendricks, Jeffrey Trent, Stephen Gately. GB-3103, an epigenetic immunomodulator, shows potent antitumor activity against tumors harboring dual loss of SMARCA4/SMARCA2 ATPases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-058.

  • histone deacetylase inhibitors synergize with catalytic inhibitors of ezh2 to exhibit antitumor activity in small cell carcinoma of the ovary hypercalcemic type
    Molecular Cancer Therapeutics, 2018
    Co-Authors: Yemin Wang, Jessica D Lang, William P D Hendricks, Krystal A Orlando, Shary Yuting Chen, Shane Colborne, Galen Lambert, Chae Young Shin, Nancy Dos Santos, Marcel B Bally
    Abstract:

    Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but extremely lethal malignancy that mainly impacts young women. SCCOHT is characterized by a diploid genome with loss of SMARCA4 and lack of SMARCA2 expression, two mutually exclusive ATPases of the SWI/SNF chromatin-remodeling complex. We and others have identified the histone methyltransferase EZH2 as a promising therapeutic target for SCCOHT, suggesting that SCCOHT cells depend on the alternation of epigenetic pathways for survival. In this study, we found that SCCOHT cells were more sensitive to pan-HDAC inhibitors compared with other ovarian cancer lines or immortalized cell lines tested. Pan-HDAC inhibitors, such as quisinostat, reversed the expression of a group of proteins that were deregulated in SCCOHT cells due to SMARCA4 loss, leading to growth arrest, apoptosis, and differentiation in vitro and suppressed tumor growth of xenografted tumors of SCCOHT cells. Moreover, combined treatment of HDAC inhibitors and EZH2 inhibitors at sublethal doses synergistically induced histone H3K27 acetylation and target gene expression, leading to rapid induction of apoptosis and growth suppression of SCCOHT cells and xenografted tumors. Therefore, our preclinical study highlighted the therapeutic potential of combined treatment of HDAC inhibitors with EZH2 catalytic inhibitors to treat SCCOHT.

  • abstract 3673 targeting the epigenome of small cell hypercalcemic carcinoma of the ovary hypercalcemic type sccoht
    Cancer Research, 2018
    Co-Authors: Yemin Wang, Jessica D Lang, William P D Hendricks, Krystal A Orlando, Anthony N. Karnezis, Shary Yuting Chen, Shane Colborne, Gregg B Morin, Bernard E Weissman, Jeffrey M. Trent
    Abstract:

    Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare and poorly differentiated cancer that impacts young women with an average 2-year survival of less than 35%. We and others have discovered the inactivating mutations of SMARCA4 as the only consistent genetic alternation in SCCOHT genomes. SMARCA4 is the ATPase of the SWI/SNF chromatin-remodeling complex, which modulates chromatin accessibility to regulate transcription and plays critical roles in many biologic processes such as cell cycle control, apoptosis, and differentiation. SCCOHT also lacks the expression of SMARCA2, the alternative ATPase in the complex, contrasting the requirement of SMARCA2 for survival of most SMARCA4-deficient cancer cells. This suggest that the complete loss of chromatin-remodeling activity may rewire the epigenome and create opportunities for synthetic lethal targeting. A rational epigenetic drug screen identified EZH2 inhibitors and HDAC inhibitors as promising therapeutic agents in SCCOHT cells. We confirm that catalytic inhibition of EZH2 selectively suppressed the growth of SCCOHT cells in vitro and in xenograft models through activation of apoptosis and differentiation. Pan-HDAC inhibitors also displayed a more robust anticancer effect in SCCOHT cells than other in other ovarian cancer cell lines. Furthermore, combined treatment of EZH2 inhibitors and pan-HDAC inhibitors increased the global acetylation level at histone H3K27 site and synergistically suppressed the growth of SCCOHT cell lines and xenografts through robust induction of apoptosis. Although EZH2 or HDAC inhibitor treatment led to re-expression of SMARCA2, depletion of SMARCA2 had only minimal effect on drug response. Proteomic analysis identified key signaling pathways underlying the efficacy of epigenetic therapy that are under investigation. Therefore, inactivation of SWI/SNF chromatin remodeling complex may drive SCCOHT development through PRC2-dependent rewiring of the epigenome. Targeting these oncogenic events can be the feasible strategies for treatment of SCCOHT that warrant clinical investigation. Citation Format: Yemin Wang, Shary Yu-ting Chen, Shane Colborne, Krystal Orlando, Jessica Lang, Anthony Karnezis, William Hendricks, Gregg Morin, Bernard Weissman, Jeffrey Trent, David Huntsman. Targeting the epigenome of small cell hypercalcemic carcinoma of the ovary, hypercalcemic type (SCCOHT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3673.

  • ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type sccoht through multikinase inhibition
    Clinical Cancer Research, 2018
    Co-Authors: Jessica D Lang, William P D Hendricks, Krystal A Orlando, Patrick Pirrotte, Elizabeth A Raupach, Chris Sereduk, Pilar Ramos, Jeffrey Kiefer, Ritin Sharma, Nanyun Tang
    Abstract:

    Purpose: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT. Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two patient-derived xenograft (PDX) models and one cell-line xenograft model of SCCOHT. Results: The receptor tyrosine kinase (RTK) family was enriched in siRNA screen hits, with FGFRs and PDGFRs being overlapping hits between drug and siRNA screens. Of multiple potent drug classes in SCCOHT cell lines, RTK inhibitors were only one of two classes with selectivity in SCCOHT relative to three SWI/SNF wild-type ovarian cancer cell lines. We further identified ponatinib as the most effective clinically approved RTK inhibitor. Reexpression of SMARCA4 was shown to confer a 1.7-fold increase in resistance to ponatinib. Subsequent proteomic assessment of ponatinib target modulation in SCCOHT cell models confirmed inhibition of nine known ponatinib target kinases alongside 77 noncanonical ponatinib targets in SCCOHT. Finally, ponatinib delayed tumor doubling time 4-fold in SCCOHT-1 xenografts while reducing final tumor volumes in SCCOHT PDX models by 58.6% and 42.5%. Conclusions: Ponatinib is an effective agent for SMARCA4-mutant SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted. Clin Cancer Res; 24(8); 1932–43. ©2018 AACR.

  • ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type sccoht through multi kinase inhibition
    bioRxiv, 2017
    Co-Authors: Jessica D Lang, William P D Hendricks, Patrick Pirrotte, Elizabeth A Raupach, Chris Sereduk, Pilar Ramos, Ritin Sharma, Holly Yin, Jeff Kiefer, Nanyun Tang
    Abstract:

    Purpose: Subunits of the SWI/SNF chromatin-remodeling complex are tumor suppressors inactivated in ~20% of all cancers. Yet, few targeted treatments for SWI/SNF-mutant cancers exist. Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits, SMARCA4 and SMARCA2. Given poor two-year survival rates for these women, a great need exists for effective targeted therapies. Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches comprehensively profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two PDX models and one cell line xenograft model of SCCOHT. Results: FGFRs and PDGFRs were overlapping hits between screens and the receptor tyrosine kinase (RTK) family was enriched in the siRNA screen hits. Evaluation of eleven RTK inhibitors in three SCCOHT cell lines identified ponatinib, an inhibitor of multiple RTKs, as the most effective clinically approved agent. Proteomics approaches confirmed inhibition of known targets of ponatinib and more than 20 non-canonical ponatinib targets. Ponatinib also delayed tumor doubling time 4-fold in SCCOHT-1 xenografts and reducing final tumor volumes in two SCCOHT patient-derived xenograft (PDX) models by 58.6% and 42.5%. Conclusion: Ponatinib is an effective agent for SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted.

Esther Oliva - One of the best experts on this subject based on the ideXlab platform.

  • swi snf protein and claudin 4 expression in anaplastic carcinomas arising in mucinous tumors of the ovary and retroperitoneum
    Histopathology, 2020
    Co-Authors: Kristine M Chaudet, Abbas Agaimy, Melinda F Lerwill, Robert H Young, Mari Minokenudson, Glenn W Mccluggage, Esther Oliva
    Abstract:

    AIMS: Anaplastic carcinoma arising in a mucinous tumor of the ovary and rarely in the retroperitoneum is an uncommon neoplasm with three morphologic patterns; rhabdoid, sarcomatoid and pleomorphic. We investigated expression of switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex components and claudin-4 expression. METHODS AND RESULTS: 22 ovarian and 3 retroperitoneal mucinous tumors were investigated using antibodies against SMARCB1, SMARCA4, SMARCA2, ARID1A and claudin-4. Loss of nuclear staining for any SWI/SNF protein was observed in the anaplastic component of 9 of 25 (36%), with retained expression within the mucinous component of all tumors. Five (56%) showed loss of more than one protein, with dual loss of SMARCA4 and SMARCA2 in two, loss of SMARCA2 and ARID1A in two, and loss of SMARCB1 and SMARCA2 in one. Retained expression of claudin-4 was seen in 39% of the anaplastic carcinomas and within the mucinous component of all tumors. Rhabdoid morphology was associated with poor prognosis (stage III or IV disease (6/6, 100% vs 4/14, 29%; p=0.0108) and death from disease (3/4, 75% vs 1/13, 8%; p=0.0223)). Although loss of a SWI/SNF protein was not significantly associated with death from disease (3/5, 60% vs 1/12, 8%; p=0.0525), it showed a trend in correlation with poor prognosis and was often noted in tumors with rhabdoid morphology within this small cohort. CONCLUSIONS: Our report adds to the growing list of female genital tract malignancies with loss of SWI/SNF proteins, underlining their broad differential diagnosis and the importance of careful, context-dependent interpretation of SWI/SNF protein loss.

  • swi snf protein and claudin 4 expression in anaplastic carcinomas arising in mucinous tumours of the ovary and retroperitoneum
    Histopathology, 2020
    Co-Authors: Kristine M Chaudet, Abbas Agaimy, Melinda F Lerwill, Robert H Young, Mari Minokenudson, Glenn W Mccluggage, Marina Kem, Esther Oliva
    Abstract:

    Aims Anaplastic carcinoma arising in a mucinous tumour of the ovary and rarely in the retroperitoneum is an uncommon neoplasm with three morphological patterns; rhabdoid, sarcomatoid and pleomorphic. We investigated expression of switch/sucrose non-fermentable (SWI/SNF) chromatin remodelling complex components and claudin-4 expression. Methods and results Twenty-two ovarian and three retroperitoneal mucinous tumours were investigated using antibodies against SMARCB1, SMARCA4, SMARCA2, ARID1A and claudin-4. Loss of nuclear staining for any SWI/SNF protein was observed in the anaplastic component of nine of 25 (36%), with retained expression within the mucinous component of all tumours. Five (56%) showed loss of more than one protein, with dual loss of SMARCA4 and SMARCA2 in two, loss of SMARCA2 and ARID1A in two and loss of SMARCB1 and SMARCA2 in one. Retained expression of claudin-4 was seen in 39% of the anaplastic carcinomas and within the mucinous component of all tumours. Rhabdoid morphology was associated with poor prognosis [stages III or IV disease (six of six, 100% versus four of 14, 29%; P = 0.0108] and death from disease (three of four, 75% versus one of 13, 8%; P = 0.0223). Although loss of a SWI/SNF protein was not significantly associated with death from disease (three of five, 60% versus one of 12, 8%; P = 0.0525), it showed a trend in correlation with poor prognosis and was often noted in tumours with rhabdoid morphology within this small cohort. Conclusions Our report adds to the growing list of female genital tract malignancies with loss of SWI/SNF proteins, underlining their broad differential diagnosis and the importance of careful, context-dependent interpretation of SWI/SNF protein loss.

  • dual loss of the swi snf complex atpases smarca4 brg1 and SMARCA2 brm is highly sensitive and specific for small cell carcinoma of the ovary hypercalcaemic type
    The Journal of Pathology, 2016
    Co-Authors: Anthony N. Karnezis, William P D Hendricks, Yemin Wang, Pilar Ramos, Esther Oliva, Emanuela Dangelo, Jaime Prat, Marisa R Nucci, Torsten O Nielsen, Christine Chow
    Abstract:

    Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a lethal and sometimes familial ovarian tumour of young women and children. We and others recently discovered that over 90% of SCCOHTs harbour inactivating mutations in the chromatin remodelling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually exclusive ATPases of the SWI/SNF chromatin remodelling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry in more than 3000 primary gynaecological tumours. Among ovarian tumours, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high-grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumour cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4-negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumours, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase inhibitor trichostatin A. Re-expression of SMARCA4 or SMARCA2 inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2, is highly sensitive and specific for SCCOHT and that restoration of either SWI/SNF ATPase can inhibit the growth of SCCOHT cell lines.

  • abstract a33 dual loss of the swi snf complex atpases smarca4 brg1 and SMARCA2 brm is highly sensitive and specific for small cell carcinoma of the ovary hypercalcemic type
    Clinical Cancer Research, 2016
    Co-Authors: Anthony N. Karnezis, William P D Hendricks, Yemin Wang, Pilar Ramos, Esther Oliva, Emanuela Dangelo, Jaime Prat, Marisa R Nucci, Holly Yin, Torsten O Nielsen
    Abstract:

    Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a lethal and sometimes familial ovarian tumor of young women and children. We and others recently discovered that over 90% of SCCOHT harbor inactivating mutations in the chromatin remodeling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually-exclusive ATPases of the SWI/SNF chromatin remodeling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry (IHC) in more than 3000 primary gynecologic tumors. Among ovarian tumors, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high-grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumor cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4-negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumors, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase (HDAC) inhibitor trichostatin A. Treatment with HDAC inhibitors or re-expression of either SMARCA4 or SMARCA2 potently inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2 loss, is the first highly sensitive and specific diagnostic immunohistochemical marker of SCCOHT, and that HDAC inhibitors are promising agents to explore for the treatment of SCCOHT. Citation Format: Anthony N. Karnezis, Yemin Wang, Pilar Ramos, William Hendricks, Holly Yin, Esther Oliva, Emanuela D9Angelo, Jaime Prat, Marisa R. Nucci, Torsten O. Nielsen, Bernard E. Weissman, Jeffrey M. Trent, C Blake Gilks, David G. Huntsman. Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcemic type. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A33.

Anthony N. Karnezis - One of the best experts on this subject based on the ideXlab platform.

  • abstract 3673 targeting the epigenome of small cell hypercalcemic carcinoma of the ovary hypercalcemic type sccoht
    Cancer Research, 2018
    Co-Authors: Yemin Wang, Jessica D Lang, William P D Hendricks, Krystal A Orlando, Anthony N. Karnezis, Shary Yuting Chen, Shane Colborne, Gregg B Morin, Bernard E Weissman, Jeffrey M. Trent
    Abstract:

    Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare and poorly differentiated cancer that impacts young women with an average 2-year survival of less than 35%. We and others have discovered the inactivating mutations of SMARCA4 as the only consistent genetic alternation in SCCOHT genomes. SMARCA4 is the ATPase of the SWI/SNF chromatin-remodeling complex, which modulates chromatin accessibility to regulate transcription and plays critical roles in many biologic processes such as cell cycle control, apoptosis, and differentiation. SCCOHT also lacks the expression of SMARCA2, the alternative ATPase in the complex, contrasting the requirement of SMARCA2 for survival of most SMARCA4-deficient cancer cells. This suggest that the complete loss of chromatin-remodeling activity may rewire the epigenome and create opportunities for synthetic lethal targeting. A rational epigenetic drug screen identified EZH2 inhibitors and HDAC inhibitors as promising therapeutic agents in SCCOHT cells. We confirm that catalytic inhibition of EZH2 selectively suppressed the growth of SCCOHT cells in vitro and in xenograft models through activation of apoptosis and differentiation. Pan-HDAC inhibitors also displayed a more robust anticancer effect in SCCOHT cells than other in other ovarian cancer cell lines. Furthermore, combined treatment of EZH2 inhibitors and pan-HDAC inhibitors increased the global acetylation level at histone H3K27 site and synergistically suppressed the growth of SCCOHT cell lines and xenografts through robust induction of apoptosis. Although EZH2 or HDAC inhibitor treatment led to re-expression of SMARCA2, depletion of SMARCA2 had only minimal effect on drug response. Proteomic analysis identified key signaling pathways underlying the efficacy of epigenetic therapy that are under investigation. Therefore, inactivation of SWI/SNF chromatin remodeling complex may drive SCCOHT development through PRC2-dependent rewiring of the epigenome. Targeting these oncogenic events can be the feasible strategies for treatment of SCCOHT that warrant clinical investigation. Citation Format: Yemin Wang, Shary Yu-ting Chen, Shane Colborne, Krystal Orlando, Jessica Lang, Anthony Karnezis, William Hendricks, Gregg Morin, Bernard Weissman, Jeffrey Trent, David Huntsman. Targeting the epigenome of small cell hypercalcemic carcinoma of the ovary, hypercalcemic type (SCCOHT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3673.

  • Loss of SMARCA4 (BRG1) protein expression as determined by immunohistochemistry in small-cell carcinoma of the ovary, hypercalcaemic type distinguishes these tumours from their mimics
    Histopathology, 2016
    Co-Authors: Blaise A. Clarke, Anthony N. Karnezis, David G Huntsman, Leora Witkowski, Tuyet N Ton Nu, Patricia Shaw, C. Blake Gilks, Neil J. Sebire, Janez Lamovec, Lawrence M. Roth
    Abstract:

    Aims Molecular investigation of small-cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) has revealed that it is a monogenetic tumour characterized by alteration of SMARCA4 (BRG1), encoding a member of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodelling complex. A large majority of cases show loss of expression of the corresponding SMARCA4/BRG1 protein. Furthermore, three cases of SCCOHT with retained SMARCA4 protein expression showed loss of SMARCB1/INI1 expression. The aim of this study was to assess the sensitivity and specificity of loss of SMARCA4 expression as a diagnostic test for SCCOHT. Methods and results We performed SMARCA4 and SMARCB1 staining in 245 tumours, many of which were potentially in the differential diagnosis of SCCOHT. We also stained 56 cases of SCCOHT for SMARCA4 and 37 of these for SMARCB1. Fifty-four of the SCCOHT cases showed complete absence of SMARCA4 expression. The two cases with retained expression showed molecular alteration of SMARCA4. Of the 217 other neoplasms with interpretable staining, all retained SMARCA4 expression. Although the majority showed diffuse, strong nuclear expression, a heterogeneous, typically weak staining pattern was present in 13% of cases. All 37 cases of SCCOHT tested and all other neoplasms, apart from three malignant rhabdoid tumours, showed retained nuclear SMARCB1 expression. Loss of SMARCA4 expression had a sensitivity of 96.55% and specificity of 100%. Conclusions Loss of SMARCA4 expression is sensitive and specific for SCCOHT. Although some mimics show heterogeneous expression, there is retention of nuclear staining in at least a part of the tumour; therefore, only complete loss of staining should be regarded as being supportive of SCCOHT.

  • dual loss of the swi snf complex atpases smarca4 brg1 and SMARCA2 brm is highly sensitive and specific for small cell carcinoma of the ovary hypercalcaemic type
    The Journal of Pathology, 2016
    Co-Authors: Anthony N. Karnezis, William P D Hendricks, Yemin Wang, Pilar Ramos, Esther Oliva, Emanuela Dangelo, Jaime Prat, Marisa R Nucci, Torsten O Nielsen, Christine Chow
    Abstract:

    Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a lethal and sometimes familial ovarian tumour of young women and children. We and others recently discovered that over 90% of SCCOHTs harbour inactivating mutations in the chromatin remodelling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually exclusive ATPases of the SWI/SNF chromatin remodelling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry in more than 3000 primary gynaecological tumours. Among ovarian tumours, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high-grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumour cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4-negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumours, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase inhibitor trichostatin A. Re-expression of SMARCA4 or SMARCA2 inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2, is highly sensitive and specific for SCCOHT and that restoration of either SWI/SNF ATPase can inhibit the growth of SCCOHT cell lines.

  • abstract a33 dual loss of the swi snf complex atpases smarca4 brg1 and SMARCA2 brm is highly sensitive and specific for small cell carcinoma of the ovary hypercalcemic type
    Clinical Cancer Research, 2016
    Co-Authors: Anthony N. Karnezis, William P D Hendricks, Yemin Wang, Pilar Ramos, Esther Oliva, Emanuela Dangelo, Jaime Prat, Marisa R Nucci, Holly Yin, Torsten O Nielsen
    Abstract:

    Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a lethal and sometimes familial ovarian tumor of young women and children. We and others recently discovered that over 90% of SCCOHT harbor inactivating mutations in the chromatin remodeling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually-exclusive ATPases of the SWI/SNF chromatin remodeling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry (IHC) in more than 3000 primary gynecologic tumors. Among ovarian tumors, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high-grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumor cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4-negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumors, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase (HDAC) inhibitor trichostatin A. Treatment with HDAC inhibitors or re-expression of either SMARCA4 or SMARCA2 potently inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2 loss, is the first highly sensitive and specific diagnostic immunohistochemical marker of SCCOHT, and that HDAC inhibitors are promising agents to explore for the treatment of SCCOHT. Citation Format: Anthony N. Karnezis, Yemin Wang, Pilar Ramos, William Hendricks, Holly Yin, Esther Oliva, Emanuela D9Angelo, Jaime Prat, Marisa R. Nucci, Torsten O. Nielsen, Bernard E. Weissman, Jeffrey M. Trent, C Blake Gilks, David G. Huntsman. Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcemic type. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A33.

  • loss of switch sucrose non fermenting complex protein expression is associated with dedifferentiation in endometrial carcinomas
    Modern Pathology, 2016
    Co-Authors: Anthony N. Karnezis, Basile Tessiercloutier, Lien N Hoang, Mackenzie Coatham, Sarah Ravn, Noorah Almadani, Julie Irving, Bo Meng, Christine Chow
    Abstract:

    Dedifferentiated endometrial carcinoma is an aggressive type of endometrial cancer that contains a mix of low-grade endometrioid and undifferentiated carcinoma components. We performed targeted sequencing of eight dedifferentiated carcinomas and identified somatic frameshift/nonsense mutations in SMARCA4, a core ATPase of the switch/sucrose non-fermenting (SWI/SNF) complex, in the undifferentiated components of four tumors. Immunohistochemical analysis confirmed the loss of SMARCA4 in the undifferentiated component of these four SMARCA4-mutated cases, whereas the corresponding low-grade endometrioid component showed retained SMARCA4 expression. An expanded survey of other members of the SWI/SNF complex showed SMARCB1 loss in the undifferentiated component of two SMARCA4-intact tumors, and all SMARCA4- or SMARCB1-deficient tumors showed concomitant loss of expression of SMARCA2. We subsequently examined the expression of SMARCA2, SMARCA4, and SMARCB1 in an additional set of 22 centrally reviewed dedifferentiated carcinomas and 31 grade 3 endometrioid carcinomas. Combining the results from the index and the expansion set, 15 of 30 (50%) of the dedifferentiated carcinomas examined showed either concurrent SMARCA4 and SMARCA2 loss (37%) or concurrent SMARCB1 and SMARCA2 loss (13%) in the undifferentiated component. The loss of SMARCA4 or SMARCB1 was mutually exclusive. All 31 grade 3 endometrioid carcinomas showed intact expression of these core SWI/SNF proteins. The majority (73%) of the SMARCA4/SMARCA2-deficient and half of SMARCB1/SMARCA2-deficient undifferentiated component developed in a mismatch repair-deficient molecular context. The observed spatial association between SWI/SNF protein loss and histologic dedifferentiation suggests that inactivation of these core SWI/SNF proteins may contribute to the development of dedifferentiated endometrial carcinoma.