Targeting progesterone signaling prevents metastatic ovarian cancer

Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (∼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene.

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Tumour Versus Germline BRCA Testing in Ovarian Cancer: A Single-Site Institution Experience in the United Kingdom

Diagnostics ◽

10.3390/diagnostics11030547 ◽

2021 ◽

Vol 11 (3) ◽

pp. 547

Author(s):

Iolia Akaev ◽

Siavash Rahimi ◽

Olubukola Onifade ◽

Francis John Edward Gardner ◽

David Castells-Rufas ◽

...

Keyword(s):

Ovarian Cancer ◽

Unknown Origin ◽

Parp Inhibitors ◽

Serous Carcinoma ◽

High Grade ◽

Brca1 And Brca2 ◽

Brca Mutations ◽

Epithelial Cancers ◽

Pathogenic Variants ◽

Pathogenic Mutations

The aim of this audit was to evaluate the usefulness and serviceability of testing for pathogenic mutations in BRCA1 or BRCA2 (BRCA1/2) genes in ovarian cancer (OC) patients. One hundred and thirty-five patients with more common histological sub-types of OC were retrospectively identified between 2011 and 2019. The fail rate of the molecular analysis was 7.4% (10/135). One hundred and twenty-five records were evaluated: 99 (79.2%) patients had wild-type BRCA (both somatic and germline); tumour BRCA1/2 (tBRCA1/2) pathogenic mutations were found in 20 (16%) patients with distribution between BRCA1 and BRCA2 being 40% and 60%, respectively; 13 (10.4%) patients with pathogenic variants had germline mutations; and tBRCA1/2 with variant of unknown significance (VUS), in the absence of pathogenic BRCA1 or BRCA2 variants, was detected in 6 (4.8%) patients. Our data show that expanding the molecular service to the routine first-tumour testing for patients with OC will potentially increase the detection rate of BRCA mutations, thereby providing early benefits of PARP inhibitors therapy. The tumour testing service should continue to be offered to newly diagnosed patients with high-grade epithelial cancers, including high-grade serous carcinoma, but also with carcinosarcomas and poorly-differentiated metastatic adenocarcinomas of unknown origin.

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Mechanisms of Chromosomal Instability in High-grade Serous Ovarian Carcinoma

10.1101/727537 ◽

2019 ◽

Cited By ~ 1

Author(s):

N. Tamura ◽

N. Shaikh ◽

D. Muliaditan ◽

J. McGuinness ◽

D. Moralli ◽

...

Keyword(s):

Ovarian Cancer ◽

Ovarian Carcinoma ◽

Single Molecule ◽

Chromosomal Instability ◽

Poor Prognosis ◽

Spindle Assembly Checkpoint ◽

Western World ◽

Cancer Type ◽

High Grade ◽

Serous Ovarian Carcinoma

AbstractChromosomal instability (CIN), the continual gain and loss of chromosomes or parts of chromosomes, occurs in the majority of cancers and confers poor prognosis. Mechanisms driving CIN remain unknown in most cancer types due to a scarcity of functional studies. High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, is the major cause of death due to gynaecological malignancy in the Western world with chemotherapy resistance developing in almost all patients. HGSC exhibits high rates of chromosome aberrations and knowledge of causative mechanisms is likely to represent an important step towards combating the poor prognosis of this disease. However, very little is known about the nature of chromosomal instability exhibited by this cancer type in particular due to a historical lack of appropriate cell line models. Here we perform the first in-depth functional characterisation of mechanisms driving CIN in HGSC by analysing eight cell lines that accurately recapitulate HGSC genetics as defined by recent studies. We show, using a range of established functional CIN assays combined with live cell imaging and single molecule DNA fibre analysis, that multiple mechanisms co-exist to drive CIN in HGSC. These include supernumerary centrosomes, elevated microtubule dynamics and DNA replication stress. By contrast, the spindle assembly checkpoint was intact. These findings are relevant for developing therapeutic approaches to manipulating CIN in ovarian cancer, and suggests that such approaches may need to be multimodal to combat multiple co-existing CIN drivers.

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Differential expression of SLIT and NTRK-like family member 3 in human epithelial ovarian cancer.

10.31219/osf.io/jdrct ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Family Member ◽

Fallopian Tube ◽

Expression Profiles ◽

Gynecologic Cancer ◽

Progression Free Survival ◽

High Grade ◽

Primary Tumors ◽

Ovarian Cancers

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published and public microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding SLIT and NTRK-like family member 3, SLITRK3, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. SLITRK3 expression was significantly lower in high-grade serous ovarian tumors relative to normal fallopian tube. SLITRK3 expression correlated with progression-free survival in patients with ovarian cancer. These data indicate that expression of SLITRK3 is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. SLITRK3 may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

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Differential expression of LSM4 homolog, U6 small nuclear RNA and mRNA degradation associated in human epithelial ovarian cancer.

10.31219/osf.io/g42sh ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Fallopian Tube ◽

Expression Profiles ◽

Mrna Degradation ◽

High Grade ◽

Small Nuclear Rna ◽

Primary Tumors ◽

Ovarian Cancers ◽

Nuclear Rna

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding LSM4 homolog, U6 small nuclear RNA and mRNA degradation associated, LSM4, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. LSM4 expression was significantly higher in high-grade serous ovarian tumors relative to normal fallopian tube. LSM4 expression correlated with overall survival in patients with ovarian cancer. These data indicate that expression of LSM4 is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. LSM4 may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

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The forkhead box L2 transcription factor (FOXL2) is differentially expressed in high-grade serous ovarian cancers.

10.31219/osf.io/8nt6v ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Expression Profiles ◽

Gynecologic Cancer ◽

Ovarian Tumors ◽

High Grade ◽

Normal Ovary ◽

Primary Tumors ◽

Forkhead Box ◽

Ovarian Cancers

Ovarian cancer is the most lethal gynecologic cancer (1). We sought to identify genes associated with high-grade serous ovarian cancer (HGSC) by comparing global gene expression profiles of normal ovary with that of primary tumors from women diagnosed with HGSC using published microarray data (2, 3). We identified the forkhead box L2, (FOXL2) (4) as among the genes whose expression was most different in HGSC ovarian tumors. FOXL2 expression was significantly lower in ovarian tumors relative to normal ovary. FOXL2 has established roles in ovarian development (4, 5), and the FOXL2 gene is mutated in granulosa-cell tumors of the ovary (6). These data indicate FOXL2 might also be perturbed, at the level of gene expression, in high-grade serous ovarian cancers.

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Differential expression of murine retrovirus integration site 1 homolog in human epithelial ovarian cancer.

10.31219/osf.io/ru5e6 ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Fallopian Tube ◽

Integration Site ◽

Expression Profiles ◽

Gynecologic Cancer ◽

High Grade ◽

Primary Tumors ◽

Ovarian Cancers ◽

Retrovirus Integration

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published and public microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding murine retrovirus integration site 1 homolog, MRVI1, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. MRVI1 expression was significantly lower in high-grade serous ovarian tumors relative to normal fallopian tube. MRVI1 expression correlated with overall survival in patients with ovarian cancer. These data indicate that expression of MRVI1 is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. MRVI1 may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

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Differential expression of sarcospan in human epithelial ovarian cancer.

10.31219/osf.io/k4ceq ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Fallopian Tube ◽

Expression Profiles ◽

Gynecologic Cancer ◽

Gene Expression Profiles ◽

Progression Free Survival ◽

High Grade ◽

Primary Tumors ◽

Ovarian Cancers

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding sarcospan, SSPN, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. SSPN expression was significantly lower in high-grade serous ovarian tumors relative to normal fallopian tube. SSPN expression correlated with progression-free survival in patients with ovarian cancer. These data indicate that expression of SSPN is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. SSPN may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

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Thyrotroph embryonic factor (TEF) is differentially expressed in high-grade serous ovarian cancers.

10.31219/osf.io/djec5 ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Ovarian Cancer ◽

Transcription Factor ◽

Differential Expression ◽

Expression Profiles ◽

Gynecologic Cancer ◽

Bzip Transcription Factor ◽

High Grade ◽

Significant Differential Expression ◽

Primary Tumors ◽

Embryonic Factor

Ovarian cancer is the most lethal gynecologic cancer (1). We sought to identify genes associated with high-grade serous ovarian cancer (HGSC) by comparing global gene expression profiles of normal ovary with that of primary tumors from women diagnosed with HGSC using published microarray data (2, 3). We previously reported differential expression of the PAR-bZIP transcription factor HLF in HGSC (4). Here, we report significant differential expression of a second PAR-bZIP transcription factor, thyrotroph embryonic factor (TEF) (5) in high-grade serous ovarian tumors.

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Differential expression of phosphodiesterase 5A in human epithelial ovarian cancer.

10.31219/osf.io/3jkpe ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Fallopian Tube ◽

Expression Profiles ◽

Gynecologic Cancer ◽

Gene Expression Profiles ◽

Progression Free Survival ◽

High Grade ◽

Primary Tumors ◽

Ovarian Cancers

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding phosphodiesterase 5A, PDE5A, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. PDE5A expression was significantly lower in high-grade serous ovarian tumors relative to normal fallopian tube. PDE5A expression correlated with progression-free survival in patients with p53 mutant ovarian cancer. These data indicate that expression of PDE5A is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. PDE5A may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

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Precision Oncology of High-Grade Ovarian Cancer Defined through Targeted Sequencing

Cancers ◽

10.3390/cancers13205240 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5240

Author(s):

Sandra Wessman ◽

Beatriz Bohorquez Fuentes ◽

Therese Törngren ◽

Anders Kvist ◽

Georgia Kokaraki ◽

...

Keyword(s):

Ovarian Cancer ◽

Molecular Characterization ◽

Parp Inhibitor ◽

Clinical Information ◽

Undifferentiated Carcinoma ◽

Serous Carcinoma ◽

Precision Oncology ◽

High Grade ◽

Histologic Diagnosis ◽

Germline Testing

Background: We examined whether molecular characterization of high-grade epithelial ovarian cancer can inform the diagnosis and/or identify potential actionable targets. Methods: All of the consecutively sequenced high-grade ovarian tumours with consent between 2014 until 2019 were included. A total of 274 tumours underwent next generation sequencing using a targeted panel. Results: Patients with high-grade ovarian epithelial cancer were consented to prospective molecular characterization. Clinical information was extracted from their medical record. Tumour DNA was subjected to sequencing, and selected patients received PARP inhibitor therapy. Conclusions: Tumours from 274 women were sequenced, including high-grade serous carcinoma (n = 252), clear cell carcinoma (n = 4), carcinosarcoma (n = 9), endometrioid carcinoma (n = 3), undifferentiated carcinoma (n = 1), and mixed tumours (n = 5). Genomic profiling did not influence histologic diagnosis. Mutations were identified in TP53, BRCA1, BRCA2, as well as additional homologous recombination repair pathway genes BARD1, ATR, CHEK2, PALB2, RAD51D, RAD50, SLX4, FANCA, RAD51C, and RAD54L. In addition, mutations in PTEN and CDKN2A were identified. Several somatic mutations with implications for germline testing were identified, including RMI1, STK11, and CDH1. Germline testing identified 16 previously unknown BRCA1/2 carriers. Finally, 20 patients were treated with the PARP inhibitor olaparib based on the sequencing results.

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