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Article ; Online: CCAAT/enhancer binding protein delta (C/EBPδ) demonstrates a dichotomous role in tumour initiation and promotion of epithelial carcinoma.

Sowamber, Ramlogan / Chehade, Rania / Bitar, Mahmoud / Dodds, Leah V / Milea, Anca / Slomovitz, Brian / Shaw, Patricia A / George, Sophia H L

EBioMedicine

2019 Volume 44, Page(s) 261–274

Abstract: Background: CCAAT/enhancer binding protein delta (C/EBPδ,CEBPD), a gene part of the highly conserved basic-leucine zipper (b-ZIP) domain of transcriptional factors, is downregulated in 65% of high grade serous carcinomas of the ovary (HGSC). ... ...

Abstract	Background: CCAAT/enhancer binding protein delta (C/EBPδ,CEBPD), a gene part of the highly conserved basic-leucine zipper (b-ZIP) domain of transcriptional factors, is downregulated in 65% of high grade serous carcinomas of the ovary (HGSC). Overexpression of C/EBPδ in different tumours, such as glioblastoma and breast cancer either promotes tumour progression or inhibits growth and has low expression in normal tissue until activated by cytotoxic stressors. Methods: Higher overall expression of C/EBPδ in the luteal phase of the menstrual cycle prompted us to investigate the role of C/EBPδ in carcinogenesis. In vitro experiments were conducted in fallopian tube cell samples and cancer cell lines to investigate the role of C/EBPδ in proliferation, migration, and the epithelial to mesenchymal transition. Findings: Expression of C/EBPδ induced premature cellular arrest and decreased soft agar colony formation. Loss of C/EBPδ in epithelial cancer cell lines did not have significant effects on proliferation, yet overexpression demonstrated downregulation of growth, similar to normal fallopian tube cells. C/EBPδ promoted a partial mesenchymal to epithelial (MET) phenotype by upregulating E-cadherin and downregulating Vimentin and N-cadherin in FTE cells and increased migratory activity, which suggests a regulatory role in the epithelial-mesenchymal plasticity of these cells. Interpretation: Our findings suggest that C/EBPδ regulates the phenotype of normal fallopian tube cells by acting on downstream regulatory factors that are implicated in the development of ovarian serous carcinogenesis. FUND: This study was funded by the CDMRP Ovarian Cancer program (W81WH-0701-0371, W81XWH-18-1-0072), the Princess Margaret Cancer Centre Foundation, Foundation for Women's Cancer - The Belinda-Sue/Mary-Jane Walker Fund, Colleen's Dream Foundation and Sylvester Comprehensive Cancer Center.
MeSH term(s)	Biomarkers, Tumor ; CCAAT-Enhancer-Binding Protein-delta/metabolism ; Carcinoma/etiology ; Carcinoma/metabolism ; Carcinoma/pathology ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Epithelial-Mesenchymal Transition/genetics ; Female ; Gene Expression ; Humans ; Immunohistochemistry ; Models, Biological ; Mucous Membrane/metabolism ; Mucous Membrane/pathology ; Neoplasm Grading ; Phenotype ; RNA Interference
Chemical Substances	Biomarkers, Tumor ; CCAAT-Enhancer-Binding Protein-delta (142662-43-9)
Language	English
Publishing date	2019-05-09
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2019.05.002
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Article: Proliferation in the normal FTE is a hallmark of the follicular phase, not BRCA mutation status.

George, Sophia H L / Milea, Anca / Shaw, Patricia A

Clinical cancer research : an official journal of the American Association for Cancer Research

2012 Volume 18, Issue 22, Page(s) 6199–6207

Abstract: Purpose: Women who have inherited germline mutations of BRCA1/BRCA2 are at increased risk of developing high-grade serous carcinoma, and many of these cancers arise in the distal fimbriated end of the fallopian tube. We have previously shown that the ... ...

Abstract	Purpose: Women who have inherited germline mutations of BRCA1/BRCA2 are at increased risk of developing high-grade serous carcinoma, and many of these cancers arise in the distal fimbriated end of the fallopian tube. We have previously shown that the fallopian tube epithelia of BRCA1 mutation carriers (FTE-BRCA) have altered signaling pathways compared to nonmutation carriers. In this study, we sought to determine whether these differences result in a proliferative advantage to the epithelia in this high-risk patient population and to investigate whether the postovulation environment of the FTE-BRCA compared to FTE from nonmutation carriers experiences a differential abundance of immune cells. Method: Immunohistochemistry for Ki67, CD3, CD8, CD20, and CD68 was performed on histologically normal tubal epithelium (ampulla, n = 83), fimbria (n = 18) with known ovarian cycle status and germline mutation status and for Ki67 on fimbrial epithelium from women (n = 144) with and without BRCA1 or BRCA2 mutations who underwent risk-reducing salpingo-oophorectomy (RRSO). Serous tubal intraepithelial carcinomas (STIC) with concomitant cancer (n = 15) were also analyzed for presence of immune infiltrates. All slides were digitized and analyzed using automated image analysis software. Results: There was no significant difference in the proliferative index in histologically normal FTE between BRCA1/BRCA2 and non-BRCA, in 144 fimbriae and 83 ampullae. The FTE-BRCA1 epithelia did not exhibit a differential presence of lymphocytes or macrophages, however more macrophages were present in the luteal phase compared to the follicular phase epithelia. In STICs macrophages were more abundant than lymphocytes with an incremental increase noted with disease progression. Conclusions: BRCA1/2 mutation carriers exhibited no significant increase in proliferation in the fallopian tube epithelial cells either in the ampulla or fimbriated ends of the tube. Rather, a significant proliferative increase was defined in the cases determined to be in the follicular, or proliferative, preovulatory phase of the ovarian cycle. Finally, we also show an incremental increase in leukocytes invading the STICs and HGSC, implicating a possible role of the leukocytes early in the progression or inhibition of tumor formation, which is independent of ovarian cycle status.
MeSH term(s)	Adult ; Aged ; Carcinoma in Situ/genetics ; Carcinoma in Situ/immunology ; Carcinoma in Situ/pathology ; Case-Control Studies ; Cell Proliferation ; Epithelium/metabolism ; Epithelium/physiology ; Fallopian Tube Neoplasms/genetics ; Fallopian Tube Neoplasms/immunology ; Fallopian Tube Neoplasms/pathology ; Fallopian Tubes/immunology ; Fallopian Tubes/metabolism ; Fallopian Tubes/pathology ; Female ; Follicular Phase ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Association Studies ; Heterozygote ; Humans ; Ki-67 Antigen/metabolism ; Lymphocytes/immunology ; Lymphocytes/metabolism ; Middle Aged ; Mutation ; Transcriptome
Chemical Substances	Ki-67 Antigen
Language	English
Publishing date	2012-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-12-2155
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Zs.A 4223: Show issues

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Article: Integrative Transcriptome Analyses of the Human Fallopian Tube: Fimbria and Ampulla-Site of Origin of Serous Carcinoma of the Ovary.

Sowamber, Ramlogan / Nelson, Omar / Dodds, Leah / DeCastro, Victoria / Paudel, Iru / Milea, Anca / Considine, Michael / Cope, Leslie / Pinto, Andre / Schlumbrecht, Matthew / Slomovitz, Brian / Shaw, Patricia A / George, Sophia H L

Cancers

2020 Volume 12, Issue 5

Abstract: Epithelial ovarian cancer represents a group of heterogeneous diseases with high grade serous cancer (HGSC) representing the most common histotype. Molecular profiles of precancerous lesions found in the fallopian tube have implicated this tissue as the ... ...

Abstract	Epithelial ovarian cancer represents a group of heterogeneous diseases with high grade serous cancer (HGSC) representing the most common histotype. Molecular profiles of precancerous lesions found in the fallopian tube have implicated this tissue as the presumptive site of origin of HGSC. Precancerous lesions are primarily found in the distal fallopian tube (fimbria), near the ovary relative to the proximal tissue (ampulla), nearer to the uterus. The proximity of the fimbria to the ovary and the link between ovulation, through follicular fluid release, and ovarian cancer risk led us to examine transcriptional responses of fallopian tube epithelia (FTE) at the different anatomical sites of the human fallopian tube. Gene expression profiles of matched FTE from the fimbria and from premenopausal women resulted in differentially expressed genes (DEGs): CYYR1, SALL1, FOXP2, TAAR1, AKR1C2/C3/C4, NMBR, ME1 and GSTA2. These genes are part of the antioxidant, stem and inflammation pathways. Comparisons between the luteal phase (post-ovulation) to the follicular phase (pre-ovulation) demonstrated greater differences in DEGs than a comparison between fimbria and fallopian tube anatomical differences alone. This data suggests that cyclical transcriptional changes experienced in pre-menopause are inherent physiological triggers that expose the FTE in the fimbria to cytotoxic stressors. These cyclical exposures induce transcriptional changes reflective of genotoxic and cytotoxic damage to the FTE in the fimbria which are closely related to transcriptional and genomic alterations observed in ovarian cancer.
Language	English
Publishing date	2020-04-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12051090
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Article ; Online: Phase I Study of the CD47 Blocker TTI-621 in Patients with Relapsed or Refractory Hematologic Malignancies.

Ansell, Stephen M / Maris, Michael B / Lesokhin, Alexander M / Chen, Robert W / Flinn, Ian W / Sawas, Ahmed / Minden, Mark D / Villa, Diego / Percival, Mary-Elizabeth M / Advani, Anjali S / Foran, James M / Horwitz, Steven M / Mei, Matthew G / Zain, Jasmine / Savage, Kerry J / Querfeld, Christiane / Akilov, Oleg E / Johnson, Lisa D S / Catalano, Tina /

Petrova, Penka S / Uger, Robert A / Sievers, Eric L / Milea, Anca / Roberge, Kathleen / Shou, Yaping / O'Connor, Owen A

Clinical cancer research : an official journal of the American Association for Cancer Research

2021 Volume 27, Issue 8, Page(s) 2190–2199

Abstract: Purpose: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/ ... ...

Abstract	Purpose: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies. Patients and methods: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR). Results: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, Conclusions: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; CD47 Antigen/antagonists & inhibitors ; Drug Resistance, Neoplasm ; Female ; Hematologic Neoplasms/drug therapy ; Hematologic Neoplasms/immunology ; Humans ; Immune Checkpoint Inhibitors/administration & dosage ; Immune Checkpoint Inhibitors/adverse effects ; Immunoglobulin G/administration & dosage ; Immunoglobulin G/adverse effects ; Infusions, Intravenous ; Male ; Maximum Tolerated Dose ; Middle Aged ; Neoplasm Recurrence, Local/drug therapy ; Neoplasm Recurrence, Local/immunology ; Treatment Outcome ; Young Adult
Chemical Substances	CD47 Antigen ; CD47 protein, human ; Immune Checkpoint Inhibitors ; Immunoglobulin G ; TTI-621
Language	English
Publishing date	2021-01-15
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-20-3706
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Zs.A 4223: Show issues

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Article ; Online: Identification of abrogated pathways in fallopian tube epithelium from BRCA1 mutation carriers.

George, Sophia Hl / Greenaway, James / Milea, Anca / Clary, Victoria / Shaw, Sanjeev / Sharma, Monika / Virtanen, Carl / Shaw, Patricia A

The Journal of pathology

2011 Volume 225, Issue 1, Page(s) 106–117

Abstract: The discovery of occult invasive and intra-epithelial tubal carcinomas in BRCA1 mutation carriers undergoing prophylactic surgery has implicated the fallopian tube epithelium as the source of serous cancer. However, little is known of the early molecular ...

Abstract	The discovery of occult invasive and intra-epithelial tubal carcinomas in BRCA1 mutation carriers undergoing prophylactic surgery has implicated the fallopian tube epithelium as the source of serous cancer. However, little is known of the early molecular events of serous oncogenesis, or why cancers in BRCA1 mutation carriers are found preferentially in tissues which are responsive to reproductive hormones. We hypothesize that molecular alterations present in morphologically normal tubal epithelium from BRCA1 heterozygotes reflect the earliest events in serous carcinogenesis and may be markers of increased cancer risk as well as targets for risk reduction. Genetic profiling of microdissected tubal epithelium from histologically normal BRCA1 mutation carriers and controls was performed. We sought to define a signature which differentiated BRCA1 mutant tubal epithelium from women with low risk of developing ovarian cancer. Molecular differences between the follicular and luteal phases were prominent and, by using filtering techniques and a two-way ANOVA without a False Discovery Rate correction, we identified 440 probe sets with a more than two-fold change in gene expression related to BRCA1 mutation status. Using gene ontology and known associations to cancer pathways, we selected five genes for further analysis by qPCR and immunohistochemistry, and were able to demonstrate statistically significant differentiation of BRCA1 and control cases in an independent set of cases. The altered expression profiles in histologically normal tubal epithelium from BRCA1 heterozygotes suggest that these cells may respond differently to microenvironmental stresses.
MeSH term(s)	Adult ; Case-Control Studies ; Cluster Analysis ; Cystadenocarcinoma, Serous/genetics ; Cystadenocarcinoma, Serous/metabolism ; Epithelium/metabolism ; Fallopian Tube Neoplasms/genetics ; Fallopian Tube Neoplasms/metabolism ; Fallopian Tubes/metabolism ; Female ; Follicular Phase/physiology ; Gene Expression Profiling/methods ; Gene Expression Regulation ; Genes, BRCA1 ; Heterozygote ; Humans ; Luteal Phase/physiology ; Microdissection/methods ; Middle Aged ; Mutation ; Oligonucleotide Array Sequence Analysis/methods ; Precancerous Conditions/genetics ; Precancerous Conditions/metabolism ; Signal Transduction/genetics
Language	English
Publishing date	2011-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3119-7
ISSN	1096-9896 ; 0022-3417
ISSN (online)	1096-9896
ISSN	0022-3417
DOI	10.1002/path.2927
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Article ; Online: Low malignant potential tumors with micropapillary features are molecularly similar to low-grade serous carcinoma of the ovary.

May, Taymaa / Virtanen, Carl / Sharma, Monika / Milea, Anca / Begley, Heather / Rosen, Barry / Murphy, K Joan / Brown, Theodore J / Shaw, Patricia A

Gynecologic oncology

2010 Volume 117, Issue 1, Page(s) 9–17

Abstract: Objective: Low-grade serous carcinoma (LGSC) is a chemoresistant ovarian neoplasm thought to potentially arise in a background of low malignant potential tumors (LMP), which are typically non-aggressive. However, LMP with micropapillary features (LMP-MP) ...

Abstract	Objective: Low-grade serous carcinoma (LGSC) is a chemoresistant ovarian neoplasm thought to potentially arise in a background of low malignant potential tumors (LMP), which are typically non-aggressive. However, LMP with micropapillary features (LMP-MP) have more aggressive clinical behavior and may represent an intermediate in progression to LGSC. The objective of this study was to obtain and compare gene expression profiles of LMP, LMP-MP and LGSC to determine if LMP-MP more closely resembles LGSC, and to identify genes involved in LGSC carcinogenesis. Methods: Epithelial cells from LMP (n=17), LMP-MP (n=9) and LGSC (n=11) were isolated by laser capture microdissection. RNA was extracted, reverse transcribed to cDNA, amplified and hybridized to Affymetrix U133 Plus2 genechip arrays. Gene expression data were checked for quality, filtered and significantly altered genes between subgroups were identified. Differential expression of selected genes was verified by RT-qPCR and immunohistochemistry. Results: Gene expression analysis identified differential expression between LMP and LMP-MP, LMP and LGSC but not LMP-MP and LGSC. Integration of differentially expressed genes into the protein interaction database CytoScape highlighted gene products in the MAPK pathway as differentially regulated between LMP and LGSC. Four genes were selected and validated by RT-qPCR performed on microarray samples (n=15) and immunohistochemistry on a representative microarray (n=57). Conclusion: The gene expression profile of LMP-MP is similar to LGSC and distinct from LMP, reflecting their more aggressive clinical behavior. Candidate genes in the MAPK pathway were highlighted which may play a role in LGSC carcinogenesis and indicate potential therapeutic targets.
MeSH term(s)	Adaptor Proteins, Signal Transducing/biosynthesis ; Adaptor Proteins, Signal Transducing/genetics ; Adult ; Aged ; Carcinoma, Papillary/genetics ; Carcinoma, Papillary/metabolism ; Carcinoma, Papillary/pathology ; Cyclin-Dependent Kinase 2/biosynthesis ; Cyclin-Dependent Kinase 2/genetics ; Cystadenocarcinoma, Serous/genetics ; Cystadenocarcinoma, Serous/metabolism ; Cystadenocarcinoma, Serous/pathology ; Female ; Gene Expression Profiling ; Humans ; Immunohistochemistry ; Intracellular Signaling Peptides and Proteins/genetics ; Middle Aged ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Phosphoproteins/biosynthesis ; Phosphoproteins/genetics ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/biosynthesis ; Poly(ADP-ribose) Polymerases/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Young Adult
Chemical Substances	Adaptor Proteins, Signal Transducing ; Intracellular Signaling Peptides and Proteins ; PEA15 protein, human ; Phosphoproteins ; TANK protein, human ; PARP1 protein, human (EC 2.4.2.30) ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; CDK2 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 2 (EC 2.7.11.22)
Language	English
Publishing date	2010-04
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2010.01.006
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Zs.A 885: Show issues

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Article ; Online: A distinct innate lymphoid cell population regulates tumor-associated T cells.

Nature medicine

2017 Volume 23, Issue 3, Page(s) 368–375

Abstract: Antitumor T cells are subject to multiple mechanisms of negative regulation. Recent findings that innate lymphoid cells (ILCs) regulate adaptive T cell responses led us to examine the regulatory potential of ILCs in the context of cancer. We identified a ...

Abstract	Antitumor T cells are subject to multiple mechanisms of negative regulation. Recent findings that innate lymphoid cells (ILCs) regulate adaptive T cell responses led us to examine the regulatory potential of ILCs in the context of cancer. We identified a unique ILC population that inhibits tumor-infiltrating lymphocytes (TILs) from high-grade serous tumors, defined their suppressive capacity in vitro, and performed a comprehensive analysis of their phenotype. Notably, the presence of this CD56
MeSH term(s)	CD3 Complex/metabolism ; CD56 Antigen/metabolism ; Cell Proliferation ; Cytokines/immunology ; Flow Cytometry ; Humans ; Immune Tolerance ; Immunity, Innate/immunology ; Immunotherapy ; Interleukins/immunology ; Killer Cells, Natural/immunology ; Lymphocytes/immunology ; Lymphocytes/metabolism ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/metabolism ; Natural Cytotoxicity Triggering Receptor 1/metabolism ; Neoplasms/immunology ; Neoplasms/therapy ; T-Lymphocytes/immunology ; Tumor Microenvironment/immunology ; Interleukin-22
Chemical Substances	CD3 Complex ; CD56 Antigen ; Cytokines ; Interleukins ; NCR1 protein, human ; Natural Cytotoxicity Triggering Receptor 1
Language	English
Publishing date	2017-02-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/nm.4278
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Article ; Online: Retinoblastoma pathway deregulatory mechanisms determine clinical outcome in high-grade serous ovarian carcinoma.

Milea, Anca / George, Sophia H L / Matevski, Donco / Jiang, Haiyan / Madunic, Mary / Berman, Hal K / Gauthier, Mona L / Gallie, Brenda / Shaw, Patricia A

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

2013 Volume 27, Issue 7, Page(s) 991–1001

Abstract: Alterations in the retinoblastoma pathway are frequent in ovarian/tubal high-grade serous cancers, but the mechanism of deregulation and the impact on patient outcome are poorly understood. A cohort of 334 high-grade serous carcinomas was studied by ... ...

Abstract	Alterations in the retinoblastoma pathway are frequent in ovarian/tubal high-grade serous cancers, but the mechanism of deregulation and the impact on patient outcome are poorly understood. A cohort of 334 high-grade serous carcinomas was studied by immunohistochemical analysis of RB1, p16, cyclin D1, cyclin E1, and Ki67. Additional detailed analyses including RB1 allelic deletion (n=42), mutation (n=75), methylation (n=31), and SNP array analyses (n=75) were performed on cases with clinical parameters, including age, debulking status, treatment, and clinical outcome. p16/RB1 expression results yielded three distinct clinically relevant subgroups upon multivariable analysis controlling for stage, debulking status, and treatment types: p16 homogeneous/RB1+ with the shortest progression-free survival (median 15 months (95% CI: 13-18); P=0.016) compared with the p16 heterogeneous/RB1+ subgroup (median 22 months (95% CI: 16-32)) and the p16 homogeneous/RB1- subgroup (median 20 months (95% CI: 15-24)). Patients in the p16 homo/RB1- subgroup showed a significant increase in overall survival (>60 months; P=0.013), which suggests an increase in sensitivity to cytotoxic agents. Analyses of Rb pathway mechanistic differences among these groups revealed frequent RB1 genomic alterations such as RB1 allelic loss and/or large spanning deletions (83%) in the p16 homo/RB1- subgroups, also indicating that RB1 deletions are frequent in high-grade serous carcinoma. CCNE1 gene gains/amplifications were frequent in the p16 homogeneous/RB1+ subgroup (68%) and cyclin D1 protein overexpression was predominantly characteristic of the p16 heterogeneous/RB1+ subgroup. These subcategories occur early in tumor progression and are seen with similar frequency in the cancer precursor lesion, serous tubal intra-epithelial carcinoma. Overall, this study uniquely identifies multiple non-synonymous mechanisms of retinoblastoma pathway deregulation that correlate with significantly different clinical outcomes. Furthermore, deregulations identified in precursor lesions suggest a key role of this pathway in serous tumor development. Recognition of these categories may identify patients with increased sensitivity to chemotherapy and new opportunities for novel therapeutics.
MeSH term(s)	Alleles ; Biomarkers, Tumor/metabolism ; Cyclin D1/metabolism ; Cyclin E/metabolism ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cystadenocarcinoma, Serous/genetics ; Cystadenocarcinoma, Serous/metabolism ; Cystadenocarcinoma, Serous/mortality ; Disease-Free Survival ; Female ; Humans ; Immunohistochemistry ; Middle Aged ; Mutation ; Oncogene Proteins/metabolism ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/mortality ; Prognosis ; Retinoblastoma Protein/genetics ; Retinoblastoma Protein/metabolism
Chemical Substances	Biomarkers, Tumor ; CCNE1 protein, human ; Cyclin E ; Cyclin-Dependent Kinase Inhibitor p16 ; Oncogene Proteins ; Retinoblastoma Protein ; Cyclin D1 (136601-57-5)
Language	English
Publishing date	2013-12-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	645073-8
ISSN	1530-0285 ; 0893-3952
ISSN (online)	1530-0285
ISSN	0893-3952
DOI	10.1038/modpathol.2013.218
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