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An Orthotopic Model of Serous Ovarian Cancer in Immunocompetent Mice for in vivo Tumor Imaging and Monitoring of Tumor Immune Responses
Published on: November 28, 2010
Survey of NF1 inactivation by surrogate immunohistochemistry in ovarian carcinomas
Martin Köbel1, Rui Zhe Yang2, Eun Young Kang1
1Department of Pathology, University of Calgary, Calgary, Alberta, Canada.
Objective:
Inhibition of the MAPK pathway by MEK inhibitors (MEKi) is currently a therapeutic standard in several cancer types, including ovarian low-grade serous carcinoma (LGSC). A common MAPK pathway alteration in tubo-ovarian high-grade serous carcinoma (HGSC) is the genomic inactivation of neurofibromin 1 (NF1). The primary objectives of our study were to survey the prevalence of NF1 inactivation in the principal ovarian carcinoma histotype as well as to evaluate its associations with clinico-pathological parameters and key biomarkers including BRCA1/2 status in HGSC.
Methods:
A recently commercialized NF1 antibody (clone NFC) was orthogonally validated on an automated immunohistochemistry (IHC) platform and IHC was performed on tissue microarrays containing 2140 ovarian carcinoma cases. Expression was interpreted as loss/inactivated (complete or subclonal) versus normal/retained.
Results:
Loss of NF1 expression was detected in 250/1429 (17.4%) HGSC including 11% with subclonal loss. Survival of NF1-inactivated HGSC patients was intermediate between favorable BRCA1/2 mutated HGSC and unfavorable CCNE1 high-level amplified HGSC. NF1 inactivation was mutually exclusive with CCNE1 high-level amplifications, co-occurred with RB1 loss and occurred at similar frequencies in BRCA1/2 mutated versus wild-type HGSC. NF1 loss was found in 21/286 (7.3%) endometrioid carcinomas with a favorable prognostic association (p = 0.048), and in 4/64 (5.9%) LGSC, mutually exclusive with other driver events.
Conclusions:
NF1 inactivation occurs in a significant subset of BRCA1/2 wild-type HGSC and a subset of LGSC. While the functional effects of NF1 inactivation need to be further characterized, this signifies a potential therapeutic opportunity to explore targeting NF1 inactivation in these tumors.
Insights
Neurofibromin 1 (NF1) inactivation occurs in 17.4% of high-grade serous ovarian carcinomas (HGSC), offering a potential therapeutic target. This finding was observed in a significant subset of BRCA1/2 wild-type HGSC and low-grade serous carcinoma (LGSC).
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MEK inhibitors (MEKi) are a standard therapy for MAPK pathway-driven cancers, including low-grade serous carcinoma (LGSC).
- Genomic inactivation of neurofibromin 1 (NF1) is a common alteration in the MAPK pathway of high-grade serous carcinoma (HGSC).
- Understanding NF1 inactivation prevalence and its clinical associations in ovarian cancer is crucial for therapeutic development.
Purpose of the Study:
- To determine the frequency of NF1 inactivation in the main ovarian carcinoma histotype (HGSC).
- To evaluate the association of NF1 inactivation with clinico-pathological parameters and BRCA1/2 status in HGSC.
- To explore the presence of NF1 inactivation in other ovarian cancer subtypes like LGSC.
Main Methods:
- Orthogonal validation of a commercial NF1 antibody (clone NFC) on an automated immunohistochemistry (IHC) platform.
- IHC analysis of NF1 expression in tissue microarrays from 2140 ovarian carcinoma cases.
- Interpretation of NF1 expression as loss/inactivated (complete or subclonal) versus normal/retained.
Main Results:
- NF1 expression loss was detected in 17.4% of HGSC cases (250/1429), with 11% showing subclonal loss.
- NF1 inactivation in HGSC showed intermediate survival rates between BRCA1/2 mutated and CCNE1-amplified tumors.
- NF1 loss was mutually exclusive with CCNE1 amplifications, co-occurred with RB1 loss, and appeared in both BRCA1/2 mutated and wild-type HGSC.
Conclusions:
- NF1 inactivation is present in a notable subset of BRCA1/2 wild-type HGSC and also in LGSC.
- The findings suggest NF1 inactivation as a potential therapeutic target in these ovarian cancer subtypes.
- Further research is needed to fully characterize the functional impact of NF1 inactivation in ovarian tumors.
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