The main objective of this study is to demonstrate the tumor suppressor role of ARID1A in the pathogenesis of endometrium-related cancer. ARID1A (BAF250A), a gene participating in the formation of a BRG1 SWI/SNF chromatin remodeling complex, has emerged as a potential tumor suppressor because we have recently demonstrated frequent somatic mutations of ARID1A in 46%-57% of ovarian clear cell carcinomas, 40% of uterine endometrioid carcinomas and 30% of ovarian endometrioid carcinomas. In our studies, the vast majority of the mutations are either the out-of-frame insertion/deletion type causing frameshift or nonsense mutations. Both mutation patterns are characteristic of classical tumor suppressor genes. Like other chromatin remodeling factors, ARID1A/BRG1 complex plays an important role in regulating transcriptional activity among many other cellular functions. Thus, we hypothesize that ARID1A is a tumor suppressor of which inactivating mutations contribute to the development of endometrium-related carcinoma by facilitating transcription of a set of cancer- related genes. To test this hypothesis, we propose three specific aims. To test the above hypotheses, we propose the following specific aims:
Aim 1 : Demonstrate the tumor suppressive effects of wild-type ARID1A.
Aim 2 : Investigate Validate and characterize candidate ARID1A-regulated genes.
Aim 3 : Analyze ARID1A in- frame deletion mutants to reveal a novel mechanism in regulating the steady-state protein levels of ARID1A. The results from this study will address several critical questions centering the roles of ARID1A in cancer biology and should have implication for translational cancer research.

Public Health Relevance

The purpose of this study is to test our hypothesis that ARID1A is a tumor suppressor of which inactivating mutations contribute to the development of endometrium-related carcinoma by facilitating transcription of a set of cancer-related genes. The expected results should be fundamental for future studies that aim at elucidating the biological roles of ARID1A and SWI/SNF complexes in endometrium-related tumorigenesis and help to understand how aberrations of chromatin remodeling participate in the development of human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA165807-01
Application #
8257679
Study Section
Special Emphasis Panel (ZRG1-OBT-A (02))
Program Officer
Yassin, Rihab R,
Project Start
2011-12-13
Project End
2013-11-30
Budget Start
2011-12-13
Budget End
2012-11-30
Support Year
1
Fiscal Year
2012
Total Cost
$176,175
Indirect Cost
$67,425
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Suryo Rahmanto, Yohan; Jung, Jin-Gyoung; Wu, Ren-Chin et al. (2016) Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells. J Biol Chem 291:9690-9
Kurman, Robert J; Shih, Ie-Ming (2016) The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded. Am J Pathol 186:733-47
Kurman, Robert J; Shih, Ie-Ming (2016) Seromucinous Tumors of the Ovary. What's in a Name? Int J Gynecol Pathol 35:78-81
Kobayashi, Yusuke; Kashima, Hiroyasu; Wu, Ren-Chin et al. (2015) Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models. Clin Cancer Res 21:4652-62
Wu, Ren-Chin; Wang, Tian-Li; Shih, Ie-Ming (2014) The emerging roles of ARID1A in tumor suppression. Cancer Biol Ther 15:655-64
Guan, Bin; Rahmanto, Yohan Suryo; Wu, Ren-Chin et al. (2014) Roles of deletion of Arid1a, a tumor suppressor, in mouse ovarian tumorigenesis. J Natl Cancer Inst 106:
Wu, Ren-Chin; Ayhan, Ayse; Maeda, Daichi et al. (2014) Frequent somatic mutations of the telomerase reverse transcriptase promoter in ovarian clear cell carcinoma but not in other major types of gynaecological malignancy. J Pathol 232:473-81
Guan, Bin; Magomi, Tae; Wang, Tian-Li et al. (2013) Establishing isogenic inducible cell lines using founder reporter lines and recombinase-mediated cassette exchange. Biotechniques 55:233-42
Maeda, Daichi; Shih, Ie-Ming (2013) Pathogenesis and the role of ARID1A mutation in endometriosis-related ovarian neoplasms. Adv Anat Pathol 20:45-52
Mao, Tsui-Lien; Ardighieri, Laura; Ayhan, Ayse et al. (2013) Loss of ARID1A expression correlates with stages of tumor progression in uterine endometrioid carcinoma. Am J Surg Pathol 37:1342-8

Showing the most recent 10 out of 14 publications