期刊
ONCOTARGET
卷 7, 期 6, 页码 6353-6368出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7047
关键词
epithelial ovarian cancer; progression free survival; genome-wide association study; PSIP1; chromosome conformation capture
资金
- Cancer Australia
- Haplotype-based genome screen for ovarian cancer loci [R01CA114343]
- Ovarian Cancer Research Fund
- U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729]
- National Health and Medical Research Council (NHMRC) of Australia [400281, 400413]
- Cancer Council Victoria
- Cancer Council Queensland
- Cancer Council New South Wales
- Cancer Council South Australia
- Cancer Foundation of Western Australia
- Cancer Council Tasmania
- NHMRC [496675, 1051698, 1058415]
- National Breast Cancer Foundation (NBCF) Australia
- Weekend to End Women's Cancer Research Grant
- University of Sydney Cancer Research Fund
- Cancer Institute NSW through the Sydney-West Translational Cancer Research Centre
- Cancer Institute NSW scholarship
- CR-UK
- ELAN Funds of the University of Erlangen-Nuremberg
- Nationaal Kankerplan
- Ministry of Health, Labour and Welfare
- American Cancer Society Early Detection Professorship [120950-SIOP-06-258- 06-COUN]
- Entertainment Industry Foundation
- National Cancer Institute, Bethesda, MD [RO1 CA 61107]
- Danish Cancer Society, Copenhagen, Denmark [94 222 52]
- Mermaid I project
- Sherie Hildreth Ovarian Cancer Research Fund
- OHSU Foundation
- Cancer Research UK [C536/A6689]
- NIH/NIGMS [K08GM089941, UO1GM61393]
- NIH/NCI [R21 CA139278]
- University of Chicago Cancer Center Support Grant [P30 CA14599]
- Breast Cancer SPORE Career Development Award
- [R01 CA122443]
- [P50 CA136393]
- Cancer Research UK [13086, 16561] Funding Source: researchfish
- National Breast Cancer Foundation [ECF-12-04] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10124] Funding Source: researchfish
- National Health and Medical Research Council of Australia [1058415] Funding Source: NHMRC
Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P= 7x10(-5), HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression.
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