Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer

French JD, Johnatty SE, Lu Y, Beesley J, Gao B, Kalimutho M, Henderson MJ, Russell AJ, Kar S, Chen X, Hillman KM, Kaufmann S, Sivakumaran H, O'Reilly M, Wang C, Korbie DJ, Lambrechts D, Despierre E, Van Nieuwenhuysen E, Lambrechts S, Vergote I, Karlan B, Lester J, Orsulic S, Walsh C, Fasching P, Beckmann M, Ekici AB, Hein A, Matsuo K, Hosono S, Pisterer J, Hillemanns P, Nakanishi T, Yatabe Y, Goodman MT, Lurie G, Matsuno RK, Thompson PJ, Pejovic T, Bean Y, Heitz F, Harter P, Du Bois A, Schwaab I, Hogdall E, Kjaer SK, Jensen A, Hogdall C, Lundvall L, Engelholm SA, Brown B, Flanagan JM, Metcalf MD, Siddiqui N, Sellers T, Fridley B, Cunningham J, Schildkraut JM, Iversen E, Weber RP, Brennan D, Berchuck A, Pharoah P, Harnett P, Norris MD, Haber M, Goode EL, Lee JS, Khanna KK, Meyer KB, Chenevix-Trench G, Defazio A, Edwards SL, Macgregor S (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 7

Pages Range: 6353-68

Journal Issue: 6

DOI: 10.18632/oncotarget.7047

Abstract

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.

Authors with CRIS profile

Involved external institutions

University of Cambridge United Kingdom (GB) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University of Sydney (USYD) Australia (AU) Mayo Clinic United States (USA) (US) Children's Cancer Institute Australia Australia (AU) Duke University United States (USA) (US) University of Queensland Australia (AU) University of Kansas (KU) United States (USA) (US) University of South Florida (USF) United States (USA) (US) Stobhill Hospital United Kingdom (GB) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB) University of Copenhagen Denmark (DK) Danish Cancer Society Research Center Denmark (DK) Institut für Humangenetik Wiesbaden Germany (DE) HELIOS Kliniken Germany (DE) Oregon Health and Science University (OSHU) United States (USA) (US) Cedars-Sinai Medical Center United States (USA) (US) Aichi Cancer Center Research Institute Japan (JP) University of Hawaii (U.H.) United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE)

How to cite

APA:

French, J.D., Johnatty, S.E., Lu, Y., Beesley, J., Gao, B., Kalimutho, M.,... Macgregor, S. (2016). Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer. Oncotarget, 7(6), 6353-68. https://doi.org/10.18632/oncotarget.7047

MLA:

French, Juliet D., et al. "Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer." Oncotarget 7.6 (2016): 6353-68.

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