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

French, Juliet D., Johnatty, Sharon E., Lu, Yi, Beesley, Jonathan, Gao, Bo, Kalimutho, Murugan, Henderson, Michelle J., Russell, Amanda J., Kar, Siddhartha, Chen, Xiaoging, Hillman, Kristine M., Kaufmann, S, Sivakumaran H., O'Reilly, Martin, Wang, Chen, Korbie, Darren J., Lambrechts, Diether, Despierre, Evelyn, Van Nieuwenhuysen, Els, Lambrechts, Sandra, Vergote, Ignace, Karlan, Beth, Lester, Jenny, Orsulic, Sandra, Walsh, Christine, Fasching, Peter A., Beckmann, Matthias W., Ekici, Arif B., Hein, Alexander, Matsuo, Keitaro, Hosono, Satoyo, Pisterer, Jacobus, Hillemanns, Peter, Nakanishi, Toru, Yatabe, Yasushi, Goodman, Marc T., Lurie, Galine, Matsuno, Rayna K., Thompson, Pamela J., Pejovic, Tanja, Bean, Yukie, Heitz, Florian, Harter, Philipp, Du Bois, Andreas, Schwaab, Ira, Hogdall, Estrid, Kjaer, Susanne K., Jensen, Allan, Hogdall, Claus, Lundvall, Lene, Engelholm, Svend Aage, Brown, Bob, Flanagan, James M., Metcalf, Michelle D., Siddiqui, Nadeem, Sellers, Thomas, Fridley, Brooke, Cunningham, Julie, Schildkraut, Joellen M., Iversen, Ed, Weber, Rachel Palmieri, Brennan, Donal, Berchuck, Andrew, Pharoah, Paul, Harnett, Paul, Norris, Murray D., Haber, Michelle, Goode, Ellen L., Lee, Jason S., Khanna, Kum Kum, Meyer, Kerstin B., Chenevix-Trench, Georgia, DeFazio, Anna, Edwards, Stacey L. and MacGregor, Stuart (2016) Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer. Oncotarget, 7 6: 6353-6368. doi:10.18632/oncotarget.7047

Author French, Juliet D.
Johnatty, Sharon E.
Lu, Yi
Beesley, Jonathan
Gao, Bo
Kalimutho, Murugan
Henderson, Michelle J.
Russell, Amanda J.
Kar, Siddhartha
Chen, Xiaoging
Hillman, Kristine M.
Kaufmann, S
Sivakumaran H.
O'Reilly, Martin
Wang, Chen
Korbie, Darren J.
Lambrechts, Diether
Despierre, Evelyn
Van Nieuwenhuysen, Els
Lambrechts, Sandra
Vergote, Ignace
Karlan, Beth
Lester, Jenny
Orsulic, Sandra
Walsh, Christine
Fasching, Peter A.
Beckmann, Matthias W.
Ekici, Arif B.
Hein, Alexander
Matsuo, Keitaro
Hosono, Satoyo
Pisterer, Jacobus
Hillemanns, Peter
Nakanishi, Toru
Yatabe, Yasushi
Goodman, Marc T.
Lurie, Galine
Matsuno, Rayna K.
Thompson, Pamela J.
Pejovic, Tanja
Bean, Yukie
Heitz, Florian
Harter, Philipp
Du Bois, Andreas
Schwaab, Ira
Hogdall, Estrid
Kjaer, Susanne K.
Jensen, Allan
Hogdall, Claus
Lundvall, Lene
Engelholm, Svend Aage
Brown, Bob
Flanagan, James M.
Metcalf, Michelle D.
Siddiqui, Nadeem
Sellers, Thomas
Fridley, Brooke
Cunningham, Julie
Schildkraut, Joellen M.
Iversen, Ed
Weber, Rachel Palmieri
Brennan, Donal
Berchuck, Andrew
Pharoah, Paul
Harnett, Paul
Norris, Murray D.
Haber, Michelle
Goode, Ellen L.
Lee, Jason S.
Khanna, Kum Kum
Meyer, Kerstin B.
Chenevix-Trench, Georgia
DeFazio, Anna
Edwards, Stacey L.
MacGregor, Stuart
Title Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer
Journal name Oncotarget   Check publisher's open access policy
ISSN 1949-2553
Publication date 2016-01-31
Year available 2016
Sub-type Article (original research)
DOI 10.18632/oncotarget.7047
Open Access Status DOI
Volume 7
Issue 6
Start page 6353
End page 6368
Total pages 16
Place of publication Albany, NY, United States
Publisher Impact Journals
Collection year 2017
Language eng
Formatted 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.
Keyword Chromosome conformation capture
Epithelial ovarian cancer
Genome-wide association study
Progression free survival
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

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