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Region Hovedstaden - en del af Københavns Universitetshospital
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Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer

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  • Juliet D French
  • Sharon E Johnatty
  • Yi Lu
  • Jonathan Beesley
  • Bo Gao
  • Murugan Kalimutho
  • Michelle J Henderson
  • Amanda J Russell
  • Siddhartha Kar
  • Xiaoqing Chen
  • Kristine M Hillman
  • Susanne Kaufmann
  • Haran Sivakumaran
  • Martin O'Reilly
  • Chen Wang
  • Darren J Korbie
  • Diether Lambrechts
  • Evelyn Despierre
  • Els Van Nieuwenhuysen
  • Sandrina Lambrechts
  • Ignace Vergote
  • Beth Karlan
  • Jenny Lester
  • Sandra Orsulic
  • Christine Walsh
  • Peter A Fasching
  • Matthias W Beckmann
  • Arif B Ekici
  • Alexander Hein
  • Keitaro Matsuo
  • Satoyo Hosono
  • Jacobus Pisterer
  • Peter Hillemanns
  • Toru Nakanishi
  • Yasushi Yatabe
  • Marc T Goodman
  • Galina Lurie
  • Rayna K Matsuno
  • Pamela J Thompson
  • Tanja Pejovic
  • Yukie Bean
  • Florian Heitz
  • Philipp Harter
  • Andreas du Bois
  • Ira Schwaab
  • Estrid Vilma Solyom Høgdall
  • Susanne K Kjaer
  • Claus Hogdall
  • Lene Lundvall
  • Svend Aage Engelholm
  • Australian Ovarian Cancer Study Group
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftOncotarget
Vol/bind7
Udgave nummer6
Sider (fra-til)6353-68
Antal sider16
ISSN1949-2553
DOI
StatusUdgivet - 9 feb. 2016

ID: 49472471