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

Publication ,  Journal Article
French, JD; Johnatty, SE; Lu, Y; Beesley, J; Gao, B; Kalimutho, M; Henderson, MJ; Russell, AJ; Kar, S; Chen, X; Hillman, KM; Kaufmann, S ...
Published in: Oncotarget
February 9, 2016

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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Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

February 9, 2016

Volume

7

Issue

6

Start / End Page

6353 / 6368

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transcription Factors
  • Survival Rate
  • Reverse Transcriptase Polymerase Chain Reaction
  • Real-Time Polymerase Chain Reaction
  • RNA, Messenger
  • Prognosis
  • Polymorphism, Single Nucleotide
  • Peritoneal Neoplasms
  • Ovarian Neoplasms
 

Citation

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Chicago
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French, J. D., Johnatty, S. E., Lu, Y., Beesley, J., Gao, B., Kalimutho, M., … Ovarian Cancer Association Consortium, . (2016). Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer. Oncotarget, 7(6), 6353–6368. https://doi.org/10.18632/oncotarget.7047
French, Juliet D., Sharon E. Johnatty, Yi Lu, Jonathan Beesley, Bo Gao, Murugan Kalimutho, Michelle J. Henderson, et al. “Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer.Oncotarget 7, no. 6 (February 9, 2016): 6353–68. https://doi.org/10.18632/oncotarget.7047.
French JD, Johnatty SE, Lu Y, Beesley J, Gao B, Kalimutho M, et al. Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer. Oncotarget. 2016 Feb 9;7(6):6353–68.
French, Juliet D., et al. “Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer.Oncotarget, vol. 7, no. 6, Feb. 2016, pp. 6353–68. Pubmed, doi:10.18632/oncotarget.7047.
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, Australian Ovarian Cancer Study Group, Australian Ovarian Cancer Study, Lambrechts D, Despierre E, Van Nieuwenhuysen E, Lambrechts S, Vergote I, Karlan B, Lester J, Orsulic S, Walsh C, Fasching PA, Beckmann MW, 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, Ovarian Cancer Association Consortium. Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer. Oncotarget. 2016 Feb 9;7(6):6353–6368.

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

February 9, 2016

Volume

7

Issue

6

Start / End Page

6353 / 6368

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transcription Factors
  • Survival Rate
  • Reverse Transcriptase Polymerase Chain Reaction
  • Real-Time Polymerase Chain Reaction
  • RNA, Messenger
  • Prognosis
  • Polymorphism, Single Nucleotide
  • Peritoneal Neoplasms
  • Ovarian Neoplasms