TY - JOUR

T1 - Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer

AU - French, Juliet D

AU - Johnatty, Sharon E

AU - Lu, Yi

AU - Beesley, Jonathan

AU - Gao, Bo

AU - Kalimutho, Murugan

AU - Henderson, Michelle J

AU - Russell, Amanda J

AU - Kar, Siddhartha

AU - Chen, Xiaoqing

AU - Hillman, Kristine M

AU - Kaufmann, Susanne

AU - Sivakumaran, Haran

AU - O'Reilly, Martin

AU - Wang, Chen

AU - Korbie, Darren J

AU - Lambrechts, Diether

AU - Despierre, Evelyn

AU - Van Nieuwenhuysen, Els

AU - Lambrechts, Sandrina

AU - Vergote, Ignace

AU - Karlan, Beth

AU - Lester, Jenny

AU - Orsulic, Sandra

AU - Walsh, Christine

AU - Fasching, Peter A

AU - Beckmann, Matthias W

AU - Ekici, Arif B

AU - Hein, Alexander

AU - Matsuo, Keitaro

AU - Hosono, Satoyo

AU - Pisterer, Jacobus

AU - Hillemanns, Peter

AU - Nakanishi, Toru

AU - Yatabe, Yasushi

AU - Goodman, Marc T

AU - Lurie, Galina

AU - Matsuno, Rayna K

AU - Thompson, Pamela J

AU - Pejovic, Tanja

AU - Bean, Yukie

AU - Heitz, Florian

AU - Harter, Philipp

AU - Du Bois, Andreas

AU - Schwaab, Ira

AU - Hogdall, Estrid

AU - Kjaer, Susanne K

AU - Jensen, Allan

AU - Hogdall, Claus

AU - Engelholm, Svend Aage

AU - Australian Ovarian Cancer Study Group

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Adaptor Proteins, Signal Transducing

KW - Apoptosis

KW - Biomarkers, Tumor

KW - Cell Proliferation

KW - Chromatin Immunoprecipitation

KW - Cohort Studies

KW - Cystadenocarcinoma, Serous

KW - Electrophoretic Mobility Shift Assay

KW - Enhancer Elements, Genetic

KW - Fallopian Tube Neoplasms

KW - Female

KW - Follow-Up Studies

KW - Germ-Line Mutation

KW - Humans

KW - Ovarian Neoplasms

KW - Peritoneal Neoplasms

KW - Polymorphism, Single Nucleotide

KW - Prognosis

KW - RNA, Messenger

KW - Real-Time Polymerase Chain Reaction

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Survival Rate

KW - Transcription Factors

KW - Tumor Cells, Cultured

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, Non-P.H.S.

U2 - 10.18632/oncotarget.7047

DO - 10.18632/oncotarget.7047

M3 - Journal article

C2 - 26840454

VL - 7

SP - 6353

EP - 6368

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 6

ER -