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

被引：24

作者：

French, Juliet D. ^{[1
]}

Johnatty, Sharon E. ^{[1
]}

Lu, Yi ^{[1
]}

Beesley, Jonathan ^{[1
]}

Gao, Bo ^{[2
,3
]}

Kalimutho, Murugan ^{[1
]}

Henderson, Michelle J. ^{[4
]}

Russell, Amanda J. ^{[4
]}

Kar, Siddhartha ^{[5
]}

Chen, Xiaoqing ^{[1
]}

Hillman, Kristine M. ^{[1
]}

Kaufmann, Susanne ^{[1
]}

Sivakumaran, Haran ^{[1
]}

O'Reilly, Martin ^{[6
]}

Wang, Chen ^{[7
]}

Korbie, Darren J. ^{[8
]}

Lambrechts, Diether ^{[10
,11
,12
]}

Despierre, Evelyn ^{[12
]}

Van Nieuwenhuysen, Els ^{[12
]}

Lambrechts, Sandrina ^{[12
]}

Vergote, Ignace ^{[12
]}

Karlan, Beth ^{[13
]}

Lester, Jenny ^{[13
]}

Orsulic, Sandra ^{[13
]}

Walsh, Christine ^{[13
]}

Fasching, Peter A. ^{[14
,15
]}

Beckmann, Matthias W. ^{[14
]}

Ekici, Arif B. ^{[47
]}

Hein, Alexander ^{[14
]}

Matsuo, Keitaro ^{[16
]}

Hosono, Satoyo ^{[16
]}

Pisterer, Jacobus ^{[17
]}

Hillemanns, Peter ^{[18
,19
]}

Nakanishi, Toru ^{[20
]}

Yatabe, Yasushi ^{[21
]}

Goodman, Marc T. ^{[22
]}

Lurie, Galina ^{[23
]}

Matsuno, Rayna K. ^{[23
]}

Thompson, Pamela J. ^{[22
]}

Pejovic, Tanja ^{[24
,25
]}

Bean, Yukie ^{[24
,25
]}

Heitz, Florian ^{[26
,27
]}

Harter, Philipp ^{[26
,27
]}

du Bois, Andreas ^{[26
,27
]}

Schwaab, Ira ^{[28
]}

Hogdall, Estrid ^{[29
,30
]}

Kjaer, Susanne K. ^{[29
,31
]}

Jensen, Allan ^{[29
]}

Hogdall, Claus ^{[31
]}

Lundvall, Lene ^{[31
]}

机构：

[1] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia

[2] Univ Sydney, Westmead Hosp, Westmead Inst Med Res, Dept Gynaecol Oncol, Sydney, NSW 2006, Australia

[3] Univ Sydney, Westmead Hosp, Westmead Inst Med Res, Ctr Canc Res, Sydney, NSW 2006, Australia

[4] Childrens Canc Inst Australia, Randwick, NSW, Australia

[5] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England

[6] Canc Res UK Cambridge Res Inst, Li Ka Shing Ctr, Cambridge, England

[7] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA

[8] Univ Queensland, Australian Inst Bioengn & Nanotechnol, Brisbane, Qld, Australia

[9] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[10] VIB, Vesalius Res Ctr, Leuven, Belgium

[11] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium

[12] Univ Hosp Leuven, Leuven Canc Inst, Gynecol Oncol, Leuven, Belgium

[13] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA

[14] Friedrich Alexander Univ Erlangen Nurember, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen Nuremberg, Erlangen, Germany

[15] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA

[16] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan

[17] Zentrum Gynakol Onkol, Kiel, Germany

[18] Hannover Med Sch, Dept Obstet, Hannover, Germany

[19] Hannover Med Sch, Dept Gynaecol, Hannover, Germany

[20] Aichi Canc Ctr Cent Hosp, Dept Gynecol, Nagoya, Aichi, Japan

[21] Aichi Canc Ctr Cent Hosp, Dept Pathol & Mol Diagnost, Nagoya, Aichi, Japan

[22] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control Program, Los Angeles, CA 90048 USA

[23] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA

[24] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA

[25] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA

[26] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany

[27] Kliniken Essen Mitte, Dept Gynecol & Gynecol Oncol, Essen, Germany

[28] Inst Humangenet Wiesbaden, Wiesbaden, Germany

[29] Danish Canc Soc Res Ctr, Unit Virus Lifestyle & Genes, Copenhagen, Denmark

[30] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark

[31] Univ Copenhagen, Rigshosp, Dept Gynecol, DK-2100 Copenhagen, Denmark

[32] Univ Copenhagen, Rigshosp, Dept Oncol, DK-2100 Copenhagen, Denmark

[33] Imperial Coll London, Dept Surg & Canc, London, England

[34] Stobhill Hosp, North Glasgow Univ Hosp NHS Trust, Glasgow, Lanark, Scotland

[35] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA

[36] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS USA

[37] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[38] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA

[39] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC USA

[40] Duke Univ, Dept Stat Sci, Durham, NC USA

[41] Queensland Ctr Gynaecol Canc, Brisbane, Qld, Australia

[42] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA

[43] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England

[44] Univ Sydney, Westmead Hosp, Westmead Inst Med Res, Crown Princess Mary Canc Ctr, Sydney, NSW 2006, Australia

[45] Univ Sydney, Westmead Hosp, Westmead Inst Med Res, Ctr Canc Res, Sydney, NSW 2006, Australia

[46] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA

[47] Friedrich Alexander Univ ErlangenNurnberg, Inst Human Genet, Erlangen, Germany

来源：

ONCOTARGET | 2016年 / 7卷 / 06期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

epithelial ovarian cancer; progression free survival; genome-wide association study; PSIP1; chromosome conformation capture; GENOME-WIDE ASSOCIATION; CLINICAL-OUTCOMES; COMMON VARIANTS; MICROARRAY DATA; GROWTH-FACTOR; PLATINUM; CHEMOTHERAPY; PROGNOSIS; THERAPY; GENES;

D O I：

10.18632/oncotarget.7047

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：6353 / 6368

页数：16

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