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Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

ABSTRACT: Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

SUBMITTER: Lawrenson K

PROVIDER: S-EPMC4580986 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

Lawrenson Kate K Li Qiyuan Q Kar Siddhartha S Seo Ji-Heui JH Tyrer Jonathan J Spindler Tassja J TJ Lee Janet J Chen Yibu Y Karst Alison A Drapkin Ronny R Aben Katja K H KK Anton-Culver Hoda H Antonenkova Natalia N Baker Helen H Bandera Elisa V EV Bean Yukie Y Beckmann Matthias W MW Berchuck Andrew A Bisogna Maria M Bjorge Line L Bogdanova Natalia N Brinton Louise A LA Brooks-Wilson Angela A Bruinsma Fiona F Butzow Ralf R Campbell Ian G IG Carty Karen K Chang-Claude Jenny J Chenevix-Trench Georgia G Chen Anne A Chen Zhihua Z Cook Linda S LS Cramer Daniel W DW Cunningham Julie M JM Cybulski Cezary C Dansonka-Mieszkowska Agnieszka A Dennis Joe J Dicks Ed E Doherty Jennifer A JA Dörk Thilo T du Bois Andreas A Dürst Matthias M Eccles Diana D Easton Douglas T DT Edwards Robert P RP Eilber Ursula U Ekici Arif B AB Fasching Peter A PA Fridley Brooke L BL Gao Yu-Tang YT Gentry-Maharaj Aleksandra A Giles Graham G GG Glasspool Rosalind R Goode Ellen L EL Goodman Marc T MT Grownwald Jacek J Harrington Patricia P Harter Philipp P Hasmad Hanis Nazihah HN Hein Alexander A Heitz Florian F Hildebrandt Michelle A T MA Hillemanns Peter P Hogdall Estrid E Hogdall Claus C Hosono Satoyo S Iversen Edwin S ES Jakubowska Anna A James Paul P Jensen Allan A Ji Bu-Tian BT Karlan Beth Y BY Kruger Kjaer Susanne S Kelemen Linda E LE Kellar Melissa M Kelley Joseph L JL Kiemeney Lambertus A LA Krakstad Camilla C Kupryjanczyk Jolanta J Lambrechts Diether D Lambrechts Sandrina S Le Nhu D ND Lee Alice W AW Lele Shashi S Leminen Arto A Lester Jenny J Levine Douglas A DA Liang Dong D Lissowska Jolanta J Lu Karen K Lubinski Jan J Lundvall Lene L Massuger Leon F A G LF Matsuo Keitaro K McGuire Valerie V McLaughlin John R JR Nevanlinna Heli H McNeish Ian I Menon Usha U Modugno Francesmary F Moysich Kirsten B KB Narod Steven A SA Nedergaard Lotte L Ness Roberta B RB Azmi Mat Adenan Noor MA Odunsi Kunle K Olson Sara H SH Orlow Irene I Orsulic Sandra S Weber Rachel Palmieri RP Pearce Celeste L CL Pejovic Tanja T Pelttari Liisa M LM Permuth-Wey Jennifer J Phelan Catherine M CM Pike Malcolm C MC Poole Elizabeth M EM Ramus Susan J SJ Risch Harvey A HA Rosen Barry B Rossing Mary Anne MA Rothstein Joseph H JH Rudolph Anja A Runnebaum Ingo B IB Rzepecka Iwona K IK Salvesen Helga B HB Schildkraut Joellen M JM Schwaab Ira I Sellers Thomas A TA Shu Xiao-Ou XO Shvetsov Yurii B YB Siddiqui Nadeem N Sieh Weiva W Song Honglin H Southey Melissa C MC Sucheston Lara L Tangen Ingvild L IL Teo Soo-Hwang SH Terry Kathryn L KL Thompson Pamela J PJ Timorek Agnieszka A Tsai Ya-Yu YY Tworoger Shelley S SS van Altena Anne M AM Van Nieuwenhuysen Els E Vergote Ignace I Vierkant Robert A RA Wang-Gohrke Shan S Walsh Christine C Wentzensen Nicolas N Whittemore Alice S AS Wicklund Kristine G KG Wilkens Lynne R LR Woo Yin-Ling YL Wu Xifeng X Wu Anna H AH Yang Hannah H Zheng Wei W Ziogas Argyrios A Monteiro Alvaro A Pharoah Paul D PD Gayther Simon A SA Freedman Matthew L ML

Nature communications 20150922

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbin ...[more]

PMID: 26391404

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Project description:Evidence indicates that high-grade serous ovarian carcinoma arises from the fallopian tube, rather than ovarian surface epithelium. This is termed the 'tubal origin' theory. The aim of the present study was to compare the immunophenotype and gene expression profiling among high-grade serous ovarian carcinoma (HGSOC), fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) based on tubal origin theory, and identify the differential genes associated with ovarian carcinogenesis. A total of 61 cases of fresh tissue samples including 21 cases of HGSOC, 20 cases of OSE, and 20 cases of FTE were obtained following surgical resection. Immunostaining was performed to detect the expression of PAX8, which has been considered as a potential immunophenotype marker of Müllerian origin. Illumina BeadChip was applied for gene expression profiling. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to confirm the differential expression of candidate genes between HGSOC and FTE. The results of the present study demonstrated that PAX8 was highly expressed in HGSOC (19/21, 90.4%) and FTE (20/20, 100%), but not in OSE (3/20, 14.3%). A dendrogram generated by cluster analysis indicated a higher similarity of gene expression profile between HGSOC and FTE than OSE. A total of 2,412 differentially expressed genes were identified (absolute fold change >2) between HGSOC and FTE, including 822 upregulated genes in cancer and 1,590 downregulated genes. S100 calcium binding protein P, Ras-interacting protein 1, Wnt family member 5A, tumor-associated calcium signal transducer 2, Dickkopf Wnt signaling pathway inhibitor 3 and tumor suppressor candidate 3 genes were identified as candidate markers, of which the differential gene expression in HGSOC and FTE was confirmed by RT-qPCR (P<0.05). The results indicate the presence of a greater similarity in the immunophenotype and gene expression profile of HGSOC and FTE, when compared with OSE, which was consistent with the tubal origin theory of HGSOC.

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Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

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Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

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