Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer.

Authors:
Shalaka S Hampras Lara E Sucheston-Campbell Rikki Cannioto Jenny Chang-Claude Francesmary Modugno Thilo Dörk Peter Hillemanns Leah Preus Keith L Knutson Paul K Wallace Chi-Chen Hong Grace Friel Warren Davis Mary Nesline Celeste L Pearce Linda E Kelemen Marc T Goodman Elisa V Bandera Kathryn L Terry Nils Schoof Kevin H Eng Alyssa Clay Prashant K Singh Janine M Joseph Katja K H Aben Hoda Anton-Culver Natalia Antonenkova Helen Baker Yukie Bean Matthias W Beckmann Maria Bisogna Line Bjorge Natalia Bogdanova Louise A Brinton Angela Brooks-Wilson Fiona Bruinsma Ralf Butzow Ian G Campbell Karen Carty Linda S Cook Daniel W Cramer Cezary Cybulski Agnieszka Dansonka-Mieszkowska Joe Dennis Evelyn Despierre Ed Dicks Jennifer A Doherty Andreas du Bois Matthias Dürst Doug Easton Diana Eccles Robert P Edwards Arif B Ekici Peter A Fasching Brooke L Fridley Yu-Tang Gao Aleksandra Gentry-Maharaj Graham G Giles Rosalind Glasspool Jacek Gronwald Patricia Harrington Philipp Harter Hanis Nazihah Hasmad Alexander Hein Florian Heitz Michelle A T Hildebrandt Claus Hogdall Estrid Hogdall Satoyo Hosono Edwin S Iversen Anna Jakubowska Allan Jensen Bu-Tian Ji Beth Y Karlan Melissa Kellar Joseph L Kelley Lambertus A Kiemeney Rüdiger Klapdor Nonna Kolomeyevskaya Camilla Krakstad Susanne K Kjaer Bridget Kruszka Jolanta Kupryjanczyk Diether Lambrechts Sandrina Lambrechts Nhu D Le Alice W Lee Shashikant Lele Arto Leminen Jenny Lester Douglas A Levine Dong Liang Jolanta Lissowska Song Liu Karen Lu Jan Lubinski Lene Lundvall Leon F A G Massuger Keitaro Matsuo Valeria McGuire John R McLaughlin Ian McNeish Usha Menon Joanna Moes-Sosnowska Steven A Narod Lotte Nedergaard Heli Nevanlinna Stefan Nickels Sara H Olson Irene Orlow Rachel Palmieri Weber James Paul Tanja Pejovic Liisa M Pelttari Barbara Perkins Jenny Permuth-Wey Malcolm C Pike Joanna Plisiecka-Halasa Elizabeth M Poole Harvey A Risch Mary Anne Rossing Joseph H Rothstein Anja Rudolph Ingo B Runnebaum Iwona K Rzepecka Helga B Salvesen Eva Schernhammer Kristina Schmitt Ira Schwaab Xiao-Ou Shu Yurii B Shvetsov Nadeem Siddiqui Weiva Sieh Honglin Song Melissa C Southey Ingvild L Tangen Soo-Hwang Teo Pamela J Thompson Agnieszka Timorek Ya-Yu Tsai Shelley S Tworoger Jonathan Tyrer Anna M van Altena Ignace Vergote Robert A Vierkant Christine Walsh Shan Wang-Gohrke Nicolas Wentzensen Alice S Whittemore Kristine G Wicklund Lynne R Wilkens Anna H Wu Xifeng Wu Yin-Ling Woo Hannah Yang Wei Zheng Argyrios Ziogas Simon A Gayther Susan J Ramus Thomas A Sellers Joellen M Schildkraut Catherine M Phelan Andrew Berchuck Georgia Chenevix-Trench Julie M Cunningham Paul P Pharoah Roberta B Ness Kunle Odunsi Ellen L Goode Kirsten B Moysich

Oncotarget 2016 10;7(43):69097-69110

Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.

Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer.

Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients.

Results: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively).

Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

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Source
http://dx.doi.org/10.18632/oncotarget.10215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340115PMC
October 2016
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