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

Hampras SS, Sucheston-Campbell LE, Cannioto R, Chang-Claude J, Modugno F, Thilo Dörk, Peter Hillemanns, Preus L, Knutson KL, Wallace PK, Hong CC, Friel G, Davis W, Nesline M, Pearce CL, Kelemen LE, Marc T. Goodman, Bandera EV, Kathryn L. Terry, Schoof N, Eng KH, Clay A, Singh PK, Joseph JM, Katja K.H. Aben, Anton-Culver H, Antonenkova N, Baker H, Bean Y, Beckmann MW, Bisogna M, Bjorge L, Natalia Bogdanova, Brinton LA, Brooks-Wilson A, Fiona Bruinsma, Butzow R, Ian Campbell, Karen Carty, Cook LS, Cramer DW, Cybulski C, Agnieszka Dansonka‐Mieszkowska, Dennis J, Despierre E, Dicks E, Doherty JA, du Bois A, Dürst M, Easton D, Diana Eccles, Edwards RP, Arif B. Ekici, Fasching PA, Fridley BL, Gao YT, Gentry-Maharaj A, Giles GG, Glasspool R, Gronwald J, Harrington P, Harter P, Hasmad HN, Alexander Hein, Florian Heitz, Hildebrandt MA, Hogdall C, Hogdall E, Hosono S, Iversen ES, Anna Jakubowska, Allan Jensen, Ji BT, Karlan BY, Kellar M, Kelley JL, Lambertus A. Kiemeney, Klapdor R, Kolomeyevskaya N, Camilla Krakstad, Kjaer SK, Kruszka B, Jolanta Kupryjańczyk, Lambrechts D, Lambrechts S, Le ND, Alice W. Lee, Lele S, Leminen A, Lester J, Douglas A. Levine, Dong Liang, Jolanta Lissowska, Liu S, Lu K, Jan Lubiński, Lundvall L, Massuger LF, Keitaro Matsuo, McGuire V, McLaughlin JR, Iain A. McNeish, Usha Menon, Moes-Sosnowska J, Narod SA, Nedergaard L, Nevanlinna H, Nickels S, Sara H. Olson, Orlow I, Rachel Palmieri Weber, Paul J, Pejovic T, Liisa M. Pelttari, Perkins B, Permuth-Wey J, Pike MC, Plisiecka-Halasa J, Poole EM, Risch HA, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Rzepecka IK, Salvesen HB, Eva Schernhammer, Schmitt K, Schwaab I, Shu XO, Shvetsov YB, Siddiqui N, Weiva Sieh, Song H, Melissa C. Southey, Tangen IL, Teo SH, Thompson PJ, Timorek A, Tsai YY, Shelley S. Tworoger, Tyrer J, van Altena AM, Vergote I, Robert A. Vierkant, Walsh C, Wang-Gohrke S, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Wu AH, Wu X, Yin Ling Woo, Yang H, Wei Zheng, Zheng W, Ziogas A, Gayther SA, Susan J. Ramus, Sellers TA, Schildkraut JM, Phelan CM, Berchuck A, Georgia Chenevix‐Trench, Cunningham JM, Pharoah PP, Ness RB, Odunsi K, Goode EL, Moysich KB
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Abstract

BackgroundRegulatory 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.MethodsIn 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.ResultsThe 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).ConclusionsCommon 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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