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Title: Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer.
Authors: Hampras SS,  Sucheston-Campbell LE,  Cannioto R,  Chang-Claude J,  Modugno F,  Dörk T,  Hillemanns P,  Preus L,  Knutson KL,  Wallace PK,  Hong CC,  Friel G,  Davis W,  Nesline M,  Pearce CL,  Kelemen LE,  Goodman MT,  Bandera EV,  Terry KL,  Schoof N,  Eng KH,  Clay A,  Singh PK,  Joseph JM,  Aben KK,  Anton-Culver H,  Antonenkova N,  Baker H,  Bean Y,  Beckmann MW,  Bisogna M,  Bjorge L,  Bogdanova N,  Brinton LA,  Brooks-Wilson A,  Bruinsma F,  Butzow R,  Campbell IG,  Carty K,  Cook LS,  Cramer DW,  Cybulski C,  Dansonka-Mieszkowska A,  Dennis J,  Despierre E,  Dicks E,  Doherty JA,  du Bois A,  Dürst M,  Easton D,  Eccles D,  Edwards RP,  Ekici AB,  Fasching PA,  Fridley BL,  Gao YT,  Gentry-Maharaj A,  Giles GG,  Glasspool R,  Gronwald J,  Harrington P,  Harter P,  Hasmad HN,  Hein A,  Heitz F,  Hildebrandt MA,  Hogdall C,  Hogdall E,  Hosono S,  Iversen ES,  Jakubowska A,  Jensen A,  Ji BT,  Karlan BY,  Kellar M,  Kelley JL,  Kiemeney LA,  Klapdor R,  Kolomeyevskaya N,  Krakstad C,  Kjaer SK,  Kruszka B,  Kupryjanczyk J,  Lambrechts D,  Lambrechts S,  Le ND,  Lee AW,  Lele S,  Leminen A,  Lester J,  Levine DA,  Liang D,  Lissowska J,  Liu S,  Lu K,  Lubinski J,  Lundvall L,  Massuger LF,  Matsuo K,  McGuire V,  McLaughlin JR,  McNeish I,  Menon U,  Moes-Sosnowska J,  Narod SA,  Nedergaard L,  Nevanlinna H,  Nickels S,  Olson SH,  Orlow I,  Weber RP,  Paul J,  Pejovic T,  Pelttari LM,  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,  Schernhammer E,  Schmitt K,  Schwaab I,  Shu XO,  Shvetsov YB,  Siddiqui N,  Sieh W,  Song H,  Southey MC,  Tangen IL,  Teo SH,  Thompson PJ,  Timorek A,  Tsai YY,  Tworoger SS,  Tyrer J,  van Altena AM,  Vergote I,  Vierkant RA,  Walsh C,  Wang-Gohrke S,  Wentzensen N,  Whittemore AS,  Wicklund KG,  Wilkens LR,  Wu AH,  Wu X,  Woo YL,  Yang H,  Zheng W,  Ziogas A,  Gayther SA,  Ramus SJ,  Sellers TA,  Schildkraut JM,  Phelan CM,  Berchuck A,  Chenevix-Trench G,  Cunningham JM,  Pharoah PP,  Ness RB,  Odunsi K,  Goode EL,  Moysich KB
Journal: Oncotarget
Date: 2016 Jun 21
Branches: CGB, OD, OEEB
PubMed ID: 27533245
PMC ID: not available
Abstract: 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.