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Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.

ABSTRACT: The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer.

SUBMITTER: Charbonneau B

PROVIDER: S-EPMC4000890 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.

Charbonneau Bridget B Moysich Kirsten B KB Kalli Kimberly R KR Oberg Ann L AL Vierkant Robert A RA Fogarty Zachary C ZC Block Matthew S MS Maurer Matthew J MJ Goergen Krista M KM Fridley Brooke L BL Cunningham Julie M JM Rider David N DN Preston Claudia C Hartmann Lynn C LC Lawrenson Kate K Wang Chen C Tyrer Jonathan J Song Honglin H deFazio Anna A Johnatty Sharon E SE Doherty Jennifer A JA Phelan Catherine M CM Sellers Thomas A TA Ramirez Starr M SM Vitonis Allison F AF Terry Kathryn L KL Van Den Berg David D Pike Malcolm C MC Wu Anna H AH Berchuck Andrew A Gentry-Maharaj Aleksandra A Ramus Susan J SJ Diergaarde Brenda B Shen Howard H Jensen Allan A Menkiszak Janusz J Cybulski Cezary C Lubiłski Jan J Ziogas Argyrios A Rothstein Joseph H JH McGuire Valerie V Sieh Weiva W Lester Jenny J Walsh Christine C Vergote Ignace I Lambrechts Sandrina S Despierre Evelyn E Garcia-Closas Montserrat M Yang Hannah H Brinton Louise A LA Spiewankiewicz Beata B Rzepecka Iwona K IK Dansonka-Mieszkowska Agnieszka A Seibold Petra P Rudolph Anja A Paddock Lisa E LE Orlow Irene I Lundvall Lene L Olson Sara H SH Hogdall Claus K CK Schwaab Ira I du Bois Andreas A Harter Philipp P Flanagan James M JM Brown Robert R Paul James J Ekici Arif B AB Beckmann Matthias W MW Hein Alexander A Eccles Diana D Lurie Galina G Hays Laura E LE Bean Yukie T YT Pejovic Tanja T Goodman Marc T MT Campbell Ian I Fasching Peter A PA Konecny Gottfried G Kaye Stanley B SB Heitz Florian F Hogdall Estrid E Bandera Elisa V EV Chang-Claude Jenny J Kupryjanczyk Jolanta J Wentzensen Nicolas N Lambrechts Diether D Karlan Beth Y BY Whittemore Alice S AS Culver Hoda Anton HA Gronwald Jacek J Levine Douglas A DA Kjaer Susanne K SK Menon Usha U Schildkraut Joellen M JM Pearce Celeste Leigh CL Cramer Daniel W DW Rossing Mary Anne MA Chenevix-Trench Georgia G Pharoah Paul D P PD Gayther Simon A SA Ness Roberta B RB Odunsi Kunle K Sucheston Lara E LE Knutson Keith L KL Goode Ellen L EL

Cancer immunology research 20140127 4

The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed geno ...[more]

PMID: 24764580

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Project description:BackgroundDefective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.MethodsIn total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.ResultsThe most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).ConclusionThese results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.

Project description:BackgroundTranscriptional cis-regulatory modules (for example, enhancers) play a critical role in regulating gene expression. While many individual regulatory elements have been characterized, they have never been analyzed as a class.ResultsWe have performed the first such large-scale study of cis-regulatory modules in order to determine whether they have common properties that might aid in their identification and contribute to our understanding of the mechanisms by which they function. A total of 280 individual, experimentally verified cis-regulatory modules from Drosophila were analyzed for a range of sequence-level and functional properties. We report here that regulatory modules do indeed share common properties, among them an elevated GC content, an increased level of interspecific sequence conservation, and a tendency to be transcribed into RNA. However, we find that dense clustering of transcription factor binding sites, especially homotypic clustering, which is commonly believed to be a general characteristic of regulatory modules, is rather a feature that belongs chiefly to a specific subclass. This has important implications for current computational approaches, many of which are biased toward this subset. We explore two new strategies to assess binding site clustering and gauge their performances with respect to their ability to detect all 280 modules and various functionally coherent subsets.ConclusionOur findings demonstrate that cis-regulatory modules share common features that help to define them as a class and that may lead to new insights into mechanisms of gene regulation. However, these properties alone may not be sufficient to reliably distinguish regulatory from non-regulatory sequences. We also demonstrate that there are distinct subclasses of cis-regulatory modules that are more amenable to in silico detection than others and that these differences must be taken into account when attempting genome-wide regulatory element discovery.

Dataset Information

Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.

Publications

Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.

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