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Title: Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.
Authors: Chornokur G,  Lin HY,  Tyrer JP,  Lawrenson K,  Dennis J,  Amankwah EK,  Qu X,  Tsai YY,  Jim HS,  Chen Z,  Chen AY,  Permuth-Wey J,  Aben KKh,  Anton-Culver H,  Antonenkova N,  Bruinsma F,  Bandera EV,  Bean YT,  Beckmann MW,  Bisogna M,  Bjorge L,  Bogdanova N,  Brinton LA,  Brooks-Wilson A,  Bunker CH,  Butzow R,  Campbell IG,  Carty K,  Chang-Claude J,  Cook LS,  Cramer DW,  Cunningham JM,  Cybulski C,  Dansonka-Mieszkowska A,  du Bois A,  Despierre E,  Dicks E,  Doherty JA,  Dörk T,  Dürst M,  Easton DF,  Eccles DM,  Edwards RP,  Ekici AB,  Fasching PA,  Fridley BL,  Gao YT,  Gentry-Maharaj A,  Giles GG,  Glasspool R,  Goodman MT,  Gronwald J,  Harrington P,  Harter P,  Hein A,  Heitz F,  Hildebrandt MA,  Hillemanns P,  Hogdall CK,  Hogdall E,  Hosono S,  Jakubowska A,  Jensen A,  Ji BT,  Karlan BY,  Kelemen LE,  Kellar M,  Kiemeney LA,  Krakstad C,  Kjaer SK,  Kupryjanczyk J,  Lambrechts D,  Lambrechts S,  Le ND,  Lee AW,  Lele S,  Leminen A,  Lester J,  Levine DA,  Liang D,  Lim BK,  Lissowska J,  Lu K,  Lubinski J,  Lundvall L,  Massuger LF,  Matsuo K,  McGuire V,  McLaughlin JR,  McNeish I,  Menon U,  Milne RL,  Modugno F,  Moysich KB,  Ness RB,  Nevanlinna H,  Eilber U,  Odunsi K,  Olson SH,  Orlow I,  Orsulic S,  Weber RP,  Paul J,  Pearce CL,  Pejovic T,  Pelttari LM,  Pike MC,  Poole EM,  Risch HA,  Rosen B,  Rossing MA,  Rothstein JH,  Rudolph A,  Runnebaum IB,  Rzepecka IK,  Salvesen HB,  Schernhammer E,  Schwaab I,  Shu XO,  Shvetsov YB,  Siddiqui N,  Sieh W,  Song H,  Southey MC,  Spiewankiewicz B,  Sucheston L,  Teo SH,  Terry KL,  Thompson PJ,  Thomsen L,  Tangen IL,  Tworoger SS,  van Altena AM,  Vierkant RA,  Vergote I,  Walsh CS,  Wang-Gohrke S,  Wentzensen N,  Whittemore AS,  Wicklund KG,  Wilkens LR,  Wu AH,  Wu X,  Woo YL,  Yang H,  Zheng W,  Ziogas A,  Hasmad HN,  Berchuck A,  Georgia Chenevix-Trench on behalf of the AOCS management group,  Iversen ES,  Schildkraut JM,  Ramus SJ,  Goode EL,  Monteiro AN,  Gayther SA,  Narod SA,  Pharoah PD,  Sellers TA,  Phelan CM
Journal: PLoS One
Date: 2015
Branches: MEB, OEEB
PubMed ID: 26091520
PMC ID: PMC4474865
Abstract: BACKGROUND: Defective 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. METHODS: In 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. RESULTS: The 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). CONCLUSION: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.