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Common genetic variation in cellular transport genes and epithelial ovarian cancer (EOC) risk

Chornokur, G and Lin, HY and Tyrer, JP and Lawrenson, K and Dennis, J and Amankwah, EK and Qu, X and Tsai, YY and Jim, HSL and Chen, Z and Chen, AY and Permuth-Wey, J and Aben, KKH and Anton-Culver, H and Antonenkova, N and Bruinsma, F and Bandera, EV and Bean, YT and Beckmann, MW and Bisogna, M and Bjorge, L and Bogdanova, N and Brinton, LA and Brooks-Wilson, A and Bunker, CH and Butzow, R and Campbell, IG and Carty, K and Chang-Claude, J and Cook, LS and Cramer, DW and Cunningham, JM and Cybulski, C and Dansonka-Mieszkowska, A and Du Bois, A and Despierre, E and Dicks, E and Doherty, JA and Dörk, T and Dürst, M and Easton, DF and Eccles, DM and Edwards, RP and Ekici, AB and Fasching, PA and Fridley, BL and Gao, YT and Gentry-Maharaj, A and Giles, GG and Glasspool, R and Goodman, MT and Gronwald, J and Harrington, P and Harter, P and Hein, A and Heitz, F and Hildebrandt, MAT and Hillemanns, P and Hogdall, CK and Hogdall, E and Hosono, S and Jakubowska, A and Jensen, A and Ji, BT and Karlan, BY and Kelemen, LE and Kellar, M and Kiemeney, LA and Krakstad, C and Kjaer, SK and Kupryjanczyk, J and Lambrechts, D and Lambrechts, S and Le, ND and Lee, AW and Lele, S and Leminen, A and Lester, J and Levine, DA and Liang, D and Lim, BK and Lissowska, J and Lu, K and Lubinski, J and Lundvall, L and Massuger, LFAG and Matsuo, K and McGuire, V and McLaughlin, JR and McNeish, I and Menon, U and Milne, RL and Modugno, F and Moysich, KB and Ness, RB and Nevanlinna, H and Eilber, U and Odunsi, K and Olson, SH and Orlow, I (2015) Common genetic variation in cellular transport genes and epithelial ovarian cancer (EOC) risk. PLoS ONE, 10 (6).

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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 = 5.66×10-4). Conclusion: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Chornokur, G
Lin, HY
Tyrer, JP
Lawrenson, K
Dennis, J
Amankwah, EK
Qu, X
Tsai, YY
Jim, HSL
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
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, RPrpe1@pitt.eduRPE10000-0003-0370-1390
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, MAT
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, LFAG
Matsuo, K
McGuire, V
McLaughlin, JR
McNeish, I
Menon, U
Milne, RL
Modugno, Fovarian@pitt.eduOVARIAN
Moysich, KB
Ness, RB
Nevanlinna, H
Eilber, U
Odunsi, K
Olson, SH
Orlow, I
ContributionContributors NameEmailPitt UsernameORCID
Centers: Other Centers, Institutes, Offices, or Units > Magee-Women's Research Institute
Date: 19 June 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 6
DOI or Unique Handle: 10.1371/journal.pone.0128106
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Epidemiology
Refereed: Yes
Date Deposited: 28 Jun 2016 17:39
Last Modified: 22 Jun 2021 13:56


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