TY - JOUR
T1 - Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk
AU - Chornokur, Ganna
AU - Lin, Hui-Yi
AU - Tyrer, Jonathan P
AU - Lawrenson, Kate
AU - Dennis, Joe
AU - Amankwah, Ernest K
AU - Qu, Xiaotao
AU - Tsai, Ya-Yu
AU - Jim, Heather S L
AU - Chen, Zhihua
AU - Chen, Ann Y
AU - Permuth-Wey, Jennifer
AU - Aben, Katja K H
AU - Anton-Culver, Hoda
AU - Antonenkova, Natalia
AU - Bruinsma, Fiona
AU - Bandera, Elisa V
AU - Bean, Yukie T
AU - Beckmann, Matthias W
AU - Bisogna, Maria
AU - Bjorge, Line
AU - Bogdanova, Natalia
AU - Brinton, Louise A
AU - Brooks-Wilson, Angela
AU - Bunker, Clareann H
AU - Butzow, Ralf
AU - Campbell, Ian G
AU - Carty, Karen
AU - Chang-Claude, Jenny
AU - Cook, Linda S
AU - Cramer, Daniel W
AU - Cunningham, Julie M
AU - Cybulski, Cezary
AU - Dansonka-Mieszkowska, Agnieszka
AU - du Bois, Andreas
AU - Despierre, Evelyn
AU - Dicks, Ed
AU - Doherty, Jennifer A
AU - Dörk, Thilo
AU - Dürst, Matthias
AU - Easton, Douglas F
AU - Eccles, Diana M
AU - Edwards, Robert P
AU - Ekici, Arif B
AU - Fasching, Peter A
AU - Fridley, Brooke L
AU - Gao, Yu-Tang
AU - Hogdall, Claus K
AU - Hogdall, Estrid
AU - Kjaer, Susanne K
AU - Georgia Chenevix-Trench
PY - 2015/6/19
Y1 - 2015/6/19
N2 - 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.
AB - 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.
KW - African Americans
KW - Alleles
KW - Asian Americans
KW - Biological Transport
KW - Carrier Proteins
KW - Case-Control Studies
KW - Female
KW - Genetic Association Studies
KW - Genetic Predisposition to Disease
KW - Genetic Variation
KW - Humans
KW - Neoplasms, Glandular and Epithelial
KW - Odds Ratio
KW - Ovarian Neoplasms
KW - Polymorphism, Single Nucleotide
KW - Risk
U2 - 10.1371/journal.pone.0128106
DO - 10.1371/journal.pone.0128106
M3 - Journal article
C2 - 26091520
SN - 1932-6203
VL - 10
SP - 1
EP - 17
JO - PLoS Computational Biology
JF - PLoS Computational Biology
IS - 6
M1 - e0128106
ER -
