Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

• Published in: PLOS ONE Vol. 10; no. 6; p. e0128106
• Main Authors: Chornokur, Ganna, Lin, Hui-Yi, Tyrer, Jonathan P., Lawrenson, Kate, Dennis, Joe, Amankwah, Ernest K., Qu, Xiaotao, Tsai, Ya-Yu, Jim, Heather S. L., Chen, Zhihua, Chen, Ann Y., Permuth-Wey, Jennifer, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Bruinsma, Fiona, Bandera, Elisa V., Bean, Yukie T., Beckmann, Matthias W., Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A., Brooks-Wilson, Angela, Bunker, Clareann H., Butzow, Ralf, Campbell, Ian G., Carty, Karen, Chang-Claude, Jenny, Cook, Linda S., Cramer, Daniel W., Cunningham, Julie M., Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, du Bois, Andreas, Despierre, Evelyn, Dicks, Ed, Doherty, Jennifer A., Dörk, Thilo, Dürst, Matthias, Easton, Douglas F., Eccles, Diana M., Edwards, Robert P., Ekici, Arif B., Fasching, Peter A., Fridley, Brooke L., Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G., Glasspool, Rosalind, Goodman, Marc T., Gronwald, Jacek, Harrington, Patricia, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle A. T., Hillemanns, Peter, Hogdall, Claus K., Hogdall, Estrid, Hosono, Satoyo, Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y., Kelemen, Linda E., Kellar, Mellissa, Kiemeney, Lambertus A., Krakstad, Camilla, Kjaer, Susanne K., Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D., Lee, Alice W., Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A., Liang, Dong, Lim, Boon Kiong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon F. A. G., Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R., McNeish, Iain, Menon, Usha, Milne, Roger L., Modugno, Francesmary, Moysich, Kirsten B., Ness, Roberta B., Nevanlinna, Heli, Eilber, Ursula, Odunsi, Kunle, Olson, Sara H., Orlow, Irene
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science (PLoS) 19.06.2015; Public Library of Science
• Subjects: 1100 Agricultural and Biological Sciences; 1300 Biochemistry; 2.1 Biological and endogenous factors; 2700 Medicine; Aetiology; African Americans; Alleles; AOCS management group; Asian; Asian Americans; Bioinformatics; Biological Sciences; Biological Transport; Biomedical and Clinical Sciences; Black or African American; Breast cancer; Cancer; Carcinoma; Carcinoma, Ovarian Epithelial; Carrier Proteins; Carrier Proteins - genetics; Carrier Proteins - metabolism; Case-Control Studies; Consortia; Deoxyribonucleic acid; DNA; DNA damage; Epidemiology; Female; Gene expression; General Agricultural and Biological Sciences; General Biochemistry; General Medicine; General Science & Technology; Genes; Genetic Association Studies; Genetic diversity; Genetic Predisposition to Disease; Genetic Variation; Genetics; Genetics and Molecular Biology; Genomes; Georgia Chenevix-Trench; Glandular and Epithelial; Gynecology; Health care; Health risks; Health sciences; Hormones; Hospitals; Humans; Invasiveness; Iron; Laboratories; Medical research; Medicine; Meta-analysis; Molecular chains; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Glandular and Epithelial - epidemiology; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - pathology; Obstetrics; Odds Ratio; Oncology; Oncology and Carcinogenesis; Ovarian Cancer; Ovarian carcinoma; Ovarian Epithelial; Ovarian Neoplasms; Ovarian Neoplasms - epidemiology; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Oxygen; Pathology; Polymorphism; Polymorphism, Single Nucleotide; Population; Prevention; Preventive medicine; Public health; Q; R; Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences; Radboudumc 17: Women's cancers RIMLS: Radboud Institute for Molecular Life Sciences; Rare Diseases; Reactive oxygen species; Regression analysis; Regression models; Research Article; Risk; Science; Single Nucleotide; Single-nucleotide polymorphism; Thyroid gland; Trace elements; Transport processes; Tumors; Oregon; New York; United Kingdom > UK; United States > US; California; Melbourne Victoria Australia; Florida; Belarus; Pennsylvania; Los Angeles California; Canada; Netherlands; Norway; New Mexico; Finland; Poland; Pittsburgh Pennsylvania; Australia; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0128106

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. 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. 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). These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.