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

Ganna Chornokur, Hui-Yi Lin, Jonathan P. Tyrer, Kate Lawrenson, Joe Dennis, Ernest K. Amankwah, Xiaotao Qu, Ya-Yu Tsai, Heather S. L. Jim, Zhihua Chen, Ann Y. Chen, Jennifer Permuth-Wey, Katja KH. Aben, Hoda Anton-Culver, Natalia Antonenkova, Fiona Bruinsma, Elisa V. Bandera, Yukie T. Bean, Matthias W. Beckmann, Maria Bisogna, Line Bjorge, Natalia Bogdanova, Louise A. Brinton, Angela Brooks-Wilson, Clareann H. Bunker, Ralf Butzow, Ian G. Campbell, Karen Carty, Jenny Chang-Claude, Linda S. Cook, Daniel W. Cramer, Julie M. Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Andreas du Bois, Evelyn Despierre, Ed Dicks, Jennifer A. Doherty, Thilo Dörk, Matthias Dürst, Douglas F. Easton, Diana M. Eccles, Robert P. Edwards, Arif B. Ekici, Peter A. Fasching, Brooke L. Fridley, Yu-Tang Gao, Aleksandra Gentry-Maharaj, Graham G. Giles, Rosalind Glasspool, Marc T. Goodman, Jacek Gronwald, Patricia Harrington, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A. T. Hildebrandt, Peter Hillemanns, Claus K. Hogdall, Estrid Hogdall, Satoyo Hosono, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Beth Y. Karlan, Linda E. Kelemen, Mellissa Kellar, Lambertus A. Kiemeney, Camilla Krakstad, Susanne K. Kjaer, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D. Le, Alice W. Lee, Shashi Lele, Arto Leminen, Jenny Lester, Douglas A. Levine, Dong Liang, Boon Kiong Lim, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F. A. G. Massuger, Keitaro Matsuo, Valerie McGuire, John R. McLaughlin, Iain McNeish, Usha Menon, Roger L. Milne, Francesmary Modugno, Kirsten B. Moysich, Roberta B. Ness, Heli Nevanlinna, Ursula Eilber, Kunle Odunsi, Sara H. Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, James Paul, Celeste L. Pearce, Tanja Pejovic, Liisa M. Pelttari, Malcolm C. Pike, Elizabeth M. Poole, Harvey A. Risch, Barry Rosen, Mary Anne Rossing, Joseph H. Rothstein, Anja Rudolph, Ingo B. Runnebaum, Iwona K. Rzepecka, Helga B. Salvesen, Eva Schernhammer, Ira Schwaab, Xiao-Ou Shu, Yurii B. Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C. Southey, Beata Spiewankiewicz, Lara Sucheston, Soo-Hwang Teo, Kathryn L. Terry, Pamela J. Thompson, Lotte Thomsen, Ingvild L. Tangen, Shelley S. Tworoger, Anne M. van Altena, Robert A. Vierkant, Ignace Vergote, Christine S. Walsh, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S. Whittemore, Kristine G. Wicklund, Lynne R. Wilkens, Anna H. Wu, Xifeng Wu, Yin-Ling Woo, Hannah Yang, Wei Zheng, Argyrios Ziogas, Hanis N. Hasmad, Andrew Berchuck, Edwin S. Iversen, Joellen M. Schildkraut, Susan J. Ramus, Ellen L. Goode, Alvaro N. A. Monteiro, Simon A. Gayther, Steven A. Narod, Paul D. P. Pharoah, Thomas A. Sellers, Catherine M. Phelan

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.