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

Ganna Chornokur(Moffitt Cancer Center), Hui‐Yi Lin(Moffitt Cancer Center), Jonathan P. Tyrer(University of Cambridge), Kate Lawrenson(University of Southern California), Joe Dennis(University of Cambridge), Ernest K. Amankwah(Johns Hopkins University), Xiaotao Qu(Moffitt Cancer Center), Ya-Yu Tsai(Moffitt Cancer Center), Heather Jim(Moffitt Cancer Center), Zhihua Chen(Moffitt Cancer Center), Y. Ann Chen(Moffitt Cancer Center), Jennifer Permuth‐Wey(Moffitt Cancer Center), Katja K.H. Aben(Radboud University Nijmegen), Hoda Anton‐Culver(University of California, Irvine), Natalia Antonenkova(N.N. Alexandrov National Cancer Centre), Fiona Bruinsma(Cancer Council Victoria), Elisa V. Bandera(Rutgers, The State University of New Jersey), Yukie T. Bean(Oregon Health & Science University), Matthias W. Beckmann(Universitätsklinikum Erlangen), Maria Bisogna(Memorial Sloan Kettering Cancer Center), Line Bjørge(Haukeland University Hospital), Natalia Bogdanova(Medizinische Hochschule Hannover), Louise A. Brinton(National Cancer Institute), Angela Brooks‐Wilson(BC Cancer Agency), Clareann H. Bunker(University of Pittsburgh), Ralf Bützow(University of Helsinki), Ian Campbell(The University of Melbourne), Karen Carty(Beatson West of Scotland Cancer Centre), Jenny Chang‐Claude(German Cancer Research Center), Linda S. Cook(University of New Mexico), Daniel W. Cramer(Brigham and Women's Hospital), Julie M. Cunningham(Mayo Clinic), Cezary Cybulski(International Hereditary Cancer Center), Agnieszka Dansonka‐Mieszkowska(The Maria Sklodowska-Curie National Research Institute of Oncology), Andreas du Bois(Helios Dr. Horst Schmidt Kliniken Wiesbaden), Evelyn Despierre(KU Leuven), Ed Dicks(University of Cambridge), Jennifer A. Doherty(Dartmouth College), Thilo Dörk(Medizinische Hochschule Hannover), Matthias Dürst(Jena University Hospital), Douglas F. Easton(University of Southern California), Diana M. Eccles(University of Southampton), Robert P. Edwards(Magee-Womens Research Institute), Arif B. Ekici(Comprehensive Cancer Center Erlangen), Peter A. Fasching(University of California, Los Angeles), Brooke L. Fridley(University of Kansas Medical Center), Yu‐Tang Gao(Shanghai Cancer Institute), Aleksandra Gentry‐Maharaj(University College London), Graham G. Giles(The University of Melbourne), Rosalind Glasspool(Beatson West of Scotland Cancer Centre), Marc T. Goodman(Cedars-Sinai Medical Center), Jacek Gronwald(International Hereditary Cancer Center), Patricia Harrington(University of Cambridge), Philipp Harter(Helios Dr. Horst Schmidt Kliniken Wiesbaden), Alexander Hein(Universitätsklinikum Erlangen), Florian Heitz(Helios Dr. Horst Schmidt Kliniken Wiesbaden), Michelle A.T. Hildebrandt(The University of Texas MD Anderson Cancer Center), Peter Hillemanns(Medizinische Hochschule Hannover), Claus Høgdall(University of Copenhagen), Estrid Høgdall(University of Copenhagen), Satoyo Hosono(Kyushu University), Anna Jakubowska(International Hereditary Cancer Center), Allan Jensen(Danish Cancer Society), Bu‐Tian Ji(National Cancer Institute), Beth Y. Karlan(Cedars-Sinai Medical Center), Linda E. Kelemen(Medical University of South Carolina), Mellissa Kellar(Oregon Health & Science University), Lambertus A. Kiemeney(Radboud University Nijmegen), Camilla Krakstad(Haukeland University Hospital), Susanne K. Kjær(University of Copenhagen), Jolanta Kupryjańczyk(The Maria Sklodowska-Curie National Research Institute of Oncology), Diether Lambrechts(VIB-KU Leuven Center for Cancer Biology), Sandrina Lambrechts(KU Leuven), Nhu D. Le(BC Cancer Agency), Alice W. Lee(University of Southern California), Shashi Lele(Roswell Park Comprehensive Cancer Center), Arto Leminen(University of Helsinki), Jenny Lester(Cedars-Sinai Medical Center), Douglas A. Levine(Memorial Sloan Kettering Cancer Center), Dong Liang(Texas Southern University), Boon Kiong Lim(University Malaya Medical Centre), Jolanta Lissowska(The Maria Sklodowska-Curie National Research Institute of Oncology), Karen H. Lu(The University of Texas MD Anderson Cancer Center), Jan Lubiński(International Hereditary Cancer Center), Lene Lundvall(University of Copenhagen), Leon F.A.G. Massuger(Radboud University Nijmegen), Keitaro Matsuo(Kyushu University), Valerie McGuire(Stanford Health Care), John R. McLaughlin(Public Health Ontario), Iain A. McNeish(Cancer Research UK Scotland Institute), Usha Menon(University College London), Roger L. Milne(Cancer Council Victoria), Francesmary Modugno(University of Pittsburgh), Kirsten B. Moysich(Roswell Park Comprehensive Cancer Center), Roberta B. Ness(The University of Texas Health Science Center at Houston), Heli Nevanlinna(University of Helsinki), Ursula Eilber(German Cancer Research Center), Kunle Odunsi(Roswell Park Comprehensive Cancer Center), Sara H. Olson(Memorial Sloan Kettering Cancer Center), Irene Orlow(Memorial Sloan Kettering Cancer Center), Sandra Oršulić(Cedars-Sinai Medical Center), Rachel Palmieri Weber(Duke Medical Center), James Paul(Beatson West of Scotland Cancer Centre), Celeste Leigh Pearce(University of Southern California), Tanja Pejović(Oregon Health & Science University), Liisa M. Pelttari(University of Helsinki), Malcolm C. Pike(University of Southern California), Elizabeth M. Poole(Brigham and Women's Hospital), Harvey A. Risch(Yale University), Barry P. Rosen(University of Toronto), Mary Anne Rossing(University of Washington), Joseph H. Rothstein(Stanford University), Anja Rudolph(German Cancer Research Center), Ingo B. Runnebaum(Jena University Hospital), Iwona K. Rzepecka(The Maria Sklodowska-Curie National Research Institute of Oncology), Helga B. Salvesen(Haukeland University Hospital), Eva Schernhammer(Brigham and Women's Hospital), Ira Schwaab(Praxis für Humangenetik), Xiao‐Ou Shu(Vanderbilt University), Yurii B. Shvetsov(University of Hawaiʻi at Mānoa), Nadeem Siddiqui(Glasgow Royal Infirmary), Weiva Sieh(Stanford University), Honglin Song(University of Cambridge), Melissa C. Southey(The University of Melbourne), Beata Śpiewankiewicz(The Maria Sklodowska-Curie National Research Institute of Oncology), Lara Sucheston(Roswell Park Comprehensive Cancer Center), Soo‐Hwang Teo(University Malaya Medical Centre), Kathryn L. Terry(Brigham and Women's Hospital), Pamela J. Thompson(Cedars-Sinai Medical Center), Lotte Thomsen(University of Copenhagen), Ingvild L. Tangen(Haukeland University Hospital), Shelley S. Tworoger(Brigham and Women's Hospital), Anne M. van Altena(Radboud University Nijmegen), Robert A. Vierkant(Mayo Clinic in Florida), Ignace Vergote(KU Leuven), Christine Walsh(Cedars-Sinai Medical Center), Shan Wang‐Gohrke(German Cancer Research Center), Nicolas Wentzensen(National Cancer Institute), Alice S. Whittemore(Stanford University), Kristine G. Wicklund(University of Washington), Lynne R. Wilkens(University of Hawaiʻi at Mānoa), Anna H. Wu(University of Southern California), Xifeng Wu(The University of Texas MD Anderson Cancer Center), Yin Ling Woo(University Malaya Medical Centre), Hannah Yang(National Cancer Institute), Wei Zheng(Vanderbilt University), Argyrios Ziogas(University of California, Irvine), Hanis Nazihah Hasmad(Cancer Research Malaysia), Andrew Berchuck(Duke Medical Center), Georgia Chenevix-Trench on behalf of the AOCS management group(Duke University), Edwin S. Iversen(Duke University), Joellen M. Schildkraut(University of Southern California), Susan J. Ramus(University of Southern California), Ellen L. Goode(Moffitt Cancer Center), Álvaro N.A. Monteiro(University of Southern California), Simon A. Gayther(University of Southern California), Steven A. Narod(University of Toronto), Paul D.P. Pharoah(University of Cambridge), Thomas A. Sellers(Moffitt Cancer Center), Catherine M. Phelan(Moffitt Cancer Center)
PLoS ONE
June 19, 2015
10.1371/journal.pone.0128106
Cited by 906Open Access
Full Text

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.

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