期刊
PLOS ONE
卷 13, 期 7, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0197561
关键词
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资金
- NIH [R01 CA-1491429]
- US National Cancer Institute [R01-CA076016, K07-CA095666, K07 CM 43047, K22-CA138563, N01-CN55424, N01-PC67001, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P01-CA087969, R01-CA016056, R01-CA017054, R01CA049449, R01-CA050385, R01-CA054419, R01CA058598]
- COGS project through a European Commission's Seventh Framework Programme [223175 HEALTH F2 2009-223175]
- Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative [U19-CA148112]
- Ovarian Cancer Research Fund [PPD/RPCI.07]
- National Health and Medical Research Council
- American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]
- National Center for Advancing Translational Sciences (NCATS) [UL1TR000124]
- Canadian Institute of Health Research New Investigator Award [MSH-87734]
- California Cancer Research Program [00-01389V-20170, N01-CN25403, 2110200]
- Canadian Institutes of Health Research [MOP-86727]
- Cancer Australia
- Cancer Council Victoria
- Cancer Council Queensland
- Cancer Council New South Wales
- Cancer Council South Australia
- Cancer Council Tasmania
- Cancer Foundation of Western Australia
- Cancer Institute of New Jersey
- Cancer Research UK [C490/A6187, C490/A10119, C490/A10124]
- Danish Cancer Society [94-222-52]
- ELAN Program of the University of Erlangen-Nuremberg
- Eve Appeal
- Helsinki University Central Hospital Research Fund
- Helse Vest
- Norwegian Cancer Society
- Norwegian Research Council
- Ovarian Cancer Research Fund
- Nationaal Kankerplan of Belgium
- Ministry of Health Labour and Welfare of Japan
- L & S Milken Foundation
- Polish Ministry of Science and Higher Education [4 P05C 02814, 2 P05A 068 27]
- Roswell Park Cancer Institute Alliance Foundation
- US Army Medical Research and Material Command [DAMD17-01-10729, DAMD17-02-1-0666, DAM D17-02-1-0669, W81XWH-07-0449, W81XWH-10-1-02802]
- US Public Health Service [PSA-042205]
- National Health and Medical Research Council of Australia [199600, 400281]
- German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01GB 9401]
- State of Baden-Wurttemberg through Medical Faculty of the University of Ulm [P.685]
- Minnesota Ovarian Cancer Alliance
- Mayo Foundation
- Fred C. and Katherine B. Andersen Foundation
- Lon V. Smith Foundation [LVS-39420]
- Oak Foundation
- OHSU Foundation
- Mermaid I project
- Rudolf-Bartling Foundation
- UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge
- Imperial College London, University College Hospital Womens Health Theme
- Royal Marsden Hospital
- WorkSafeBC
- MRC [G0601891, G0501974] Funding Source: UKRI
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify bio-features and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10(-6)). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.
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