Five endometrial cancer risk loci identified through genome-wide association analysis
NATURE GENETICS
Authors: Cheng, Timothy H. T.; Thompson, Deborah J.; O'Mara, Tracy A.; Painter, Jodie N.; Glubb, Dylan M.; Flach, Susanne; Lewis, Annabelle; French, Juliet D.; Freeman-Mills, Luke; Church, David; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Webb, Penelope M.; Attia, John; Holliday, Elizabeth G.; McEvoy, Mark; Scott, Rodney J.; Henders, Anjali K.; Martin, Nicholas G.; Montgomery, Grant W.; Nyholt, Dale R.; Ahmed, Shahana; Healey, Catherine S.; Shah, Mitul; Dennis, Joe; Fasching, Peter A.; Beckmann, Matthias W.; Hein, Alexander; Ekici, Arif B.; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Doerk, Thilo; Duerst, Matthias; Hillemanns, Peter; Runnebaum, Ingo; Amant, Frederic; Schrauwen, Stefanie; Zhao, Hui; Lambrechts, Diether; Depreeuw, Jeroen; Dowdy, Sean C.; Goode, Ellen L.; Fridley, Brooke L.; Winham, Stacey J.; Njolstad, Tormund S.; Salvesen, Helga B.; Trovik, Jone; Werner, Henrica M. J.; Ashton, Katie; Otton, Geoffrey; Proietto, Tony; Liu, Tao; Mints, Miriam; Tham, Emma; Li, Mulin Jun; Yip, Shun H.; Wang, Junwen; Bolla, Manjeet K.; Michailidou, Kyriaki; Wang, Qin; Tyrer, Jonathan P.; Dunlop, Malcolm; Houlston, Richard; Palles, Claire; Hopper, John L.; Peto, Julian; Swerdlow, Anthony J.; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J.; Giles, Graham G.; Kristensen, Vessela N.; Cox, Angela; Cunningham, Julie M.; Pharoah, Paul D. P.; Dunning, Alison M.; Edwards, Stacey L.; Easton, Douglas F.; Tomlinson, Ian; Spurdle, Amanda B.
Abstract
We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.
Mapping the H+ (V)-ATPase interactome: identification of proteins involved in trafficking, folding, assembly and phosphorylation
SCIENTIFIC REPORTS
Authors: Merkulova, Maria; Paunescu, Teodor G.; Azroyan, Anie; Marshansky, Vladimir; Breton, Sylvie; Brown, Dennis
Abstract
V-ATPases (H+ ATPases) are multisubunit, ATP-dependent proton pumps that regulate pH homeostasis in virtually all eukaryotes. They are involved in key cell biological processes including vesicle trafficking, endosomal pH sensing, membrane fusion and intracellular signaling. They also have critical systemic roles in renal acid excretion and blood pH balance, male fertility, bone remodeling, synaptic transmission, olfaction and hearing. Furthermore, V-ATPase dysfunction either results in or aggravates various other diseases, but little is known about the complex protein interactions that regulate these varied V-ATPase functions. Therefore, we performed a proteomic analysis to identify V-ATPase associated proteins and construct a V-ATPase interactome. Our analysis using kidney tissue revealed V-ATPase-associated protein clusters involved in protein quality control, complex assembly and intracellular trafficking. ARHGEF7, DMXL1, EZR, NCOA7, OXR1, RPS6KA3, SNX27 and 9 subunits of the chaperonin containing TCP1 complex (CCT) were found to interact with V-ATPase for the first time in this study. Knockdown of two interacting proteins, DMXL1 and WDR7, inhibited V-ATPase-mediated intracellular vesicle acidification in a kidney cell line, providing validation for the utility of our interactome as a screen for functionally important novel V-ATPase-regulating proteins. Our data, therefore, provide new insights and directions for the analysis of V-ATPase cell biology and (patho)physiology.
COA
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