Genome-wide association study identifies a common variant associated with risk of endometrial cancer

Spurdle, Amanda B.; Thompson, Deborah J.; Ahmed, Shahana; Ferguson, Kaltin; Healey, Catherine S.; O’Mara, Tracy A.; Walker, Logan C.; Montgomery, S; Dermitzakis, Emmanouil T.; Fahey, Paul; Montgomery, Grant W.; Webb, Penelope M.; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Hein, Alexander; Lambrechts, Diether; Coenegrachts, Lieve; Vergote, Ignace; Amant, Frédéric; Salvesen, Helga B.; Trovik, Jone; Njølstad, Tormund S.; Helland, Harald; Scott, Rodney J.; Ashton, Katie A.; Proietto, Tony; Otton, Geoffrey; Tomlinson, Ian; Gorman, Maggie; Howarth, Kimberley; Hodgson, Shirley; García-Closas, Montserrat; Wentzensen, Nicolas; Yang, Hannah; Chanock, Stephen J.; Hall, Per; Czene, Kamila; Li, Jianjun; Li, Jingmei; Shu, Xiao‐Ou; Wang, Zheng; Long, Jirong; Xiang, Yong‐Bing; Shah, Mitul; Morrison, Jonathan J.; Michailidou, Kyriaki; Pharoah, Paul D.P.; Dunning, Alison M.; Easton, Douglas F.

doi:10.1038/ng.812

Cited by 142 publications

(162 citation statements)

References 39 publications

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“…It remains possible that HNF1B may cooperate with ERBB2 to drive transformation in a manner analogous to what has been observed for YAP1 and CIAP1, which reside in a single amplicon in hepatocellular cancer (Zender et al 2006). HNF1B has previously been described as an essential gene in ovarian clear cell carcinoma, where it is highly expressed (Tsuchiya et al 2003), and genome-wide association studies have associated SNPs in the HNF1B locus with risk for prostate and endometrial cancers (Schumacher et al 2011;Spurdle et al 2011), although HNF1B may also be epigenetically inactivated in certain contexts (Terasawa et al 2006). Developmentally, HNF1B is required for visceral endoderm formation (Barbacci et al 1999) and proper development of the genitourinary tract (Ryffel 2001;Bellanne-Chantelot et al 2005), but appears to be dispensable in adult tissue (Verdeguer et al 2009), making it a reasonable candidate for therapeutic targeting.…”

Section: Discussionmentioning

confidence: 85%

ATARiS: Computational quantification of gene suppression phenotypes from multisample RNAi screens

et al. 2012

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Genome-scale RNAi libraries enable the systematic interrogation of gene function. However, the interpretation of RNAi screens is complicated by the observation that RNAi reagents designed to suppress the mRNA transcripts of the same gene often produce a spectrum of phenotypic outcomes due to differential on-target gene suppression or perturbation of off-target transcripts. Here we present a computational method, Analytic Technique for Assessment of RNAi by Similarity (ATARiS), that takes advantage of patterns in RNAi data across multiple samples in order to enrich for RNAi reagents whose phenotypic effects relate to suppression of their intended targets. By summarizing only such reagent effects for each gene, ATARiS produces quantitative, gene-level phenotype values, which provide an intuitive measure of the effect of gene suppression in each sample. This method is robust for data sets that contain as few as 10 samples and can be used to analyze screens of any number of targeted genes. We used this analytic approach to interrogate RNAi data derived from screening more than 100 human cancer cell lines and identified HNF1B as a transforming oncogene required for the survival of cancer cells that harbor HNF1B amplifications. ATARiS is publicly available at http://broadinstitute.org/ataris.

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Section: Discussionmentioning

confidence: 85%

ATARiS: Computational quantification of gene suppression phenotypes from multisample RNAi screens

et al. 2012

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“…Mutations of HNF1B have been described in renal cell carcinoma (33), and epigenetic silencing of the gene has been reported in ovarian cancer, as well as gastric, pancreatic, and colorectal cell lines (34). GWAS have implicated variants in the HNF1B locus in diabetes and endometrial cancer risk (35,36). SLC22A3 is a member of the solute carrier family 22; it functions as a cation transporter in various organs, including prostate tissue, and plays a role eliminating small organic cations and toxins.…”

Section: Discussionmentioning

confidence: 99%

Genetic and functional analyses implicate the NUDT11 , HNF1B , and SLC22A3 genes in prostate cancer pathogenesis

Grisanzio¹,

Werner²,

Takeda

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

103

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One of the central goals of human genetics is to discover the genes and pathways driving human traits. To date, most of the common risk alleles discovered through genome-wide association studies (GWAS) map to nonprotein-coding regions. Because of our relatively poorer understanding of this part of the genome, the functional consequences of trait-associated variants pose a considerable challenge. To identify the genes through which risk loci act, we hypothesized that the risk variants are regulatory elements. For each of 12 known risk polymorphisms, we evaluated the correlation between risk allele status and transcript abundance for all annotated protein-coding transcripts within a 1-Mb interval. A total of 103 transcripts were evaluated in 662 prostate tissue samples [normal (n = 407) and tumor (n = 255)] from 483 individuals [European Americans (n = 233), Japanese (n = 127), and African Americans (n = 123)]. In a pooled analysis, 4 of the 12 risk variants were strongly associated with five transcripts (NUDT11, MSMB, NCOA4, SLC22A3, and HNF1B) in histologically normal tissue (P ≤ 0.001). Although associations were also observed in tumor tissue, they tended to be more attenuated. Previously, we showed that MSMB and NCOA4 participate in prostate cancer pathogenesis. Suppressing the expression of NUDT11, SLC22A3, and HNF1B influences cellular phenotypes associated with tumor-related properties in prostate cancer cells. Taken together, the data suggest that these transcripts contribute to prostate cancer pathogenesis.expression quantitative trait loci | prostate cancer risk SNPs | multi-ethnic

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“…Later, the two SNPs (rs4430796 and rs11649743) in HNF1B associated with prostate cancer risk were identified (20,21). Further study indicated that the rs4430796 is also associated with endometrial cancer risk in women of European background (22). Similarly, rs7501939 in HNF1B is associated with the risk of prostate cancer (22) and endometrial cancer (22).…”

Section: Introductionmentioning

confidence: 99%

“…Further study indicated that the rs4430796 is also associated with endometrial cancer risk in women of European background (22). Similarly, rs7501939 in HNF1B is associated with the risk of prostate cancer (22) and endometrial cancer (22). In ovarian cancer, HNF1B is identified as a subtype-specific susceptibility gene (24-26).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer

Zhang²,

Gao

et al. 2014

Oncology Reports

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Abstract. The expression of HNF1 homeobox B (HNF1B) is associated with cancer risk in several tumors, including ovarian cancer, and its decreased expression play roles in cancer development. However, the study of HNF1B and cancer is limited, and its association with drug resistance in cancer has never been reported. On the basis of array data retrieved from Oncomine and Gene Expression Omnibus (GEO) online database, we found that the mRNA expression of HNF1B in 586 ovarian serous cystadenocarcinomas and in platinum-resistant A2780 epithelial ovarian cancer cells was significantly decreased, indicating a potential role of HNF1B in drug resistance in ovarian cancer. Based on this finding, comprehensive bioinformatics analyses, including protein/ gene interaction, protein-small molecule/chemical interaction, biological process annotation, gene co-occurrence and pathway enrichment analysis and microRNA-mRNA interaction, were performed to illustrate the association of HNF1B with drug resistance in ovarian cancer. We found that among the proteins/ genes, small molecules/chemicals and microRNAs which directly interacted with HNF1B, the majority was associated with drug resistance in cancer, particularly in ovarian cancer. Biological process annotation revealed that HNF1B closely related to 24 biological processes which were all notably associated with ovarian cancer and drug resistance. These results indicated that the downregulation of HNF1B may contribute to drug resistance in ovarian cancer, via its direct interactions with these drug resistance-related proteins/genes, small molecules/chemicals and microRNAs, and via its regulations on the drug resistance-related biological processes. Pathway enrichment analysis of 36 genes which co-occurred with HNF1B, ovarian cancer and drug resistance indicated that the HNF1B may perform its drug resistance-related functions through 4 pathways including ErbB signaling, focal adhesion, apoptosis and p53 signaling. Collectively, in this study, we illustrated for the first time that HNF1B may contribute to drug resistance in ovarian cancer, potentially through the 4 pathways. The present study may pave the way for further investigation of the drug resistance-related functions of HNF1B in ovarian cancer.

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Genome-wide association study identifies a common variant associated with risk of endometrial cancer

Cited by 142 publications

References 39 publications

ATARiS: Computational quantification of gene suppression phenotypes from multisample RNAi screens

ATARiS: Computational quantification of gene suppression phenotypes from multisample RNAi screens

Genetic and functional analyses implicate the NUDT11 , HNF1B , and SLC22A3 genes in prostate cancer pathogenesis

Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer

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