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Identification of nine new susceptibility loci for endometrial cancer.

ABSTRACT: Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.

SUBMITTER: O'Mara TA

PROVIDER: S-EPMC6085317 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Identification of nine new susceptibility loci for endometrial cancer.

O'Mara Tracy A TA Glubb Dylan M DM Amant Frederic F Annibali Daniela D Ashton Katie K Attia John J Auer Paul L PL Beckmann Matthias W MW Black Amanda A Bolla Manjeet K MK Brauch Hiltrud H Brenner Hermann H Brinton Louise L Buchanan Daniel D DD Burwinkel Barbara B Chang-Claude Jenny J Chanock Stephen J SJ Chen Chu C Chen Maxine M MM Cheng Timothy H T THT Clarke Christine L CL Clendenning Mark M Cook Linda S LS Couch Fergus J FJ Cox Angela A Crous-Bous Marta M Czene Kamila K Day Felix F Dennis Joe J Depreeuw Jeroen J Doherty Jennifer Anne JA Dörk Thilo T Dowdy Sean C SC Dürst Matthias M Ekici Arif B AB Fasching Peter A PA Fridley Brooke L BL Friedenreich Christine M CM Fritschi Lin L Fung Jenny J García-Closas Montserrat M Gaudet Mia M MM Giles Graham G GG Goode Ellen L EL Gorman Maggie M Haiman Christopher A CA Hall Per P Hankison Susan E SE Healey Catherine S CS Hein Alexander A Hillemanns Peter P Hodgson Shirley S Hoivik Erling A EA Holliday Elizabeth G EG Hopper John L JL Hunter David J DJ Jones Angela A Krakstad Camilla C Kristensen Vessela N VN Lambrechts Diether D Marchand Loic Le LL Liang Xiaolin X Lindblom Annika A Lissowska Jolanta J Long Jirong J Lu Lingeng L Magliocco Anthony M AM Martin Lynn L McEvoy Mark M Meindl Alfons A Michailidou Kyriaki K Milne Roger L RL Mints Miriam M Montgomery Grant W GW Nassir Rami R Olsson Håkan H Orlow Irene I Otton Geoffrey G Palles Claire C Perry John R B JRB Peto Julian J Pooler Loreall L Prescott Jennifer J Proietto Tony T Rebbeck Timothy R TR Risch Harvey A HA Rogers Peter A W PAW Rübner Matthias M Runnebaum Ingo I Sacerdote Carlotta C Sarto Gloria E GE Schumacher Fredrick F Scott Rodney J RJ Setiawan V Wendy VW Shah Mitul M Sheng Xin X Shu Xiao-Ou XO Southey Melissa C MC Swerdlow Anthony J AJ Tham Emma E Trovik Jone J Turman Constance C Tyrer Jonathan P JP Vachon Celine C VanDen Berg David D Vanderstichele Adriaan A Wang Zhaoming Z Webb Penelope M PM Wentzensen Nicolas N Werner Henrica M J HMJ Winham Stacey J SJ Wolk Alicja A Xia Lucy L Xiang Yong-Bing YB Yang Hannah P HP Yu Herbert H Zheng Wei W Pharoah Paul D P PDP Dunning Alison M AM Kraft Peter P De Vivo Immaculata I Tomlinson Ian I Easton Douglas F DF Spurdle Amanda B AB Thompson Deborah J DJ

Nature communications 20180809 1

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of en ...[more]

PMID: 30093612

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Project description:Given that substantial genetic components have been shown in ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), heritability may be higher in early-onset than late-onset individuals with these conditions. Although genome-wide association studies (GWASs) have identified various genes and loci significantly associated with ischemic stroke, ICH, or intracranial aneurysm mainly in European ancestry populations, genetic variants that contribute to susceptibility to these disorders remain to be identified definitively. We performed exome-wide association studies (EWASs) to identify genetic variants that confer susceptibility to ischemic stroke, ICH, or SAH in early-onset subjects with these conditions. A total of 6,649 individuals aged ≤65 years were examined. For the EWAS of ischemic or hemorrhagic stroke, 6,224 individuals (450 subjects with ischemic stroke, 5,774 controls) or 6,179 individuals (261 subjects with ICH, 176 subjects with SAH, 5,742 controls), respectively, were examined. EWASs were performed with the use of Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip. To compensate for multiple comparisons of allele frequencies with ischemic stroke, ICH, or SAH, we applied a false discovery rate (FDR) of <0.05 for statistical significance of association. The association of allele frequencies of 31,245 single nucleotide polymorphisms (SNPs) that passed quality control to ischemic stroke was examined with Fisher's exact test, and 31 SNPs were significantly (FDR <0.05) associated with ischemic stroke. The association of allele frequencies of 31,253 or 30,970 SNPs to ICH or SAH, respectively, was examined with Fisher's exact test, and six or two SNPs were significantly associated with ICH or SAH, respectively. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension and diabetes mellitus revealed that 12 SNPs were significantly [P<0.0004 (0.05/124)] related to ischemic stroke. Similar analysis with adjustment for age, sex, and the prevalence of hypertension revealed that six or two SNPs were significantly [P<0.0016 (0.05/32)] related to ICH or SAH, respectively. After examination of linkage disequilibrium of identified SNPs and results of previous GWASs, we identified HHIPL2, CTNNA3, LOC643770, UTP20, and TRIB3 as susceptibility loci for ischemic stroke, DNTTIP2 and FAM205A as susceptibility loci for ICH, and FAM160A1 and OR52E4 as such loci for SAH. Therefore, to the best of our knowledge, we have newly identified nine genes that confer susceptibility to early-onset ischemic stroke, ICH, or SAH. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for ischemic stroke, ICH, or SAH in Japanese.

Project description:Background & aimsKnown genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC.MethodsThis discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases.ResultsWe identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10(-8) to 1.24 × 10(-12): 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P < .05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2.ConclusionsWe identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

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Identification of nine new susceptibility loci for endometrial cancer.

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Identification of nine new susceptibility loci for endometrial cancer.

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