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Common variation in Nemo-like kinase is associated with risk of ovarian cancer.

ABSTRACT: Overexpression of mitotic kinases has been associated with prognosis, histologic grade, and clinical stage in ovarian cancer, but the relationship between inherited variation in these genes and ovarian cancer risk has not been well defined.We measured associations between 397 single nucleotide polymorphisms (SNPs) from 67 mitotic kinases and invasive epithelial ovarian cancer risk in two case-control studies (n = 671 cases; n = 939 controls). Thirty-six candidate SNPs (P < 0.05) were assessed in a replication analysis consisting of three additional studies (n = 1,094 cases; n = 829 controls).In initial analysis, thirty-six SNPs were suggestive of association with risk of serous ovarian cancer, all subtypes of ovarian cancer, or both (P < 0.05). Replication analyses suggested an association between rs2125846 in the Nemo-like kinase (NLK) gene and ovarian cancer (serous OR = 1.36, 95% CI: 1.11-1.67, P = 1.77 × 10(-3); all subtypes OR = 1.30, 95% CI: 1.08-1.56, P = 2.97 × 10(-3)). Furthermore, rs2125846 was associated with risk in the combined discovery and replication sets (serous OR = 1.33, 95% CI: 1.15-1.54; all subtypes OR = 1.27, 95% CI: 1.12-1.45).Variation in NLK may be associated with risk of invasive epithelial ovarian cancer. Further studies are needed to confirm and understand the biologic relationship between this mitotic kinase and ovarian cancer risk.An association between SNPs in NLK and ovarian cancer may provide biologic insight into the development of this disease.

SUBMITTER: Stevens KN

PROVIDER: S-EPMC3297683 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Common variation in Nemo-like kinase is associated with risk of ovarian cancer.

Stevens Kristen N KN Kelemen Linda E LE Wang Xianshu X Fridley Brooke L BL Vierkant Robert A RA Fredericksen Zachary Z Armasu Sebastian M SM Tsai Ya-Yu YY Berchuck Andrew A Narod Steven A SA Phelan Catherine M CM Sutphen Rebecca R Birrer Michael J MJ Schildkraut Joellen M JM Sellers Thomas A TA Goode Ellen L EL Couch Fergus J FJ

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20120117 3

<h4>Background</h4>Overexpression of mitotic kinases has been associated with prognosis, histologic grade, and clinical stage in ovarian cancer, but the relationship between inherited variation in these genes and ovarian cancer risk has not been well defined.<h4>Methods</h4>We measured associations between 397 single nucleotide polymorphisms (SNPs) from 67 mitotic kinases and invasive epithelial ovarian cancer risk in two case-control studies (n = 671 cases; n = 939 controls). Thirty-six candida ...[more]

PMID: 22253297

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Project description:BackgroundEMSY could be involved in low-level susceptibility to breast and ovarian cancer. Gene amplification is seen in a proportion of breast and ovarian tumours and correlates with poor prognosis in breast cancer patients. Furthermore, the EMSY protein silences a transcription activation domain in BRCA2 exon 3.MethodsWe used a genetic association study design to determine if common genetic variation (frequency > or = 5%) in EMSY was associated with breast or ovarian cancer risk in the British population. Haplotype tagging single-nucleotide polymorphisms (htSNPs) were selected from the HapMap database and genotyped using Taqman in two large study sets of white British women (n [breast set] = 2343 cases and 2284 controls, n [ovarian set] = 864 cases and 864 controls). HapMap data might be insufficient to tag genetic variation in EMSY comprehensively. We therefore screened the gene promoter and coding sequences with denaturing high performance liquid chromatography in order to identify additional SNPs that are most likely to be functional.ResultsHapMap data on 22 SNPs show that 4 htSNPs tag 4 common haplotypes: rs2282611 (5'up t > g), rs4245443 (IVS7 g > a), rs2513511 (IVS16 a > g), rs2155220 (3'down c > t). We observed no association between any of the genotypes or associated haplotypes and breast or ovarian cancer risk. Seventeen out of the 18 remaining HapMap polymorphisms (94%) were well tagged by the 4 selected htSNPs (r2s > 0.8). Genotype frequencies for two further SNPs identified by screening and located near exon-intron boundaries, rs2508740 (IVS9 a > g) and rs11600501 (IVS10 c > t), were also similar in cases and controls. In order to simulate unidentified SNPs, we performed the leave-one-out cross-validation procedure on the HapMap data; over 95% of the common genetic variation was well represented by tagging polymorphisms. We are therefore likely to have tagged any common, functional variants present in our population.ConclusionWe found no association between common genetic variation in EMSY and risk of breast or ovarian cancer in two large study sets of white British women.

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Common variation in Nemo-like kinase is associated with risk of ovarian cancer.

Publications

Common variation in Nemo-like kinase is associated with risk of ovarian cancer.

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