Association of Single Nucleotide Polymorphisms in Glycosylation Genes with Risk of Epithelial Ovarian Cancer

Sellers, Thomas A.; Huang, Yifan; Cunningham, Julie M.; Goode, Ellen L.; Sutphen, Rebecca; Vierkant, Robert A.; Kelemen, Linda E.; Fredericksen, Zachary S.; Liebow, Mark; Pankratz, V. Shane; Hartmann, Lynn C.; Myer, Jeff; Iversen, Edwin S.; Schildkraut, Joellen M.; Phelan, Catherine M.

doi:10.1158/1055-9965.epi-07-0565

Cited by 48 publications

(41 citation statements)

References 35 publications

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“…GALNT1 is a glycosyltransferase that initiates O-linked glycosylation in the Golgi apparatus. Single-nucleotide polymorphisms in GALNT1 are associated with the risk of ovarian cancer (69), in agreement with data indicating altered glycosylation of proteins in ovarian cancer (70).…”

Section: Discussionsupporting

confidence: 88%

A Link between mir-100 and FRAP1/mTOR in Clear Cell Ovarian Cancer

Nagaraja¹,

Creighton²,

Yu³

et al. 2010

Molecular Endocrinology

220

174

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MicroRNAs (miRNAs) are small noncoding RNAs that direct gene regulation through translational repression and degradation of complementary mRNA. Although miRNAs have been implicated as oncogenes and tumor suppressors in a variety of human cancers, functional roles for individual miRNAs have not been described in clear cell ovarian carcinoma, an aggressive and chemoresistant subtype of ovarian cancer. We performed deep sequencing to comprehensively profile miRNA expression in 10 human clear cell ovarian cancer cell lines compared with normal ovarian surface epithelial cultures and discovered 54 miRNAs that were aberrantly expressed. Because of the critical roles of the phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin (mTOR) pathway in clear cell ovarian cancer, we focused on mir-100, a putative tumor suppressor that was the most down-regulated miRNA in our cancer cell lines, and its up-regulated target, FRAP1/mTOR. Overexpression of mir-100 inhibited mTOR signaling and enhanced sensitivity to the rapamycin analog RAD001 (everolimus), confirming the key relationship between mir-100 and the mTOR pathway. Furthermore, overexpression of the putative tumor suppressor mir-22 repressed the EVI1 oncogene, which is known to suppress apoptosis by stimulating phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1 signaling. In addition to these specific effects, reversing the expression of mir-22 and the putative oncogene mir-182 had widespread effects on target and nontarget gene populations that ultimately caused a global shift in the cancer gene signature toward a more normal state. Our experiments have revealed strong candidate miRNAs and their target genes that may contribute to the pathogenesis of clear cell ovarian cancer, thereby highlighting alternative therapeutic strategies for the treatment of this deadly cancer.

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Section: Discussionsupporting

confidence: 88%

A Link between mir-100 and FRAP1/mTOR in Clear Cell Ovarian Cancer

Nagaraja¹,

Creighton²,

Yu³

et al. 2010

Molecular Endocrinology

220

174

View full text Add to dashboard Cite

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“…For instance, loss of GALNT1 activity in mice results in bleeding disorder (7). Risk of epithelial ovarian cancer (8) and coronary artery disease (9) have been associated with single nucleotide polymorphisms of GALNT1 and GALNT2, respectively. GALNT3 expression is a potential diagnostic marker for lung (10) and pancreatic (11) cancers.…”

Section: Introductionmentioning

confidence: 99%

Mucin Glycosylating Enzyme GALNT2 Regulates the Malignant Character of Hepatocellular Carcinoma by Modifying the EGF Receptor

Liu²,

Hu³

et al. 2011

Cancer Research

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Extracellular glycosylation is a critical determinant of malignant character. Here, we report that N-acetylgalactosaminyltransferase 2 (GALNT2), the enzyme that mediates the initial step of mucin type-O glycosylation, is a critical mediator of malignant character in hepatocellular carcinoma (HCC) that acts by modifying the activity of the epidermal growth factor receptor (EGFR). GALNT2 mRNA and protein were downregulated frequently in HCC tumors where these events were associated with vascular invasion and recurrence. Restoring GALNT2 expression in HCC cells suppressed EGF-induced cell growth, migration, and invasion in vitro and in vivo. Mechanistic investigations revealed that the status of the O-glycans attached to the EGFR was altered by GALNT2, changing EGFR responses after EGF binding. Inhibiting EGFR activity with erlotinib decreased the malignant characters caused by siRNA-mediated knockdown of GALNT2 in HCC cells, establishing the critical role of EGFR in mediating the effects of GALNT2 expression. Taken together, our results suggest that GALNT2 dysregulation contributes to the malignant behavior of HCC cells, and they provide novel insights into the significance of O-glycosylation in EGFR activity and HCC pathogenesis. Cancer Res; 71(23); 7270-9. Ó2011 AACR.

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“…Thus, there is emerging consensus that most of the genetic component of ovarian cancer risk is due to genetic polymorphisms that confer low to moderate risk. A common approach to identify risk variants is to rely on known biology to identify plausible candidate genes [4]. A gene thought to have an important role in ovarian cancer is MUC16 (mucin 16) gene that encodes the tumor marker CA125 [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in the MUC16 Gene: Potential Implication in Epithelial Ovarian Cancer

Bouanene

Kacem

Fatma

et al. 2010

Pathol. Oncol. Res.

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MUC16 plays an important role in epithelial ovarian cancer. In this paper, we studied the association between two tags SNPs of MUC16 and the risk of epithelial ovarian cancer. We aimed also to test the association between these tags SNPs and elevated level of the protein CA125. We analyzed a collection of 117 cases. Forty-one samples of patients with epithelial ovarian cancer and 76 samples from Tunisian volunteers were genotyped for two synonymous coding tags SNPs of the MUC16 gene (rs1596797, A/C and rs2547065, C/G) using polymerase chain reaction and sequencing. For the rs1596797 SNP, there was no significant difference in genotype distribution, a rare variation observed in only one patient. For the polymorphism rs2547065, mean CA125 levels were 24 and 78 UI/ml in patients with GG and GC genotypes versus 230 UI/ml in patients with CC genotype (P = 0.36). Compared to the C/C genotype, the 'G' allele (C/G+G/G genotypes) did not significantly modified the risk of developing epithelial ovarian cancer (OR = 0.43; 95% CI). As for the polymorphism rs1596797, compared to the C/C genotype, the 'A' allele (C/A+A/A genotypes) did not significantly modified the risk of developing epithelial ovarian cancer (OR = 881.7; 95% CI). MUC16 gene polymorphisms selected in this study are neither involved in genetic predisposition to epithelial ovarian cancer nor associated with CA125 level.

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Association of Single Nucleotide Polymorphisms in Glycosylation Genes with Risk of Epithelial Ovarian Cancer

Cited by 48 publications

References 35 publications

A Link between mir-100 and FRAP1/mTOR in Clear Cell Ovarian Cancer

A Link between mir-100 and FRAP1/mTOR in Clear Cell Ovarian Cancer

Mucin Glycosylating Enzyme GALNT2 Regulates the Malignant Character of Hepatocellular Carcinoma by Modifying the EGF Receptor

Polymorphisms in the MUC16 Gene: Potential Implication in Epithelial Ovarian Cancer

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