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Int J Mol Epidemiol Genet 2011;2(1):9-18.
Original Article
Genetic and epigenetic association studies suggest a role of microRNA
biogenesis gene exportin-5 (XPO5) in breast tumorigenesis
Derek Leaderer, Aaron E. Hoffman, Tongzhang Zheng, Alan Fu, Joanne Weidhaas, Trupti Paranjape, and Yong Zhu
Department of Epidemiology and Public Health, Yale School of Medicine; and Department of Therapeutic Radiology, Yale
School of Medicine, New Haven, Connecticut; Current address: Department of Epidemiology, Tulane School of Public Health
and Tropical Medicine and Tulane Cancer Center, New Orleans, Louisiana
Received September 27, 2010; accepted November 23, 2010; Epub November 25, 2010; published January 1, 2011
Abstract: Given strong evidence implicating an important role of altered microRNA expression in cancer initiation and
progression, the genes responsible for microRNA biogenesis may also play a role in tumorigenesis. Exportin-5 (XPO5) is
responsible for exporting pre-miRNAs through the nuclear membrane to the cytoplasm, and is thus critical in miRNA
biogenesis. In the current study, we performed both genetic and epigenetic association studies of XPO5 in a case control
study of breast cancer. We first genotyped two missense SNPs in XPO5, rs34324334 (S241N) and rs11544382 (M1115T), and
further analyzed methylation levels in the XPO5 promoter region for blood DNA samples from a breast cancer case-control
study. We found the variant genotypes of rs11544382 to be associated with breast cancer risk (OR=1.59, 95% CI: 1.06 - 2.39),
compared to the homozygous common genotype. When stratified by menopausal status, the variant alleles of both rs11544382
(OR=1.82, 95% CI: 1.09-3.03) and rs34324334 (OR=1.76, 95% CI: 1.10-2.83) were significantly associated with breast cancer
risk in post-menopausal women. The methylation analysis showed that the “high” and combined “high/middle” tertiles of
methylation index were associated with reduced risk of breast cancer (OR=0.34, 95% CI:0.15- 0.81 and OR=0.47, 95% CI:0.24-
0.94, respectively; Ptrend=0.015). These results were corroborated by data from a publicly available tissue array, which showed
lower levels of XPO5 expression in healthy controls relative to tumor or adjacent tissues from breast cancer patients with tumor
tissue exhibiting the highest expression levels. These findings support the hypothesis that variations in components of the
miRNA biogenesis pathway, in this case XPO5, may affect an individual’s risk of developing breast cancer. (IJMEG10009005).
Key words: XPO5, breast cancer, microRNA biogenesis
Full Text PDF
Address all correspondence to:
Yong Zhu, PhD
Department of Epidemiology and Public Health
Yale University School of Medicine
New Haven, CT 06520.
Phone: (203) 785-4844; Fax: (203) 737-6023
Email: yong.zhu@yale.edu
Original Article
Genetic and epigenetic association studies suggest a role of microRNA
biogenesis gene exportin-5 (XPO5) in breast tumorigenesis
Derek Leaderer, Aaron E. Hoffman, Tongzhang Zheng, Alan Fu, Joanne Weidhaas, Trupti Paranjape, and Yong Zhu
Department of Epidemiology and Public Health, Yale School of Medicine; and Department of Therapeutic Radiology, Yale
School of Medicine, New Haven, Connecticut; Current address: Department of Epidemiology, Tulane School of Public Health
and Tropical Medicine and Tulane Cancer Center, New Orleans, Louisiana
Received September 27, 2010; accepted November 23, 2010; Epub November 25, 2010; published January 1, 2011
Abstract: Given strong evidence implicating an important role of altered microRNA expression in cancer initiation and
progression, the genes responsible for microRNA biogenesis may also play a role in tumorigenesis. Exportin-5 (XPO5) is
responsible for exporting pre-miRNAs through the nuclear membrane to the cytoplasm, and is thus critical in miRNA
biogenesis. In the current study, we performed both genetic and epigenetic association studies of XPO5 in a case control
study of breast cancer. We first genotyped two missense SNPs in XPO5, rs34324334 (S241N) and rs11544382 (M1115T), and
further analyzed methylation levels in the XPO5 promoter region for blood DNA samples from a breast cancer case-control
study. We found the variant genotypes of rs11544382 to be associated with breast cancer risk (OR=1.59, 95% CI: 1.06 - 2.39),
compared to the homozygous common genotype. When stratified by menopausal status, the variant alleles of both rs11544382
(OR=1.82, 95% CI: 1.09-3.03) and rs34324334 (OR=1.76, 95% CI: 1.10-2.83) were significantly associated with breast cancer
risk in post-menopausal women. The methylation analysis showed that the “high” and combined “high/middle” tertiles of
methylation index were associated with reduced risk of breast cancer (OR=0.34, 95% CI:0.15- 0.81 and OR=0.47, 95% CI:0.24-
0.94, respectively; Ptrend=0.015). These results were corroborated by data from a publicly available tissue array, which showed
lower levels of XPO5 expression in healthy controls relative to tumor or adjacent tissues from breast cancer patients with tumor
tissue exhibiting the highest expression levels. These findings support the hypothesis that variations in components of the
miRNA biogenesis pathway, in this case XPO5, may affect an individual’s risk of developing breast cancer. (IJMEG10009005).
Key words: XPO5, breast cancer, microRNA biogenesis
Full Text PDF
Address all correspondence to:
Yong Zhu, PhD
Department of Epidemiology and Public Health
Yale University School of Medicine
New Haven, CT 06520.
Phone: (203) 785-4844; Fax: (203) 737-6023
Email: yong.zhu@yale.edu
