Common variants in the UBC9 gene encoding the SUMO-conjugating enzyme are associated with breast tumor grade.
UBC9 encodes a protein that conjugates small ubiquitin-related modifier (SUMO) to target proteins resulting in a change of their localization, activity or stability. Genetic variability may affect expression and activity of UBC9 and may have an impact on breast tumor progression. We investigated associations between UBC9 genotypes and histopathological parameters in 1,021 breast cancer cases of the GENICA collection using a single nucleotide polymorphism (SNP) tagging approach. Genotyping analyses were performed by TaqMan(R) allelic discrimination. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by ordinal logistic regression. Multiple imputation based on HapMap data was applied to boost the power of the study. The study revealed significant associations of three UBC9 SNPs with histological grade (rs7187167, p(trend) = 0.001; rs11248866, p(trend) = 0.009; rs8052688, p(trend) = 0.008). Model selection identified a recessive penetrance model for rs7187167 as the best representation of tumor grade (global p = 0.001). This model did not improve by inclusion of additional SNPs in linkage disequilibrium. Imputation of SNPs in a 300 kb region around the genotyped SNPs supported rs7187167 as a major contributor to tumor grade. Compared with common allele carriers, rare homozygotes presented less frequently with high grade tumors (G3 vs. G1: OR 0.26, 95% CI 0.11-0.62; G3 vs. G2: OR 0.45, 95% CI 0.23-0.86). In addition to tumor size, nodal status and estrogen receptor status, multivariate analyses confirmed an independent role of rs7187167 as predictor of tumor grade (p = 0.0003). The present results underline the value of genetic variation in UBC9 for breast cancer prognosis.
Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Thomas
T
Dünnebier
Justo Lorenzo
JL
Bermejo
Susanne
S
Haas
Hans-Peter
HP
Fischer
Christiane B
CB
Pierl
Christina
C
Justenhoven
Hiltrud
H
Brauch
Christian
C
Baisch
Michael
M
Gilbert
Volker
V
Harth
Anne
A
Spickenheuer
Sylvia
S
Rabstein
Beate
B
Pesch
Thomas
T
Brüning
Yon-Dschun
YD
Ko
Ute
U
Hamann
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008207:Lymphatic Metastasis; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011960:Receptors, Estrogen / Q000378:metabolism; D025842:SUMO-1 Protein / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D011960:Receptors, Estrogen; D025842:SUMO-1 Protein; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9