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Small ubiquitin-like modifier (SUMO) proteins are covalently attached to target proteins to modify their function. SUMO conjugation participates in processes tightly linked to tumorigenesis. Recently USPL1 (ubiquitin-specific peptidase-like (1) was identified as a SUMO isopeptidase. We report here on the first exploratory study investigating the relationship between genetic variability in USPL1 and breast cancer. Three potentially functional nonsynonymous coding SNPs (rs3742303, rs17609459, rs7984952) were genotyped in 1,021 breast cancer cases and 1,015 controls from the population-based GENICA study. We took advantage of multiple genotype imputation based on HapMap and the 1000 Genomes Project data to refine the association screening in the investigated region. Public genetic databases were also used to investigate the relationship with USPL1 expression in lymphoblastoid cell lines and breast tissue. Women homozygous for the minor C allele of rs7984952 showed a lower risk of Grade 3 breast tumors compared to TT homozygotes (OR 0.50, 95% CI 0.30-0.81). Case-only analyses confirmed the association between rs7984952 and tumor grade (OR 0.60, 95% CI 0.39-0.93). Imputation results in a 238 kb region around rs7984952 based on HapMap and the 1000 Genomes Project data were similar. No imputed variant showed an association signal stronger than rs7984952. USPL1 expression in tumor breast tissue increased with the number of C alleles. The present study illustrates the contribution of multiple imputation of genotypes using public data repositories to standard genotyping laboratory. The provided information may facilitate the design of independent studies to validate the association between USPL1 rs7984952 and risk of Grade 3 breast tumors., (Copyright © 2013 UICC.)

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.