Exploring the association between genetic variation in the SUMO isopeptidase gene USPL1 and breast cancer through integration of data from the population‐based GENICA study and external genetic databases

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.

[1]  H. Brauch,et al.  Polymorphisms in the UBC9 and PIAS3 genes of the SUMO-conjugating system and breast cancer risk , 2010, Breast Cancer Research and Treatment.

[2]  Zhaohui S. Qin,et al.  A second generation human haplotype map of over 3.1 million SNPs , 2007, Nature.

[3]  Jaclyn R. Gareau,et al.  The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition , 2010, Nature Reviews Molecular Cell Biology.

[4]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[5]  Michael Krawczak,et al.  Technology-specific error signatures in the 1000 Genomes Project data , 2011, Human Genetics.

[6]  R. Hay,et al.  SUMO-specific proteases: a twist in the tail. , 2007, Trends in cell biology.

[7]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumors , 2012, Nature.

[8]  Nancy Hopkins,et al.  Identification of 315 genes essential for early zebrafish development. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[9]  D. Lane,et al.  P14ARF promotes accumulation of SUMO‐1 conjugated (H)Mdm2 , 2002, FEBS letters.

[10]  M. Karamouzis,et al.  SUMO and estrogen receptors in breast cancer , 2007, Breast Cancer Research and Treatment.

[11]  J. Błasiak,et al.  Efficacy of DNA double-strand breaks repair in breast cancer is decreased in carriers of the variant allele of the UBC9 gene c.73G>A polymorphism. , 2010, Mutation research.

[12]  R. Hay,et al.  SUMO‐1 modification activates the transcriptional response of p53 , 1999, The EMBO journal.

[13]  Shuomin Zhu,et al.  MicroRNA-mediated Regulation of Ubc9 Expression in Cancer Cells , 2009, Clinical Cancer Research.

[14]  Y. Furuichi,et al.  Covalent Modification of the Werner's Syndrome Gene Product with the Ubiquitin-related Protein, SUMO-1* , 2000, The Journal of Biological Chemistry.

[15]  O. Jänne,et al.  The Nuclear Receptor Interaction Domain of GRIP1 Is Modulated by Covalent Attachment of SUMO-1* , 2002, The Journal of Biological Chemistry.

[16]  Edward T H Yeh,et al.  SUMO Losing Balance: SUMO Proteases Disrupt SUMO Homeostasis to Facilitate Cancer Development and Progression. , 2010, Genes & cancer.

[17]  S. Thorgeirsson,et al.  Genome-scale profiling of gene expression in hepatocellular carcinoma: classification, survival prediction, and identification of therapeutic targets. , 2004, Gastroenterology.

[18]  Erica S. Johnson,et al.  Protein modification by SUMO. , 2004, Annual review of biochemistry.

[19]  Liming Wang,et al.  Differential PIAS3 expression in human malignancy. , 2004, Oncology reports.

[20]  Luke Jostins,et al.  Imputation of low-frequency variants using the HapMap3 benefits from large, diverse reference sets , 2011, European Journal of Human Genetics.

[21]  Jinke Cheng,et al.  Role of desumoylation in the development of prostate cancer. , 2006, Neoplasia.

[22]  A. Dejean,et al.  c-Jun and p53 Activity Is Modulated by SUMO-1 Modification* , 2000, The Journal of Biological Chemistry.

[23]  Jing Liang,et al.  Coordinated Regulation of AIB1 Transcriptional Activity by Sumoylation and Phosphorylation* , 2006, Journal of Biological Chemistry.

[24]  Y. Mo,et al.  A role for Ubc9 in tumorigenesis , 2005, Oncogene.

[25]  Oliver Pelz,et al.  PromoterSweep: a tool for identification of transcription factor binding sites , 2010 .

[26]  E. Milgrom,et al.  Sumoylation of the Progesterone Receptor and of the Steroid Receptor Coactivator SRC-1* , 2003, The Journal of Biological Chemistry.

[27]  M. Leversha,et al.  Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification. , 2005, Human molecular genetics.

[28]  D. Schaid,et al.  Score tests for association between traits and haplotypes when linkage phase is ambiguous. , 2002, American journal of human genetics.

[29]  Pascal Reynier,et al.  Two-step differential expression analysis reveals a new set of genes involved in thyroid oncocytic tumors. , 2005, The Journal of clinical endocrinology and metabolism.

[30]  Sharon R Grossman,et al.  Integrating common and rare genetic variation in diverse human populations , 2010, Nature.

[31]  A. Hengstermann,et al.  Activation of p53 by conjugation to the ubiquitin‐like protein SUMO‐1 , 1999, The EMBO journal.

[32]  Angus I Lamond,et al.  Cajal bodies: a long history of discovery. , 2005, Annual review of cell and developmental biology.

[33]  F. Melchior,et al.  Concepts in sumoylation: a decade on , 2007, Nature Reviews Molecular Cell Biology.

[34]  Life Technologies,et al.  A map of human genome variation from population-scale sequencing , 2011 .

[35]  Timothy D. Veenstra,et al.  A Human Telomerase Holoenzyme Protein Required for Cajal Body Localization and Telomere Synthesis , 2009, Science.

[36]  R. Hipskind,et al.  Down-Regulation of c-Fos/c-Jun AP-1 Dimer Activity by Sumoylation , 2005, Molecular and Cellular Biology.

[37]  L. Excoffier,et al.  Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. , 1995, Molecular biology and evolution.

[38]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[39]  Aleix Prat Aparicio Comprehensive molecular portraits of human breast tumours , 2012 .

[40]  B. Oh,et al.  DeSUMOylating isopeptidase: a second class of SUMO protease , 2012, EMBO reports.

[41]  Ji Luo,et al.  A SUMOylation-Dependent Transcriptional Subprogram Is Required for Myc-Driven Tumorigenesis , 2012, Science.

[42]  T. Illig,et al.  The CYP1B1_1358_GG genotype is associated with estrogen receptor-negative breast cancer , 2008, Breast Cancer Research and Treatment.

[43]  A. Dejean,et al.  Conjugation with the ubiquitin‐related modifier SUMO‐1 regulates the partitioning of PML within the nucleus , 1998, The EMBO journal.

[44]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[45]  Gregory A. Poland,et al.  Score tests for association of traits with haplotypes when linkage phase is ambiguous , 2002 .

[46]  Simak Ali,et al.  Estrogen Receptor Alpha in Human Breast Cancer: Occurrence and Significance , 2000, Journal of Mammary Gland Biology and Neoplasia.

[47]  Zhengxin Wang,et al.  SENP1 Enhances Androgen Receptor-Dependent Transcription through Desumoylation of Histone Deacetylase 1 , 2004, Molecular and Cellular Biology.

[48]  R. Redon,et al.  Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes , 2007, Science.

[49]  P. Donnelly,et al.  A new multipoint method for genome-wide association studies by imputation of genotypes , 2007, Nature Genetics.

[50]  H. Ovaa,et al.  Ubiquitin‐specific protease‐like 1 (USPL1) is a SUMO isopeptidase with essential, non‐catalytic functions , 2012, EMBO reports.

[51]  H. Brauch,et al.  Factors Modifying the Association Between Hormone-Replacement Therapy and Breast Cancer Risk , 2005, European Journal of Epidemiology.

[52]  B. Weir,et al.  ESTIMATING F‐STATISTICS FOR THE ANALYSIS OF POPULATION STRUCTURE , 1984, Evolution; international journal of organic evolution.

[53]  H. Brauch,et al.  Common variants in the UBC9 gene encoding the SUMO‐conjugating enzyme are associated with breast tumor grade , 2009, International journal of cancer.