lunes, 16 de abril de 2012

Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk

Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk

Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk

  1. Mark A. Rubina,i,1,2
+ Author Affiliations
  1. aDepartment of Pathology and Laboratory Medicine,
  2. eDepartment of Public Health,
  3. iDepartment of Urology,
  4. fDivision of Hematology and Medical Oncology, and
  5. bInstitute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065;
  6. cCentre for Integrative Biology, University of Trento, 38122 Trento, Italy;
  7. dDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
  8. gDepartment of Urology, Innsbruck Medical University, 6020 Innsbruck, Austria;
  9. jDepartment of Urology and
  10. hMichigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
  11. kBiostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, MA 02115; and
  12. lDepartment of Urology, Beth Israel Deaconess Medical Center, Boston, MA 02115
  1. Edited* by Patricia K. Donahoe, Massachusetts General Hospital and Harvard Medical School, Boston, MA, and approved March 8, 2012 (received for review October 22, 2011)

Abstract

Copy number variants (CNVs) are a recently recognized class of human germ line polymorphisms and are associated with a variety of human diseases, including cancer. Because of the strong genetic influence on prostate cancer, we sought to identify functionally active CNVs associated with susceptibility of this cancer type. We queried low-frequency biallelic CNVs from 1,903 men of Caucasian origin enrolled in the Tyrol Prostate Specific Antigen Screening Cohort and discovered two CNVs strongly associated with prostate cancer risk. The first risk locus (P = 7.7 × 10−4, odds ratio = 2.78) maps to 15q21.3 and overlaps a noncoding enhancer element that contains multiple activator protein 1 (AP-1) transcription factor binding sites. Chromosome conformation capture (Hi-C) data suggested direct cis-interactions with distant genes. The second risk locus (P = 2.6 × 10−3, odds ratio = 4.8) maps to the α-1,3-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase C (MGAT4C) gene on 12q21.31. In vitro cell-line assays found this gene to significantly modulate cell proliferation and migration in both benign and cancer prostate cells. Furthermore, MGAT4C was significantly overexpressed in metastatic versus localized prostate cancer. These two risk associations were replicated in an independent PSA-screened cohort of 800 men (15q21.3, combined P = 0.006; 12q21.31, combined P = 0.026). These findings establish noncoding and coding germ line CNVs as significant risk factors for prostate cancer susceptibility and implicate their role in disease development and progression.

Footnotes

  • Author contributions: F.D., S.R.S., C.L., H.K., and M.A.R. designed research; F.D., S.R.S., D.C., J.Y.H.C., C.X.C., J.H., N.K., and D.S.R. performed research; H.B., B.S., G.S., W.H., J.B., A.M.C., S.G., J.S., M.M.R., M.K., J.T.W., D.S.S., M.A.S., G.B., H.K., and M.A.R. contributed new reagents/analytic tools; F.D., S.R.S., S.B., D.A.O., T.D.S., and O.E. analyzed data; and F.D., S.R.S., C.L., and M.A.R. wrote the paper.
  • The authors declare no conflict of interest.
  • *This Direct Submission article had a prearranged editor.
  • Data deposition: Genotype and phenotype data reported in this paper have been deposited in the database of Genotypes and Phenotypes, http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000487.v1.p1.
  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1117405109/-/DCSupplemental.

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