title: Rare Variation in TET2 Is Associated with Clinically Relevant Prostate Carcinoma in African Americans.
abstract: Common variants have been associated with prostate cancer risk. Unfortunately, few are reproducibly linked to aggressive disease, the phenotype of greatest clinical relevance. One possible explanation is that rare genetic variants underlie a significant proportion of the risk for aggressive disease.
  
  
  
  To identify such variants, we performed a two-stage approach using whole-exome sequencing followed by targeted sequencing of 800 genes in 652 aggressive prostate cancer patients and 752 disease-free controls in both African and European Americans. In each population, we tested rare variants for association using two gene-based aggregation tests. We established a study-wide significance threshold of 3.125 × 10-5to correct for multiple testing.
  
  
  
  TET2 in African Americans was associated with aggressive disease, with 24.4% of cases harboring a rare deleterious variant compared with 9.6% of controls (FET P = 1.84 × 10-5, OR = 3.0; SKAT-O P = 2.74 × 10-5). We report 8 additional genes with suggestive evidence of association, including the DNA repair genes PARP2 and MSH6 Finally, we observed an excess of rare truncation variants in 5 genes, including the DNA repair genes MSH6, BRCA1, and BRCA2 This adds to the growing body of evidence that DNA repair pathway defects may influence susceptibility to aggressive prostate cancer.
  
  
  
  Our findings suggest that rare variants influence risk of clinically relevant prostate cancer and, if validated, could serve to identify men for screening, prophylaxis, and treatment.
  
  
  
  This study provides evidence that rare variants in TET2 may help identify African American men at increased risk for clinically relevant prostate cancer. Cancer Epidemiol Biomarkers Prev; 25(11); 1456-63. ©2016 AACR.
authors.affiliation: The McDonnell Genome Institute at Washington University, St. Louis, Missouri.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Koboldt
authors.affiliation: The McDonnell Genome Institute at Washington University, St. Louis, Missouri.
authors.forename: Krishna L
authors.initials: KL
authors.lastname: Kanchi
authors.affiliation: Division of Urology, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Bin
authors.initials: B
authors.lastname: Gui
authors.affiliation: The McDonnell Genome Institute at Washington University, St. Louis, Missouri.
authors.forename: David E
authors.initials: DE
authors.lastname: Larson
authors.affiliation: The McDonnell Genome Institute at Washington University, St. Louis, Missouri.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.affiliation: Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland.
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.affiliation: Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Aldi
authors.initials: A
authors.lastname: Kraja
authors.affiliation: Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.affiliation: Division of Urology, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Li
authors.initials: L
authors.lastname: Jia
authors.affiliation: The McDonnell Genome Institute at Washington University, St. Louis, Missouri.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: The McDonnell Genome Institute at Washington University, St. Louis, Missouri.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: Division of Urology, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. akibel@partners.org.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Kibel
mesh_terms: D001741:Black or African American / Q000235:genetics; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D004252:DNA Mutational Analysis; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D011110:Polymorphism, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C541081:TET2 protein, human; C483041:PARP2 protein, human; D011065:Poly(ADP-ribose) Polymerases