title: Germline missense variants in the BTNL2 gene are associated with prostate cancer susceptibility.
abstract: BACKGROUND
  Rare, inherited mutations account for 5% to 10% of all prostate cancer cases. However, to date, few causative mutations have been identified.
  
  
  METHODS
  To identify rare mutations for prostate cancer, we conducted whole-exome sequencing (WES) in multiple kindreds (n = 91) from 19 hereditary prostate cancer (HPC) families characterized by aggressive or early-onset phenotypes. Candidate variants (n = 130) identified through family- and bioinformatics-based filtering of WES data were then genotyped in an independent set of 270 HPC families (n = 819 prostate cancer cases; n = 496 unaffected relatives) for replication. Two variants with supportive evidence were subsequently genotyped in a population-based case-control study (n = 1,155 incident prostate cancer cases; n = 1,060 age-matched controls) for further confirmation. All participants were men of European ancestry.
  
  
  RESULTS
  The strongest evidence was for two germline missense variants in the butyrophilin-like 2 (BTNL2) gene (rs41441651, p.Asp336Asn and rs28362675, p.Gly454Cys) that segregated with affection status in two of the WES families. In the independent set of 270 HPC families, 1.5% (rs41441651; P = 0.0032) and 1.2% (rs28362675; P = 0.0070) of affected men, but no unaffected men, carried a variant. Both variants were associated with elevated prostate cancer risk in the population-based study (rs41441651: OR, 2.7; 95% CI, 1.27-5.87; P = 0.010; rs28362675: OR, 2.5; 95% CI, 1.16-5.46; P = 0.019).
  
  
  CONCLUSIONS
  Results indicate that rare BTNL2 variants play a role in susceptibility to both familial and sporadic prostate cancer.
  
  
  CONCLUSIONS
  Results implicate BTNL2 as a novel prostate cancer susceptibility gene.
authors.affiliation: Division of Public Health Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Liesel M
authors.initials: LM
authors.lastname: Fitzgerald
authors.forename: Akash
authors.initials: A
authors.lastname: Kumar
authors.forename: Evan A
authors.initials: EA
authors.lastname: Boyle
authors.forename: Yuzheng
authors.initials: Y
authors.lastname: Zhang
authors.forename: Laura M
authors.initials: LM
authors.lastname: McIntosh
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kolb
authors.forename: Marni
authors.initials: M
authors.lastname: Stott-Miller
authors.forename: Tiffany
authors.initials: T
authors.lastname: Smith
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Karyadi
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Ostrander
authors.forename: Li
authors.initials: L
authors.lastname: Hsu
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stanford
mesh_terms: D000368:Aged; D000071797:Butyrophilins; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020125:Mutation, Missense; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
chemical_list: C408263:BTNL2 protein, human; D000071797:Butyrophilins; D008562:Membrane Glycoproteins