title: Germline predictors of androgen deprivation therapy response in advanced prostate cancer.
abstract: OBJECTIVE
  To evaluate whether germline variations in genes involved in sex steroid biosynthesis and metabolic pathways predict time to treatment failure for patients with advanced prostate cancer undergoing androgen deprivation therapy (ADT), because there are few known clinical predictors of response.
  
  
  METHODS
  In a cohort of 304 patients with advanced prostate cancer undergoing ADT, we genotyped 746 single-nucleotide polymorphisms (SNPs) from 72 genes from germline DNA (680 tagSNPs from 58 genes and 66 candidate SNPs from 20 genes [6 genes common in both]). Association with the primary end point of time to ADT failure was assessed using proportional hazards regression models at the gene level (for genes with tagging SNPs) and at the SNP level. False discovery rates (FDRs) of 0.10 or less were considered noteworthy to account for multiple testing.
  
  
  RESULTS
  At the gene level, TRMT11 showed the strongest association with time to ADT failure (P<.001; FDR=0.008). Two of 4 TRMT11 tagSNPs were associated with time to ADT failure. Median time to ADT failure for rs1268121 (A>G) was 3.05 years for the AA, 4.27 years for the AG, and 6.22 years for the GG genotypes (P=.002), and for rs6900796 (G>A), it was 2.42 years for the GG, 3.52 years for the AG, and 4.18 years for the AA genotypes (P<.001). No other gene level or SNP level tests had an FDR of 0.10 or less.
  
  
  CONCLUSIONS
  Genetic variation in TRMT11 was associated with time to ADT failure. Confirmation of these preliminary findings in an independent cohort is needed.
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. kohli.manish@mayo.edu
authors.forename: Manish
authors.initials: M
authors.lastname: Kohli
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Riska
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Mahoney
authors.forename: High S
authors.initials: HS
authors.lastname: Chai
authors.forename: David W
authors.initials: DW
authors.lastname: Hillman
authors.forename: David N
authors.initials: DN
authors.lastname: Rider
authors.forename: Brian A
authors.initials: BA
authors.lastname: Costello
authors.forename: Rui
authors.initials: R
authors.lastname: Qin
authors.forename: Jatinder
authors.initials: J
authors.lastname: Lamba
authors.forename: Deepak M
authors.initials: DM
authors.lastname: Sahasrabudhe
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use*; D056726:Genetic Association Studies; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011237:Predictive Value of Tests; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D013094:Spermatozoa / Q000378:metabolism*; D017211:Treatment Failure; D012359:tRNA Methyltransferases / Q000235:genetics
chemical_list: D000726:Androgen Antagonists; D005819:Genetic Markers; D012359:tRNA Methyltransferases