title: RNA biomarkers associated with metastatic progression in prostate cancer: a multi-institutional high-throughput analysis of SChLAP1.
abstract: BACKGROUND
  Improved clinical predictors for disease progression are needed for localised prostate cancer, since only a subset of patients develop recurrent or refractory disease after first-line treatment. Therefore, we undertook an unbiased analysis to identify RNA biomarkers associated with metastatic progression after prostatectomy.
  
  
  METHODS
  Prostate cancer samples from patients treated with radical prostatectomy at three academic institutions were analysed for gene expression by a high-density Affymetrix GeneChip platform, encompassing more than 1 million genomic loci. In a discovery cohort, all protein-coding genes and known long non-coding RNAs were ranked by fold change in expression between tumours that subsequently metastasised versus those that did not. The top ranked gene was then validated for its prognostic value for metastatic progression in three additional independent cohorts. 95% of the gene expression assays were done in a Clinical Laboratory Improvements Amendments certified laboratory facility. All genes were assessed for their ability to predict metastatic progression by receiver-operating-curve area-under-the-curve analyses. Multivariate analyses were done for the primary endpoint of metastatic progression, with variables including Gleason score, preoperative prostate-specific antigen concentration, seminal vesicle invasion, surgical margin status, extracapsular extension, lymph node invasion, and expression of the highest ranked gene.
  
  
  RESULTS
  1008 patients were included in the study: 545 in the discovery cohort and 463 in the validation cohorts. The long non-coding RNA SChLAP1 was identified as the highest-ranked overexpressed gene in cancers with metastatic progression. Validation in three independent cohorts confirmed the prognostic value of SChLAP1 for metastatic progression. On multivariate modelling, SChLAP1 expression (high vs low) independently predicted metastasis within 10 years (odds ratio [OR] 2·45, 95% CI 1·70-3·53; p<0·0001). The only other variable that independently predicted metastasis within 10 years was Gleason score (8-10 vs 5-7; OR 2·14, 95% CI 1·77-2·58; p<0·0001).
  
  
  CONCLUSIONS
  We identified and validated high SChLAP1 expression as significantly prognostic for metastatic disease progression of prostate cancer. Our findings suggest that further development of SChLAP1 as a potential biomarker, for treatment intensification in aggressive prostate cancer, warrants future study.
  
  
  BACKGROUND
  Prostate Cancer Foundation, National Institutes of Health, Department of Defense, Early Detection Research Network, Doris Duke Charitable Foundation, and Howard Hughes Medical Institute.
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Prensner
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: GenomeDx Biosciences, Vancouver, BC, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Erho
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Schipper
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Iyer
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Saravana M
authors.initials: SM
authors.lastname: Dhanasekaran
authors.affiliation: Anatomic Pathology, Robert J Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Magi-Galluzzi
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Anirban
authors.initials: A
authors.lastname: Sahu
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Javed
authors.initials: J
authors.lastname: Siddiqui
authors.affiliation: GenomeDx Biosciences, Vancouver, BC, Canada.
authors.forename: Elai
authors.initials: E
authors.lastname: Davicioni
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Den
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, MN, USA.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Karnes
authors.affiliation: Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Wei
authors.affiliation: Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Klein
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: ffeng@med.umich.edu.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D018450:Disease Progression; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D009367:Neoplasm Staging; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D062085:RNA, Long Noncoding / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D062085:RNA, Long Noncoding; D017430:Prostate-Specific Antigen