title: The use of exome genotyping to predict pathological Gleason score upgrade after radical prostatectomy in low-risk prostate cancer patients.
abstract: BACKGROUND
  Active surveillance (AS) is a promising option for patients with low-risk prostate cancer (PCa), however current criteria could not select the patients correctly, many patients who fulfilled recent AS criteria experienced pathological Gleason score upgrade (PGU) after radical prostatectomy (RP). In this study, we aimed to develop an accurate model for predicting PGU among low-risk PCa patients by using exome genotyping.
  
  
  METHODS
  We genotyped 242,221 single nucleotide polymorphisms (SNP)s on a custom HumanExome BeadChip v1.0 (Illuminam Inc.) in blood DNA from 257 low risk PCa patients (PSA <10 ng/ml, biopsy Gleason score (GS) ≤6 and clinical stage ≤T2a) who underwent radical prostatectomy. Genetic data were analyzed using an unconditional logistic regression to calculate an odds ratio as an estimate of relative risk of PGU, which defined pathologic GS above 7. Among them, we selected persistent SNPs after multiple testing using FDR method, and we compared accuracies from the multivariate logistic model incorporating clinical factors between included and excluded selected SNP information.
  
  
  RESULTS
  After analysis of exome genotyping, 15 SNPs were significant to predict PGU in low risk PCa patients. Among them, one SNP--rs33999879 remained significant after multiple testing. When a multivariate model incorporating factors in Epstein definition--PSA density, biopsy GS, positive core number, tumor per core ratio and age was devised for the prediction of PGU, the predictive accuracy of the multivariate model was 78.4% (95%CI: 0.726-0.834). By addition the factor of rs33999879 in aforementioned multivariate model, the predictive accuracy was 82.9%, which was significantly increased (p = 0.0196).
  
  
  CONCLUSIONS
  The rs33999879 SNP is a predictor for PGU. The addition of genetic information from the exome sequencing effectively enhanced the predictive accuracy of the multivariate model to establish suitable active surveillance criteria.
authors.affiliation: Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Jong Jin
authors.initials: JJ
authors.lastname: Oh
authors.affiliation: Department of Electrical and Computer Engineering, Seoul National University, Seoul, Korea; School of Electrical Engineering, Korea University, Seoul, Korea.
authors.forename: Seunghyun
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Sung Kyu
authors.initials: SK
authors.lastname: Hong
authors.affiliation: Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Sangchul
authors.initials: S
authors.lastname: Lee
authors.affiliation: Departments of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Gheeyoung
authors.initials: G
authors.lastname: Choe
authors.affiliation: Department of Electrical and Computer Engineering, Seoul National University, Seoul, Korea.
authors.forename: Sungroh
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Seok-Soo
authors.initials: SS
authors.lastname: Byun
mesh_terms: D000328:Adult; D000368:Aged; D059472:Exome / Q000235:genetics*; D060005:Genotyping Techniques / Q000379:methods*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery*; D012372:ROC Curve; D012307:Risk Factors
references.citation: J Urol. 2008 Apr;179(4):1587-92
references.pmid: 18295257
references.citation: Eur Urol. 2007 May;51(5):1244-50; discussion 1251
references.pmid: 17161520
references.citation: BJU Int. 2010 Jun;105(11):1526-30
references.pmid: 19912202
references.citation: Eur Urol. 2009 Jun;55(6):1321-30
references.pmid: 19286302
references.citation: BJU Int. 2013 May;111(6):914-20
references.pmid: 23320782
references.citation: Cancer Epidemiol Biomarkers Prev. 2001 May;10(5):533-8
references.pmid: 11352865
references.citation: Am J Hum Genet. 2004 Apr;74(4):765-9
references.pmid: 14997420
references.citation: N Engl J Med. 2003 Jul 24;349(4):366-81
references.pmid: 12878745
references.citation: JAMA. 1994 Feb 2;271(5):368-74
references.pmid: 7506797
references.citation: Eur Urol. 2012 Dec;62(6):976-83
references.pmid: 22698574
references.citation: Hum Mol Genet. 2011 Oct 1;20(19):3867-75
references.pmid: 21743057
references.citation: J Clin Oncol. 2013 Aug 20;31(24):2991-7
references.pmid: 23775960
references.citation: Asian J Androl. 2000 Mar;2(1):13-20
references.pmid: 11228931
references.citation: Eur Urol. 2008 Nov;54(5):1081-8
references.pmid: 18602209
references.citation: J Natl Cancer Inst. 2006 Mar 1;98(5):355-7
references.pmid: 16507832
references.citation: Am J Hum Genet. 2001 Apr;68(4):978-89
references.pmid: 11254454
references.citation: Eur Urol. 2008 Dec;54(6):1306-13
references.pmid: 18083294
references.citation: Nat Genet. 2013 Apr;45(4):385-91, 391e1-2
references.pmid: 23535732
references.citation: Am J Surg Pathol. 1988 Dec;12(12):897-906
references.pmid: 3202246
references.citation: Urology. 2006 Oct;68(4):820-4
references.pmid: 17070360
references.citation: Behav Brain Res. 2001 Nov 1;125(1-2):279-84
references.pmid: 11682119
references.citation: J Urol. 2009 Apr;181(4):1628-33; discussion 1633-4
references.pmid: 19233388
references.citation: J Natl Cancer Inst. 2003 May 7;95(9):634-5
references.pmid: 12734304
references.citation: J Urol. 2008 Oct;180(4):1330-4; discussion 1334-5
references.pmid: 18707731
references.citation: Cancer. 2004 Nov 1;101(9):2001-5
references.pmid: 15372478
references.citation: Genetics. 1987 Oct;117(2):331-41
references.pmid: 3666445
references.citation: Urology. 2010 Feb;75(2):414-8
references.pmid: 19963249
references.citation: Cancer. 2008 Aug 15;113(4):701-9
references.pmid: 18553365
references.citation: J Clin Oncol. 2005 Nov 10;23(32):8165-9
references.pmid: 16278468
references.citation: Oncol Rep. 2012 Oct;28(4):1263-8
references.pmid: 22842912