Novel Gene Expression Signature Predictive of Clinical Recurrence After Radical Prostatectomy in Early Stage Prostate Cancer Patients.
Current clinical tools have limited accuracy in differentiating patients with localized prostate cancer who are at risk of recurrence from patients with indolent disease. We aimed to identify a gene expression signature that jointly with clinical variables could improve upon the prediction of clinical recurrence after RP for patients with stage T2 PCa.



The study population includes consented patients who underwent a radical retropubic prostatectomy (RP) and bilateral pelvic lymph node dissection at the University of Southern California in the PSA-era (1988-2008). We used a nested case-control study of 187 organ-confined patients (pT2N0M0): 154 with no recurrence ("controls") and 33 with clinical recurrence ("cases"). RNA was obtained from laser capture microdissected malignant glands representative of the overall Gleason score of each patient. Whole genome gene expression profiles (29,000 transcripts) were obtained using the Whole Genome DASL HT platform (Illumina, Inc). A gene expression signature of PCa clinical recurrence was identified using stability selection with elastic net regularized logistic regression. Three existing datasets generated with the Affymetrix Human Exon 1.0ST array were used for validation: Mayo Clinic (MC, n = 545), Memorial Sloan Kettering Cancer Center (SKCC, n = 150), and Erasmus Medical Center (EMC, n = 48). The areas under the ROC curve (AUCs) were obtained using repeated fivefold cross-validation.



A 28-gene expression signature was identified that jointly with key clinical variables (age, Gleason score, pre-operative PSA level, and operation year) was predictive of clinical recurrence (AUC of clinical variables only was 0.67, AUC of clinical variables, and 28-gene signature was 0.99). The AUC of this gene signature fitted in each of the external datasets jointly with clinical variables was 0.75 (0.72-0.77) (MC), 0.90 (0.86-0.94) (MSKCC), and 0.82 (0.74-0.91) (EMC), whereas the AUC for clinical variables only in each dataset was 0.72 (0.70-0.74), 0.86 (0.82-0.91), and 0.76 (0.67-0.85), respectively.



We report a novel gene-expression based classifier identified using agnostic approaches from whole genome expression profiles that can improve upon the accuracy of clinical indicators to stratify early stage localized patients at risk of clinical recurrence after RP. Prostate 76:1239-1256, 2016. © 2016 Wiley Periodicals, Inc.
Department of Preventive Medicine, Keck School of Medicine of USC, Norris Comprehensive Cancer Center, Los Angeles, California.
Ahva
A
Shahabi
Department of Preventive Medicine, Keck School of Medicine of USC, Norris Comprehensive Cancer Center, Los Angeles, California.
Juan Pablo
JP
Lewinger
Department of Preventive Medicine, Keck School of Medicine of USC, Norris Comprehensive Cancer Center, Los Angeles, California.
Jie
J
Ren
Illumina, Inc., San Diego, California.
Craig
C
April
Department of Pathology, Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, California.
Andy E
AE
Sherrod
Department of Biochemistry and Molecular Biology, Keck School of Medicine of USC, Los Angeles, California.
Joseph G
JG
Hacia
Department of Urology and USC Institute of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, California.
Siamak
S
Daneshmand
Department of Urology and USC Institute of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, California.
Inderbir
I
Gill
Department of Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, California.
Jacek K
JK
Pinski
Illumina, Inc., San Diego, California.|AnchorDx Corporation, Guangzhou, China.
Jian-Bing
JB
Fan
Department of Preventive Medicine, Keck School of Medicine of USC, Norris Comprehensive Cancer Center, Los Angeles, California.|Department of Urology and USC Institute of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, California.
Mariana C
MC
Stern
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005500:Follow-Up Studies; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics* / Q000601:surgery; D011237:Predictive Value of Tests; D011468:Prostatectomy / Q000379:methods; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000601:surgery
clinical recurrence; gene expression; stability selection; stage II