Expression signature defined by FOXM1-CCNB1 activation predicts disease recurrence in non-muscle-invasive bladder cancer.
OBJECTIVE
Although standard treatment with transurethral resection and intravesical therapy (IVT) is known to be effective to address the clinical behavior of non-muscle-invasive bladder cancer (NMIBC), many patients fail to respond to the treatment and frequently experience disease recurrence. Here, we aim to identify a prognostic molecular signature that predicts the NMIBC heterogeneity and response to IVT.


METHODS
We analyzed the genomic profiles of 102 patients with NMIBC to identify a signature associated with disease recurrence. The validity of the signature was verified in three independent patient cohorts (n = 658). Various statistical methods, including a leave-one-out cross-validation and multivariate Cox regression analyses, were applied to identify a signature. We confirmed an association between the signature and tumor aggressiveness with experimental assays using bladder cancer cell lines.


RESULTS
Gene expression profiling in 102 patients with NMIBC identified a CCNB1 signature associated with disease recurrence, which was validated in another three independent cohorts of 658 patients. The CCNB1 signature was shown to be an independent risk factor by a multivariate analysis and subset stratification according to stage and grade [HR, 2.93; 95% confidence intervals (CI), 1.302-6.594; P = 0.009]. The subset analysis also revealed that the signature could identify patients who would benefit from IVT. Finally, gene network analyses and experimental assays indicated that NMIBC recurrence could be mediated by FOXM1-CCNB1-Fanconi anemia pathways.


CONCLUSIONS
The CCNB1 signature represents a promising diagnostic tool to identify patients with NMIBC who have a high risk of recurrence and to predict response to IVT.
Authors' Affiliations: Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon; Department of Biology, College of Natural Science, Dong-A University, Busan; Department of Urology, Chungbuk National University College of Medicine, Cheongju, Chungbuk, Korea; and Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Seon-Kyu
SK
Kim
Authors' Affiliations: Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon; Department of Biology, College of Natural Science, Dong-A University, Busan; Department of Urology, Chungbuk National University College of Medicine, Cheongju, Chungbuk, Korea; and Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Yun-Gil
YG
Roh
Authors' Affiliations: Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon; Department of Biology, College of Natural Science, Dong-A University, Busan; Department of Urology, Chungbuk National University College of Medicine, Cheongju, Chungbuk, Korea; and Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Kiejung
K
Park
Authors' Affiliations: Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon; Department of Biology, College of Natural Science, Dong-A University, Busan; Department of Urology, Chungbuk National University College of Medicine, Cheongju, Chungbuk, Korea; and Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Tae-Hong
TH
Kang
Authors' Affiliations: Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon; Department of Biology, College of Natural Science, Dong-A University, Busan; Department of Urology, Chungbuk National University College of Medicine, Cheongju, Chungbuk, Korea; and Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Wun-Jae
WJ
Kim
Authors' Affiliations: Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon; Department of Biology, College of Natural Science, Dong-A University, Busan; Department of Urology, Chungbuk National University College of Medicine, Cheongju, Chungbuk, Korea; and Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Ju-Seog
JS
Lee
Authors' Affiliations: Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon; Department of Biology, College of Natural Science, Dong-A University, Busan; Department of Urology, Chungbuk National University College of Medicine, Cheongju, Chungbuk, Korea; and Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas chu@kribb.re.kr shleem@dau.ac.kr.
Sun-Hee
SH
Leem
Authors' Affiliations: Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon; Department of Biology, College of Natural Science, Dong-A University, Busan; Department of Urology, Chungbuk National University College of Medicine, Cheongju, Chungbuk, Korea; and Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas chu@kribb.re.kr shleem@dau.ac.kr.
In-Sun
IS
Chu
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002454:Cell Differentiation; D049109:Cell Proliferation; D015331:Cohort Studies; D056744:Cyclin B1 / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D055815:Young Adult
D014408:Biomarkers, Tumor; C534699:CCNB1 protein, human; D056744:Cyclin B1; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger