Time to recurrence and survival in serous ovarian tumors predicted from integrated genomic profiles Journal Article

Authors: Mankoo, P. K.; Shen, R.; Schultz, N.; Levine, D. A.; Sander, C.
Article Title: Time to recurrence and survival in serous ovarian tumors predicted from integrated genomic profiles
Abstract: Background: Serous ovarian cancer (SeOvCa) is an aggressive disease with differential and often inadequate therapeutic outcome after standard treatment. The Cancer Genome Atlas (TCGA) has provided rich molecular and genetic profiles from hundreds of primary surgical samples. These profiles confirm mutations of TP53 in ~100% of patients and an extraordinarily complex profile of DNA copy number changes with considerable patient-to-patient diversity. This raises the joint challenge of exploiting all new available datasets and reducing their confounding complexity for the purpose of predicting clinical outcomes and identifying disease relevant pathway alterations. We therefore set out to use multi-data type genomic profiles (mRNA, DNA methylation, DNA copy-number alteration and microRNA) available from TCGA to identify prognostic signatures for the prediction of progression-free survival (PFS) and overall survival (OS). Methodology/Principal Findings: We implemented a multivariate Cox Lasso model and median time-to-event prediction algorithm and applied it to two datasets integrated from the four genomic data types. We (1) selected features through cross-validation; (2) generated a prognostic index for patient risk stratification; and (3) directly predicted continuous clinical outcome measures, that is, the time to recurrence and survival time. We used Kaplan-Meier p-values, hazard ratios (HR), and concordance probability estimates (CPE) to assess prediction performance, comparing separate and integrated datasets. Data integration resulted in the best PFS signature (withheld data: p-value = 0.008; HR = 2.83; CPE = 0.72). Conclusions/Significance: We provide a prediction tool that inputs genomic profiles of primary surgical samples and generates patient-specific predictions for the time to recurrence and survival, along with outcome risk predictions. Using integrated genomic profiles resulted in information gain for prediction of outcomes. Pathway analysis provided potential insights into functional changes affecting disease progression. The prognostic signatures, if prospectively validated, may be useful for interpreting therapeutic outcomes for clinical trials that aim to improve the therapy for SeOvCa patients. © 2011 Mankoo et al.
Keywords: survival; adult; cancer survival; controlled study; middle aged; survival analysis; major clinical study; overall survival; genetics; mutation; cancer recurrence; outcome assessment; ovarian neoplasms; progression free survival; ovary cancer; microrna; gene expression profiling; recurrence; pathology; validation study; protein p53; dna methylation; prediction; risk assessment; dna; messenger rna; probability; ovary tumor; tumor suppressor protein p53; recurrent disease; multivariate analysis; hazard ratio; kaplan meier method; copy number variation; rna analysis
Journal Title: PLoS ONE
Volume: 6
Issue: 11
ISSN: 1932-6203
Publisher: Public Library of Science  
Date Published: 2011-01-01
Start Page: e24709
Language: English
DOI: 10.1371/journal.pone.0024709
PROVIDER: scopus
PMCID: PMC3207809
PUBMED: 22073136
Notes: --- - "Export Date: 9 December 2011" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Douglas A Levine
    369 Levine
  2. Ronglai Shen
    158 Shen
  3. Parminder Kaur Mankoo
    3 Mankoo
  4. Chris Sander
    205 Sander
  5. Nikolaus D Schultz
    318 Schultz