Faculty Collaboration Database

Next generation sequencing demonstrates association between tumor suppressor gene aberrations and poor outcome in patients with cancer. Cell Cycle 2015;14(11):1730-7

Date

05/01/2015

Pubmed ID

25928476

Pubmed Central ID

PMC4614790

DOI

10.1080/15384101.2015.1033596

Scopus ID

2-s2.0-84943780413 (requires institutional sign-in at Scopus site)   9 Citations

Abstract

Next generation sequencing is transforming patient care by allowing physicians to customize and match treatment to their patients' tumor alterations. Our goal was to study the association between key molecular alterations and outcome parameters. We evaluated the characteristics and outcomes (overall survival (OS), time to metastasis/recurrence, and best progression-free survival (PFS)) of 392 patients for whom next generation sequencing (182 or 236 genes) had been performed. The Kaplan-Meier method and Cox regression models were used for our analysis, and results were subjected to internal validation using a resampling method (bootstrap analysis). In a multivariable analysis (Cox regression model), the parameters that were statistically associated with a poorer overall survival were the presence of metastases at diagnosis (P = 0.014), gastrointestinal histology (P < 0.0001), PTEN (P < 0.0001), and CDKN2A alterations (P = 0.0001). The variables associated with a shorter time to metastases/recurrence were gastrointestinal histology (P = 0.004), APC (P = 0.008), PTEN (P = 0.026) and TP53 (P = 0.044) alterations. TP53 (P = 0.003) and PTEN (P = 0.034) alterations were independent predictors of a shorter best PFS. A personalized treatment approach (matching the molecular aberration with a cognate targeted drug) also correlated with a longer best PFS (P = 0.046). Our study demonstrated that, across diverse cancers, anomalies in specific tumor suppressor genes (PTEN, CDKN2A, APC, and/or TP53) were independently associated with a worse outcome, as reflected by time to metastases/recurrence, best PFS on treatment, and/or overall survival. These observations suggest that molecular diagnostic tests may provide important prognostic information in patients with cancer.

Author List

Schwaederle M, Daniels GA, Piccioni DE, Kesari S, Fanta PT, Schwab RB, Shimabukuro KA, Parker BA, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenomatous Polyposis Coli Protein
Female
Genes, Tumor Suppressor
High-Throughput Nucleotide Sequencing
Humans
Kaplan-Meier Estimate
Male
Middle Aged
Neoplasm Metastasis
Neoplasms
PTEN Phosphohydrolase
Patient Outcome Assessment
Precision Medicine
Regression Analysis
Time Factors
Tumor Suppressor Protein p53
Tumor Suppressor Proteins