Genomic alterations predictive of poor clinical outcomes in pan-cancer
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Crystal S. Seldon1,*, Karthik Meiyappan2,*, Hannah Hoffman3, Jimmy A. Guo4,5, Neha Goel1, William L. Hwang3,4, Paul L. Nguyen6, Brandon A. Mahal1 and Mohammed Alshalalfa1
1 Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
2 Miller School of Medicine, University of Miami, Miami, FL 33136, USA
3 Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA
4 Broad Institute of MIT, Cambridge, MA 02142, USA
5 School of Medicine, University of California San Francisco, San Francisco, CA 94143, USA
6 Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA 02215, USA
* Co-first authors
Keywords: genomic alterations; TP53; TCGA; poor prognosis
Received: March 04, 2022 Accepted: September 13, 2022 Published: September 28, 2022
Background: Genomic alterations are highly frequent across cancers, but their prognostic impact is not well characterized in pan-cancer cohorts. Here, we use pan-cancer cohorts from TCGA and MSK-IMPACT to evaluate the associations of common genomic alterations with poor clinical outcome.
Materials and Methods: Genomic alterations in commonly altered genes were extracted from Pan-Cancer TCGA and MSK-IMPACT cohorts. Multivariable Cox regression analyses stratified by cancer type defined adjusted hazard ratios (AHRs) for disease-specific survival (DSS), progression-free survival (PFS) and overall survival (OS).
Results: Using TCGA we identified 32 mutated genes, and 15 copy number (CN) genes with frequency >= 4% in 9,104 patients across 28 cancers. On UVA, having a TP53-mutations or any mutation in the 31 genes (mut31) were associated with worse PFS (HR: 1.22, p < 0.0001 and HR: 1.1, p = 0.04, respectively) and DSS (HR: 1.38, p < 0.0001, and HR: 1.16, p = 0.03, respectively). CDKN2A, PTEN deletions, and MYC-amplifications were associated with PFS and DSS (p < 0.05 for all).
On MVA, including TP53-mutations, mut31, CDKN2A-deletion, PTEN-deletion, and MYC-amplification, all five alterations were independently prognostic of poor PFS and DSS.
Similar results were observed in an independent cohort from MSK-IMPACT (n = 7,051) where TP53 was associated with poor OS independent of mut31 and CN alterations in CDKN2A, PTEN, and MYC in primary tumors (p < 0.0001).
Conclusions: TP53-mutations, CDKN2A-deletion, PTEN-deletion, and MYC-amplification are independent pan-cancer prognostic genomic alterations.
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