Research Papers:

Genomic alterations predictive of poor clinical outcomes in pan-cancer

Crystal S. Seldon, Karthik Meiyappan, Hannah Hoffman, Jimmy A. Guo, Neha Goel, William L. Hwang, Paul L. Nguyen, Brandon A. Mahal and Mohammed Alshalalfa _

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Oncotarget. 2022; 13:1069-1077. https://doi.org/10.18632/oncotarget.28276

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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

Correspondence to:

Mohammed Alshalalfa, email: [email protected]

Keywords: genomic alterations; TP53; TCGA; poor prognosis

Received: March 04, 2022     Accepted: September 13, 2022     Published: September 28, 2022

Copyright: © 2022 Seldon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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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