Oncotarget | Genomic Alterations Predictive of Poor Clinical Outcomes in Pan-cancer

“There is growing interest in genomic profiling (i.e. tumor mutations, copy number (CN) alterations) for cancer therapy and precision oncology to inform treatment decisions and identify patients for relevant clinical trials.”

BUFFALO, NY- October 4, 2022 – A new research paper was published in Oncotarget's Volume 13 on September 28, 2022, entitled, “Genomic alterations predictive of poor clinical outcomes in pan-cancer.”

Genomic alterations are highly frequent across cancers, but their prognostic impact is not well characterized in pan-cancer cohorts.

In this new study, researchers Crystal S. Seldon, Karthik Meiyappan, Hannah Hoffman, Jimmy A. Guo, Neha Goel, William L. Hwang, Paul L. Nguyen, Brandon A. Mahal, and Mohammed Alshalalfa from the University of Miami, Massachusetts General Hospital, Broad Institute of MIT, University of California San Francisco, and Dana-Farber Cancer Institute and Brigham and Women’s Hospital used pan-cancer cohorts from The Cancer Genome Atlas (TCGA) and the MSK-IMPACT study to evaluate the associations of common genomic alterations with poor clinical outcome.

“There is growing interest in genomic profiling (i.e. tumor mutations, copy number (CN) alterations) for cancer therapy and precision oncology to inform treatment decisions and identify patients for relevant clinical trials [1].”

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). The researchers identified 32 mutated genes, and 15 copy number (CN) genes with frequency >= 4% in 9,104 patients across 28 cancers. 

“In the current study, we utilized data from both the MSK-IMPACT cohort and the Pan-Cancer TCGA cohort of more than 8,000 patients with PFS and DSS outcomes to conduct the first and largest comprehensive analysis of prognostic genomic alterations across cancers.”

Upon univariable analysis, 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 and PTEN deletions, and MYC-amplifications were associated with PFS and DSS (p < 0.05 for all). Upon multivariable analysis, 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). TP53-mutations, CDKN2A-deletion, PTEN-deletion, and MYC-amplification are independent pan-cancer prognostic genomic alterations.

“This finding indicates that primary tumors with any of these alterations or any combinations of them should have more aggressive treatment. Clinical trials enriching for these alterations could identify treatment options for patients harbouring one or more of these alterations.”

DOI: https://doi.org/10.18632/oncotarget.28276 

Correspondence to: Mohammed Alshalalfa - mohamed.alshalalfa@gmail.com 

Keywords: genomic alterations, TP53, TCGA, poor prognosis

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