Analysis of Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies.

Purpose: amplification can promote tumorigenesis directly or indirectly through p53 inhibition. has increasing clinical relevance because inhibitors are under evaluation in clinical trials, and amplification is a possible genomic correlate of accelerated progression, known as hyperprogression, after anti-PD-1/PD-L1 immunotherapy. We used next-generation sequencing (NGS) to ascertain amplification status across a large number of diverse cancers.

Methods: We interrogated the molecular profiles of 102,878 patients with diverse malignancies for amplification and co-altered genes using clinical-grade NGS (182 to 465 genes).

Results: amplification occurred in 3.5% of patients (3,650 of 102,878). The majority of tumor types had a small subset of patients with amplification. Most of these patients (99.0% [3,613/3,650]) had co-alterations that accompanied amplification. Various pathways, including those related to tyrosine kinase (37.9% [1,385 of 3,650]), signaling (25.4% [926 of 3,650]), (24.9% [910 of 3,650]), and signaling (23.6% [863 of 3,650]), were involved. Although infrequent, mismatch repair genes and amplification also were co-altered (2.2% [79 of 3,650]). Most patients (97.6% [3,563 of 3,650]) had one or more co-alterations potentially targetable with either a Food and Drug Administration-approved or investigational agent. amplifications were less frequently associated with high tumor mutation burden compared with the wild-type population (2.9% 6.5%; < .001). An illustrative patient who harbored amplification and experienced hyperprogression with an immune checkpoint inhibitor is presented.

Conclusion: amplification was found in 3.5% of 102,878 patients, 97.6% of whom harbored genomic co-alterations that were potentially targetable. This study suggests that a small subset of most tumor types have amplification as well as pharmacologically tractable co-alterations.