Analysis of Cell-Free DNA from 32,989 Advanced Cancers Reveals Novel Co-occurring Activating RET Alterations and Oncogenic Signaling Pathway Aberrations
| Autor: | Jonathan W. Riess, Victoria M. Raymond, Wade T. Iams, Thereasa A. Rich, Stephen R. Fairclough, David R. Trevarthen, Michael S. Oh, Vivek Subbiah, Oliver Gautschi, Karen L. Reckamp, Young Kwang Chae, Thomas E. Stinchcombe, Richard B. Lanman, Jennifer Yen, Robert C. Doebele |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cancer Research Mutation endocrine system diseases Somatic cell Cell Cancer Biology medicine.disease_cause medicine.disease 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis medicine Cancer research Missense mutation Signal transduction Gene |
| Zdroj: | Clinical Cancer Research. 25:5832-5842 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: RET is an emerging oncogenic target showing promise in phase I/II clinical trials. An understudied aspect of RET-driven cancers is the extent to which co-occurring genomic alterations exist and how they may impact prognosis or therapeutic response. Experimental Design: Somatic activating RET alterations were identified among 32,989 consecutive patients with metastatic solid tumors tested with a clinical cell-free circulating tumor DNA (cfDNA) assay. This comprehensive next-generation sequencing (NGS) assay evaluates single-nucleotide variants, and select indels, fusions, and copy number gains in 68–73 clinically relevant cancer genes. Results: A total of 176 somatic activating RET alterations were detected in 170 patients (143 fusions and 33 missense mutations). Patients had non–small cell lung (NSCLC, n = 125), colorectal (n = 15), breast (n = 8), thyroid (n = 8), or other (n = 14) cancers. Alterations in other oncogenic signaling pathway genes were frequently identified in RET-positive samples and varied by specific RET fusion gene partner. RET fusions involving partners other than KIF5B were enriched for alterations in MAPK pathway genes and other bona fide oncogenic drivers of NSCLC, particularly EGFR. Molecular and clinical data revealed that these variants emerged later in the genomic evolution of the tumor as mechanisms of resistance to EGFR tyrosine kinase inhibitors. Conclusions: In the largest cancer cohort with somatic activating RET alterations, we describe novel co-occurrences of oncogenic signaling pathway aberrations. We find that KIF5B-RET fusions are highly specific for NSCLC. In our study, only non-KIF5B-RET fusions contributed to anti-EGFR therapy resistance. Knowledge of specific RET fusion gene partner may have clinical significance. |
| Databáze: | OpenAIRE |
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