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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Identification of recurrent FGFR3-TACC3 fusion oncogenes from lung adenocarcinoma
Marzia Capelletti1, Michael E Dodge1, Dalia Ercan1
1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Purpose:
Targetable oncogenic alterations are detected more commonly in patients with non-small cell lung cancer (NSCLC) who never smoked cigarettes. For such patients, specific kinase inhibitors have emerged as effective clinical treatments. However, the currently known oncogenic alterations do not account for all never smokers who develop NSCLC. We sought to identify additional oncogenic alterations from patients with NSCLC to define additional treatment options.
Experimental Design:
We analyzed 576 lung adenocarcinomas from patients of Asian and Caucasian ethnicity. We identified a subset of cancers that did not harbor any known oncogenic alteration. We performed targeted next-generation sequencing (NGS) assay on 24 patients from this set with >75% tumor cell content.
Results:
EGFR mutations were the most common oncogenic alteration from both Asian (53%) and Caucasian (41.6%) patients. No known oncogenic alterations were present in 25.7% of Asian and 31% of Caucasian tumor specimens. We identified a FGFR3-TACC3 fusion event in one of 24 patients from this subset using targeted NGS. Two additional patients harboring FGFR3-TACC3 were identified by screening our entire cohort (overall prevalence, 0.5%). Expression of FGFR3-TACC3 led to IL3 independent growth in Ba/F3 cells. These cells were sensitive to pan-fibroblast growth factor receptor (pan-FGFR) inhibitors but not the epidermal growth factor (EGFR) inhibitor gefitinib.
Conclusions:
FGFR3-TACC3 rearrangements occur in a subset of patients with lung adenocarcinoma. Such patients should be considered for clinical trials featuring FGFR inhibitors.
Insights
New oncogenic alterations, including FGFR3-TACC3 fusions, were identified in never-smoker lung cancer patients. These findings may lead to new treatment options targeting fibroblast growth factor receptor (FGFR) inhibitors.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Targetable oncogenic alterations are more common in never-smokers with non-small cell lung cancer (NSCLC).
- Existing treatments target known alterations, but some never-smokers lack identified drivers.
- Further research is needed to uncover additional oncogenic alterations for improved treatment strategies.
Purpose of the Study:
- To identify novel oncogenic alterations in never-smokers with NSCLC.
- To expand treatment options for this patient population.
- To investigate the prevalence and therapeutic implications of newly discovered alterations.
Main Methods:
- Analysis of 576 lung adenocarcinomas from Asian and Caucasian patients.
- Targeted next-generation sequencing (NGS) on tumors lacking known alterations.
- Functional studies using cell lines to assess the impact of identified fusions.
Main Results:
- EGFR mutations were common (53% Asian, 41.6% Caucasian).
- FGFR3-TACC3 fusion identified in 0.5% of NSCLC patients.
- FGFR3-TACC3 drove IL3-independent cell growth and responded to pan-FGFR inhibitors.
Conclusions:
- FGFR3-TACC3 rearrangements are a targetable alteration in a subset of lung adenocarcinomas.
- Patients with FGFR3-TACC3 fusions may benefit from FGFR inhibitor therapies.
- Clinical trials investigating FGFR inhibitors are warranted for these patients.
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