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Published on: August 1, 2018
Profiling Receptor Tyrosine Kinase Fusions in Chinese Breast Cancers
Zhonghua Tao1,2, Jianxia Liu3, Ting Li1,2
1Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
Background:
Receptor tyrosine kinases (RTKs) are a class of tyrosine kinases that regulate cell-to-cell communication and control a variety of complex biological functions. Dysregulation of RTK signaling partly due to chromosomal rearrangements leads to novel tyrosine kinase fusion oncoproteins that are possibly driver alterations to cancers. Targeting some RTK fusions with specific tyrosine kinases inhibitors (TKIs) is an effective therapeutic strategy across a spectrum of RTK fusion-related cancers. However, there is still a paucity of extensive RTK fusion investigations in breast cancer. This study aims to characterize RTK fusions in Chinese breast cancer patients.
Methods:
An in-house DNA sequencing database of 1440 Chinese breast cancer patients with a capture-based panel (520 gene or 108 gene-panel) was thoroughly reviewed. A total of 2,229 samples including 1,045 tissues and 1,184 plasmas were analyzed. RTK fusion was defined as an in-frame fusion with the tyrosine kinase domain of the RTK completely retained. Concomitant mutations were also analyzed and tumor mutational burden (TMB) was calculated. Patients' clinical characteristics were retrieved from case records.
Results:
A total of 30 RTK fusion events were identified from 27 breast cancer patients with a prevalence of 1.875%%. FGFR2 fusions were seen the most commonly (n=7), followed by RET (n=5), ROS1 (n=3), NTRK3 (n=3), BRAF (n=2), and NTRK1 (n=2). Other RTK fusions including ALK, EGFR, FGFR1, FGFR3, MET, and NTRK2 were identified in one patient each. A total of 27 unique resultant fusion proteins (22 with a novel partner) were discovered including 19 intrachromosomal rearrangements and 8 interchromosomal ones. Twenty-one fusions had the tyrosine kinase domain in-frame fused with a partner gene and six were juxtaposed with an intergenic space. Among the 27 fusions, FGFR2-WDR11 (E17: intergenic) (n=3) and ETV6-NTRK3 (E5:E15) (n=2) occurred recurrently. Of note, the normalized abundance of RTK fusion (fusion AF/max AF) correlated negatively with TMB (r=-0.48, P=0.017). Patients with TMB < 8 (Mutations/Mb) displayed a higher fusion abundance than those with TMB ≥ 8 (Mutations/Mb) (P=0.025). Moreover, CREBBP mutation only co-occurred with FGFR2 fusion (P=0.012), while NTRK3 fusion and TP53 mutation were mutually exclusive (P=0.019).
Conclusion:
This is the first study comprehensively delineating the prevalence and spectrum of RTK fusions in Chinese breast cancers. Further study is ongoing to identify the enriched subpopulation who may benefit from RTK fusion inhibitors.
Insights
Receptor tyrosine kinase (RTK) fusions occur in 1.875% of Chinese breast cancers, with FGFR2 fusions being most common. This finding aids in identifying patients who may benefit from targeted RTK fusion inhibitors.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Receptor tyrosine kinases (RTKs) regulate cell communication; their dysregulation via chromosomal rearrangements can create fusion oncoproteins driving cancer.
- Targeting RTK fusions with tyrosine kinase inhibitors (TKIs) is effective, but RTK fusions in breast cancer remain understudied.
- This study investigates the prevalence and spectrum of RTK fusions in Chinese breast cancer patients.
Purpose of the Study:
- To characterize the prevalence and spectrum of receptor tyrosine kinase (RTK) fusions in Chinese breast cancer patients.
- To identify novel RTK fusion proteins and their partners.
- To analyze the correlation between RTK fusions, tumor mutational burden (TMB), and concomitant mutations.
Main Methods:
- Reviewed an in-house DNA sequencing database of 1440 Chinese breast cancer patients using a capture-based panel.
- Analyzed 2,229 samples (1,045 tissues, 1,184 plasmas) for RTK fusions, defined as in-frame fusions retaining the tyrosine kinase domain.
- Assessed concomitant mutations, calculated tumor mutational burden (TMB), and retrieved clinical characteristics.
Main Results:
- Identified 30 RTK fusion events in 27 patients (1.875% prevalence), with FGFR2 fusions being most common (n=7).
- Discovered 27 unique fusion proteins, including novel partners, with FGFR2-WDR11 and ETV6-NTRK3 occurring recurrently.
- Found a negative correlation between RTK fusion abundance and TMB (r=-0.48, P=0.017); CREBBP mutations co-occurred with FGFR2 fusions, while NTRK3 fusions and TP53 mutations were mutually exclusive.
Conclusions:
- This study provides the first comprehensive delineation of RTK fusion prevalence and spectrum in Chinese breast cancer.
- Ongoing research aims to identify patient subpopulations who could benefit from RTK fusion inhibitors.
- The findings highlight specific RTK fusions and their associated mutations, offering potential therapeutic targets.
