ALK, ROS1 and RET fusions in 1139 lung adenocarcinomas: A comprehensive study of common and fusion pattern-specific clinicopathologic, histologic and cytologic features
Introduction
Lung adenocarcinoma, which is the most common histologic subtype of lung cancer, is now a disease that could be largely classified into clinically relevant molecular subsets by oncogenic driver mutations, each with unique clinicopathologic features and potential opportunities for targeted therapies.
Recently, gene fusions have been identified as recurrent oncogenic events in lung adenocarcinoma. The first reported fusion oncokinase is ALK rearrangement [1], which occurs in approximately 5% of lung adenocarcinomas [2], [3]. In ALK-positive lung cancer patients, crizotinib has demonstrated its treatment efficacy in terms of a higher response rate and improved progression free survival compared with standard chemotherapy [4]. ROS1 is another identified receptor tyrosine kinase that forms fusions, and is reported to be present in about 1–2% of lung adenocarcinomas [2], [5], [6]. ROS1 fusions also serve as therapeutic targets for crizotinib [6]. RET fusions have been identified as the novel oncogenic drivers in about 1–2% of lung adenocarcinomas [2], [7], [8], [9], [10], and the potential therapeutic targets of multi-targeted kinase inhibitors, vandetanib, sunitinib and sorafenib [2], [7], [8].
As the prevalence of fusion genes in lung adenocarcinoma is comparatively low, identifying the enriched population has definite implications for efficient screening. However, despite their critical importance in targeted therapies, the three fusion genes have not been examined together along with other well-identified driver mutations in a large cohort of lung adenocarcinoma to comprehensively define their common and fusion-pattern specific clinicopathologic, histologic and cytologic features.
In this study, we used a combination strategy of quantitative real-time reverse transcriptase PCR (qRT-PCR) and reverse transcriptase PCR (RT-PCR) for screening of ALK, ROS1 and RET fusion genes in over 1139 lung adenocarcinoma patients, with validation of positive results using fluorescence in situ hybridization (FISH). Mutational analyses of EGFR, KRAS, HER2 and BRAF were also carried out in the same cohort of patients. Clinicopathologic, histologic and cytologic features of fusion-positive lung adenocarcinomas were comprehensively analyzed and compared to those of other well-identified molecular subsets of lung adenocarcinoma.
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Patients and samples
From April 2007 to October 2012, we consecutively collected lung tumors resected at the Department of Thoracic Surgery, Fudan University Shanghai Cancer Center. Eligible subjects must have pathologically confirmed lung adenocarcinoma, a minimum of 50% of tumor cells and sufficient tissue for comprehensive mutational analyses. Patients who received neoajuvant chemotherapy were excluded. Total RNA were extracted as per standard protocols (RNeasy Mini Kitt; Qiagen, Hilden, Germany) after frozen
Results
Tumor samples from 1139 lung adenocarcinoma patients were included in the comprehensive mutational analysis. There were 58 (5.1%) ALK fusions, 11 (1.0%) ROS1 fusions and 15 (1.3%) RET fusions. Mutations in EGFR, KRAS, HER2 and BRAF were detected in 735 (64.5%), 86 (7.6%), 27 (2.4%) and 14 (1.2%) patients, respectively. The spectrum of well-identified oncogenic driver mutations in 1139 lung adenocarcinoma was shown in Fig. 1.
Discussion
Our previous studies have investigated ALK and RET fusions in non-small cell lung cancer in relatively smaller samples [9], [12]. In this study, we extended the fusion gene detection to more lung adenocarcinoma samples and also included ROS1 fusions. Some previous studies reported that lung cancers harboring ALK, ROS1 or RET fusions shared some clinical characteristics, such as younger age of onset and never/light smoking history [2], [6], [14]. In this study, we also found some clinical
Conclusion
In conclusion, through comprehensive analysis of ALK, ROS1 and RET fusions along with other well-identified driver mutations in 1139 lung adenocarcinomas, we have comprehensively defined the common and fusion-pattern specific clinicopathologic, histologic and cytologic features of fusion-positive lung adenocarcinomas. Our results have implications for clinical trials seeking to enrich for patients with fusion genes as well as therapeutic strategies.
Conflict of interest
The authors declare no conflicts of interest.
Funding source
This work was supported by the funds from Key Construction Program of the National “985” Project (985III-YFX0102), the National Natural Science Foundation of China (81172218, 81101760, 81101761, and 81372525), the Science and Technology Commission of Shanghai Municipality (Program of Shanghai Subject Chief Scientist; Grant No. 12XD1402000), and the Shanghai Hospital Development Center (No. SHDC12012308).
Acknowledgements
We thank the AstraZeneca Innovation Center China for excellent technical support.
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