Abstract B13: Non-small cell lung cancer with double driver mutations.
Authors: Osoegawa Atsushi , Toyokawa Gouji , Ohba Taro , Miyawaki Michiyo , Yamaguchi Masafumi , Taguchi Kenichi , Seto Takashi , Takenoyama Mitsuhiro , Ichinose Yukito , Sugio Kenji 
Published: August 2014

Abstract
Background: Driver mutations, such as an epidermal growth factor receptor (EGFR) mutation or an echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion, generally occur independently in non-small cell lung cancer (NSCLC), as such driver mutations are able to cause cancers by themselves. However, we discovered the first reported lung cancer case that simultaneously harbored both an EML4-ALK fusion and an exon 19 EGFR mutation. We subsequently examined the driver gene mutations in a panel of consecutive, surgically resected, pathological Stage I lung adenocarcinomas to determine the frequency and clinicopathological characteristics in cases with double driver mutations.
Patients and Methods: The initial case, which we reported previously (J Thorac Oncol. 2012, 7:e39-41), was a 72-year-old male ex-smoker who underwent right lower lobectomy for a lung peripheral mass of 4.5 cm in diameter. An EGFR mutation and EML4-ALK fusion were found in the tumor by immunohistochemistry and direct sequencing. To further examine the frequency of double driver mutations, a consecutive panel of 256 patients with pathological Stage I lung adenocarcinoma was analyzed for mutations of EGFR, K-ras, EML4-ALK and BRAF.
Results: The initial case turned out to have both an exon 19 EGFR mutation and EML4-ALK fusion. Pathologically, the tumor comprised mixed papillary, acinar and lepidic adenocarcinoma, with small cell carcinoma in the central area. An EML4-ALK fusion was detected from the small cell component, while the EGFR mutation was detected from the peripheral lepidic adenocarcinoma component. Next, we analyzed the driver gene mutations in 256 Stage I lung adenocarcinoma cases. Mutations of the EGFR, K-ras, EML4-ALK and BRAF genes were detected in 120 (46.8%), 14 (5.5%), seven (2.7%) and three (1.2%) cases, respectively. Among them, double driver mutations were detected from two cases; one had an EML4-ALK fusion and exon 19 EGFR mutation, and another had a BRAF mutation (V600E) and exon 19 EGFR mutation.
Discussion: Although the tumor from the initial case exhibited double driver mutations as a whole, a detailed examination of each histological component enabled us to distinguish one mutation from another. In other words, the driver mutations did not co-exist in a single cancer cell. Accordingly, similar molecular pathological investigations need to be done on newly identified cases with double driver mutations, because such studies may clarify how multiple mutations occur in one tumor.
Conclusion: We demonstrated the frequency and the manifestations of rare double driver mutations in NSCLC. Further studies are warranted to clarify the mechanisms underlying the development of double driver mutations.
Citation Format: Atsushi Osoegawa, Gouji Toyokawa, Taro Ohba, Michiyo Miyawaki, Masafumi Yamaguchi, Kenichi Taguchi, Takashi Seto, Mitsuhiro Takenoyama, Yukito Ichinose, Kenji Sugio. Non-small cell lung cancer with double driver mutations. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B13.