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Annals of Oncology 25: 138–142, 2014 doi:10.1093/annonc/mdt495 Published online 1 December 2013

T. Kinno1,2, K. Tsuta1*, K. Shiraishi3, T. Mizukami3, M. Suzuki1,2, A. Yoshida1, K. Suzuki2, H. Asamura4, K. Furuta1, T. Kohno3 & R. Kushima1 1

Division of Pathology and Clinical Laboratories, National Cancer Center Hospital; 2Division of General Thoracic Surgery, Juntendo University School of Medicine; Division of Genome Biology, National Cancer Center Research Institute; 4Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan


Received 8 June 2013; revised 2 October 2013; accepted 7 October 2013

Background: Recently, driver tyrosine kinase gene mutations have been detected in malignant tumors, including lung tumors. Notwithstanding their attractiveness as targets for molecular therapy, limited information is available regarding BRAF-mutated lung carcinomas. Materials and methods: BRAF mutation status was determined in 2001 surgically resected nonsmall-cell lung cancer (NSCLC) cases using high-resolution melting analysis (HRMA) followed by Sanger sequencing and/or deep sequencing using next generation sequencer. Results: BRAF mutations were detected in 26 (1.3%) of 2001 NSCLC cases (25 adenocarcinomas and 1 squamous cell carcinoma). In the 26 cases, 13 mutation genotypes were identified, including V600E (8 of 26; 30.8%), G469A (6 of 26; 23.1%), K601E (4 of 26; 15.4%), and other residual mutations (1 of 26; 0.04%). Of the 13 genotypes, 4 genotypes (G464E, G596R, A598T, and G606R) had not been previously reported in lung cancer. The overall survival rate was not significantly different between patients with wild-type BRAF and those with V600E or non-V600E BRAF mutations (P = 0.49 and P = 0.15, respectively). Histomorphological analysis revealed that focal clear cell changes were present in 75% of V600Emutated tumors. All V600E BRAF-mutated tumors were negative for other driver gene alterations including epidermal growth factor receptor (EGFR) and KRAS mutations and the anaplastic lymphoma kinase gene translocation, whereas five tumors with non-V600E BRAF mutations (four G469A and one G464E/G466R) showed concomitant EGFR mutations. Conclusion: The frequency of BRAF mutations in lung cancer was low in an Asian cohort. Furthermore, BRAF mutation status lacked prognostic significance in this patient population. Key words: Asian, BRAF gene mutation, lung carcinoma

introduction BRAF, one of three RAF isoforms, is a serine–threonine-specific protein kinase that is activated downstream of RAS. RAF *Correspondence to: Dr Koji Tsuta, Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. Tel: +81-3-3542-2511; Fax: +81-3-3545-3567; E-mail: [email protected]

activates mitogen-activated protein kinase, which in turn activates extracellular signal-regulated kinase (ERK) [1, 2]. Mutations in BRAF constitutively activate ERK signaling through hyperactivation of the RAS–ERK pathway, resulting in enhanced cell proliferation and survival [2]. BRAF mutations have been identified in a variety of tumors [3–6], including lung carcinoma [7–11]. BRAF mutations in

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Clinicopathological features of nonsmall cell lung carcinomas with BRAF mutations

original articles

Annals of Oncology

materials and methods

statistical analysis Statistical analysis was carried out using the SPSS Statistics 21 program (IBM Corporation, Somers, NY). Survival curves were calculated by the Kaplan– Meier method. A P value of

Clinicopathological features of nonsmall cell lung carcinomas with BRAF mutations.

Recently, driver tyrosine kinase gene mutations have been detected in malignant tumors, including lung tumors. Notwithstanding their attractiveness as...
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