Intra‑tumor heterogeneity of BRAF V600E mutation in lung adenocarcinomas

Tatematsu,Tsutomu; Sasaki,Hidefumi; Shimizu,Shigeki; Hikosaka,Yu; Okuda,Katsuhiro; Haneda,Hiroshi; Moriyama,Satoru; Yano,Motoki; Fujii,Yoshitaka

doi:10.3892/etm.2015.2298

Intra‑tumor heterogeneity of BRAF V600E mutation in lung adenocarcinomas

Authors:
- Tsutomu Tatematsu
- Hidefumi Sasaki
- Shigeki Shimizu
- Yu Hikosaka
- Katsuhiro Okuda
- Hiroshi Haneda
- Satoru Moriyama
- Motoki Yano
- Yoshitaka Fujii
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Affiliations: Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467‑8601, Japan, Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
Published online on: February 17, 2015 https://doi.org/10.3892/etm.2015.2298
Pages: 1719-1722

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Abstract

BRAF mutations exist in numerous types of cancer, including melanomas, colorectal cancers and lung cancers. The V600E‑specific inhibitor vemurafenib has marked clinical activity in patients with BRAF V600E‑mutated melanoma. However, there are many cases of resistance to vemurafenib. This may be due to the reported intra‑tumor heterogeneity of the BRAF V600E mutation in primary melanomas. BRAF mutations are found in 1‑5% of non‑small cell carcinomas (NSCLCs), almost exclusively in adenocarcinoma. A few cases have been reported in which vemurafenib was effective against BRAF V600E‑mutated lung cancers. In a previous study, five lung adenocarcinomas with BRAF V600E mutation were detected by direct sequencing. The present study analyzed these tumors for the percentage of mutation (%mutation) by competitive allele‑specific polymerase chain reaction (CAST‑PCR) assay. In addition, sections of all components of the adenocarcinomas were obtained by laser microdissection and analyzed. The %mutations of BRAF V600E within the macrodissected tumors (cases 1‑5) were: Case 1, 10.0%; case 2, 8.0%; case 3, 8.9%; case 4, 21.5%; and case 5, 14.9%. In four cases (cases 2‑5), the %mutations of each adenocarcinoma component were as follows: Case 2, lepidic growth 6.5‑24.5%, papillary 1.3‑11.2% and acinar 9.8%; case 3, solid 2.5‑69.9%, acinar 12.4‑27.1% and papillary 3.7‑17.4%; case 4, acinar 10.0‑45.0% and papillary 44.0%; and case 5, papillary 3.7‑93.4%. Sensitive BRAF mutation detection methods were used and evidence for heterogeneity of the BRAF V600E mutation in these lung adenocarcinoma cases was observed. Targeted therapy with a BRAF V600E inhibitor such as vemurafenib may have potential in the treatment of lung cancer with this mutation; however, it is necessary to consider how the treatment effect of and drug resistance to BRAF V600E inhibitors are affected by the presence of heterogeneity in future studies.

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