title: Intra-tumor heterogeneity ofBRAF V600Emutation in lung adenocarcinomas.
abstract: BRAFmutations exist in numerous types of cancer, including melanomas, colorectal cancers and lung cancers. TheV600E-specific inhibitor vemurafenib has marked clinical activity in patients withBRAF V600E-mutated melanoma. However, there are many cases of resistance to vemurafenib. This may be due to the reported intra-tumor heterogeneity of theBRAF V600Emutation in primary melanomas.BRAFmutations 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 againstBRAF V600E-mutated lung cancers. In a previous study, five lung adenocarcinomas withBRAF V600Emutation 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 ofBRAF V600Ewithin 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%. SensitiveBRAFmutation detection methods were used and evidence for heterogeneity of theBRAF V600Emutation in these lung adenocarcinoma cases was observed. Targeted therapy with aBRAF V600Einhibitor 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 toBRAF V600Einhibitors are affected by the presence of heterogeneity in future studies.
authors.affiliation: Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tatematsu
authors.affiliation: Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Y U
authors.initials: YU
authors.lastname: Hikosaka
authors.affiliation: Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Okuda
authors.affiliation: Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Haneda
authors.affiliation: Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Moriyama
authors.affiliation: Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Motoki
authors.initials: M
authors.lastname: Yano
authors.affiliation: Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Fujii
keywords: BRAF mutation; V600E; competitive allele-specific polymerase chain reaction; heterogeneity; lung cancer