title: Rare discrepancies in a driver gene alteration within histologically heterogeneous primary lung cancers.
abstract: OBJECTIVE
  Most lung adenocarcinomas consist of mixtures of histological subtypes harboring different frequencies of driver gene mutations. However, little is known about intratumoral heterogeneity(ITH) within histologically heterogeneous primary lung cancers. Investigating key driver genes in respective morphological pattern is crucial to personalized treatment.
  
  
  METHODS
  Morphologically different areas within the same surgically resected adenocarcinomas were extracted from tissues to analyze gene status in each growth pattern. Driver genes, epidermal growth factor receptor (EGFR), KRAS and EML4-ALK, were assessed by assays with different sensitivities.
  
  
  RESULTS
  Seventy-nine consecutive eligible patients harboring a driver gene (EGFR=65; KRAS=10; EML4-ALK=4) were enrolled. For EGFR mutations, ITH occurred in 13.3% (8/60) by direct sequencing (DS) and 1.7% (1/60) by amplification refractory mutation system (ARMS) (P=0.016) among adenocarcinomas, but consistent within five adeno-squamous cell carcinomas by both methods. ITH among KRAS mutations were detected in 20% (2/10) by DS, whereas consistent (10/10) by high resolution melting. No discrepancies in EML4-ALK rearrangements existed according to fluorescence in situ hybridization.
  
  
  CONCLUSIONS
  Rare ITHs of EGFR/KRAS/EML4-ALK alterations within histologically heterogeneous primary lung adenocarcinomas existed by methods with higher sensitivity. Discrepancies might be due to abundance of mutant tumor cells and detection assays.
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors.forename: Wen-zhao
authors.initials: WZ
authors.lastname: Zhong
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Pathology and Laboratory Medicine, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors.forename: Fang-ping
authors.initials: FP
authors.lastname: Xu
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors.forename: Hao-ran
authors.initials: HR
authors.lastname: Zhai
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors.forename: Xu-chao
authors.initials: XC
authors.lastname: Zhang
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors.forename: Xue-ning
authors.initials: XN
authors.lastname: Yang
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors.forename: Zhi-yong
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors.forename: Zhi-hong
authors.initials: ZH
authors.lastname: Chen
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors.forename: Song
authors.initials: S
authors.lastname: Dong
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors.forename: Jin-ji
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors.forename: Yan-hui
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China. Electronic address: syylwu@live.cn.
authors.forename: Yi-long
authors.initials: YL
authors.lastname: Wu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; C512478:EGFR protein, human; D066246:ErbB Receptors; D018631:ras Proteins
keywords: EML4-ALK; Epidermal growth factor receptor; Intratumor heterogeneity; KRAS; Lung cancer