title: Intratumoral Heterogeneity of ALK-Rearranged and ALK/EGFR Coaltered Lung Adenocarcinoma.
abstract: OBJECTIVE
  Genetic intratumoral heterogeneity has a profound influence on the selection of clinical treatment strategies and on addressing resistance to targeted therapy. The purpose of this study was to explore the potential effect of intratumoral heterogeneity on both genetic and pathologic characteristics of ALK-rearranged lung adenocarcinoma (LADC).
  
  
  METHODS
  We tested ALK fusions and EGFR mutations in 629 patients with LADC by using laser-capture microdissection to capture spatially separated tumor cell subpopulations in various adenocarcinoma subtypes and to test for ALK fusions and EGFR mutations in ALK-rearranged, EGFR-mutated, and ALK/EGFR coaltered LADCs to compare the oncogenic driver status between different tumor cell subpopulations in the same primary tumor.
  
  
  RESULTS
  Among the 629 patients, 30 (4.8%) had ALK fusions, 364 (57.9%) had EGFR mutations, and two had ALK fusions that coexisted with EGFR mutations. Intratumoral heterogeneity of ALK fusions were identified in nine patients by reverse-transcriptase polymerase chain reaction. In the two patients with an ALK/EGFR coaltered status, genetic intratumoral heterogeneity was observed both between different growth patterns and within the same growth pattern. The relative abundance of ALK and EGFR alterations was different in the same captured area. ALK fusions were positively associated with a micropapillary pattern (P = .002) and were negatively associated with a lepidic pattern (P = .008) in an expanded statistical analysis of 900 individual adenocarcinoma components, although they appeared to be more common in acinar-predominant LADCs in the analysis of 629 patients.
  
  
  CONCLUSIONS
  Intratumoral genetic heterogeneity was demonstrated to coexist with histologic heterogeneity in both single-driver and ALK/EGFR coaltered LADCs. Altered oncogenic drivers in spatially separated subclones of the same tumor may be different.
authors.affiliation: Weijing Cai, Chunyan Wu, Xuefei Li, Chao Zhao, Ke Fei, and Caicun Zhou, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai; Dongmei Lin, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing; Limou Zheng, Xiamen University, Xiamen; Shannon Chuai, Burning Rock Biotech, Guangzhou, People's Republic of China; and Fred R. Hirsch, University of Colorado Cancer Center, Aurora, CO.
authors.forename: Weijing
authors.initials: W
authors.lastname: Cai
authors.affiliation: Weijing Cai, Chunyan Wu, Xuefei Li, Chao Zhao, Ke Fei, and Caicun Zhou, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai; Dongmei Lin, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing; Limou Zheng, Xiamen University, Xiamen; Shannon Chuai, Burning Rock Biotech, Guangzhou, People's Republic of China; and Fred R. Hirsch, University of Colorado Cancer Center, Aurora, CO.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Lin
authors.affiliation: Weijing Cai, Chunyan Wu, Xuefei Li, Chao Zhao, Ke Fei, and Caicun Zhou, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai; Dongmei Lin, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing; Limou Zheng, Xiamen University, Xiamen; Shannon Chuai, Burning Rock Biotech, Guangzhou, People's Republic of China; and Fred R. Hirsch, University of Colorado Cancer Center, Aurora, CO.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wu
authors.affiliation: Weijing Cai, Chunyan Wu, Xuefei Li, Chao Zhao, Ke Fei, and Caicun Zhou, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai; Dongmei Lin, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing; Limou Zheng, Xiamen University, Xiamen; Shannon Chuai, Burning Rock Biotech, Guangzhou, People's Republic of China; and Fred R. Hirsch, University of Colorado Cancer Center, Aurora, CO.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Li
authors.affiliation: Weijing Cai, Chunyan Wu, Xuefei Li, Chao Zhao, Ke Fei, and Caicun Zhou, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai; Dongmei Lin, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing; Limou Zheng, Xiamen University, Xiamen; Shannon Chuai, Burning Rock Biotech, Guangzhou, People's Republic of China; and Fred R. Hirsch, University of Colorado Cancer Center, Aurora, CO.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Weijing Cai, Chunyan Wu, Xuefei Li, Chao Zhao, Ke Fei, and Caicun Zhou, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai; Dongmei Lin, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing; Limou Zheng, Xiamen University, Xiamen; Shannon Chuai, Burning Rock Biotech, Guangzhou, People's Republic of China; and Fred R. Hirsch, University of Colorado Cancer Center, Aurora, CO.
authors.forename: Limou
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Weijing Cai, Chunyan Wu, Xuefei Li, Chao Zhao, Ke Fei, and Caicun Zhou, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai; Dongmei Lin, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing; Limou Zheng, Xiamen University, Xiamen; Shannon Chuai, Burning Rock Biotech, Guangzhou, People's Republic of China; and Fred R. Hirsch, University of Colorado Cancer Center, Aurora, CO.
authors.forename: Shannon
authors.initials: S
authors.lastname: Chuai
authors.affiliation: Weijing Cai, Chunyan Wu, Xuefei Li, Chao Zhao, Ke Fei, and Caicun Zhou, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai; Dongmei Lin, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing; Limou Zheng, Xiamen University, Xiamen; Shannon Chuai, Burning Rock Biotech, Guangzhou, People's Republic of China; and Fred R. Hirsch, University of Colorado Cancer Center, Aurora, CO.
authors.forename: Ke
authors.initials: K
authors.lastname: Fei
authors.affiliation: Weijing Cai, Chunyan Wu, Xuefei Li, Chao Zhao, Ke Fei, and Caicun Zhou, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai; Dongmei Lin, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing; Limou Zheng, Xiamen University, Xiamen; Shannon Chuai, Burning Rock Biotech, Guangzhou, People's Republic of China; and Fred R. Hirsch, University of Colorado Cancer Center, Aurora, CO. caicunzhoudr@163.com.
authors.forename: Caicun
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Weijing Cai, Chunyan Wu, Xuefei Li, Chao Zhao, Ke Fei, and Caicun Zhou, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai; Dongmei Lin, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing; Limou Zheng, Xiamen University, Xiamen; Shannon Chuai, Burning Rock Biotech, Guangzhou, People's Republic of China; and Fred R. Hirsch, University of Colorado Cancer Center, Aurora, CO.
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D061346:Laser Capture Microdissection; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D015514:Oncogene Proteins, Fusion; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases