title: Exome sequencing deciphers a germline MET mutation in familial epidermal growth factor receptor-mutant lung cancer.
abstract: Lung cancer accompanied by somatic activating mutations in the epidermal growth factor receptor (EGFR) gene, which is associated with a significant clinical response to the targeted therapy, is frequently found in never-smoking Asian women with adenocarcinoma. Although this implies genetic factors underlying the carcinogenesis, the etiology remains unclear. To gain insight into the pathogenic mechanisms, we sequenced the exomes in the peripheral-blood DNA from six siblings, four affected and two unaffected siblings, of a family with familial EGFR-mutant lung adenocarcinoma. We identified a heterozygous missense mutation in MET proto-oncogene, p.Asn375Lys, in all four affected siblings. Combined with somatic loss of heterozygosity for MET, the higher allele frequency in a Japanese sequencing database supports a causative role of the MET mutation in EGFR-mutant lung cancer. Functional assays showed that the mutation reduces the binding affinity of MET for its ligand, hepatocyte growth factor, and damages the subsequent cellular processes, including proliferation, clonogenicity, motility and tumorigenicity. The MET mutation was further observed to abrogate the ERBB3-mediated AKT signal transduction, which is shared downstream by EGFR. These findings provide an etiological view that the MET mutation is involved in the pathogenesis of EGFR-mutant lung cancer because it generates oncogenic stress that induces compensatory EGFR activation. The identification of MET in a family with familial EGFR-mutant lung cancer is insightful to explore the pathogenic mechanism of not only familial, but also sporadic EGFR-mutant lung cancer by underscoring MET-related signaling molecules.
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tode
authors.affiliation: Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Toshiaki
authors.identifier: http://orcid.org/0000-0001-7428-1245
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sakakibara
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Taizou
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Department of Palliative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ohkouchi
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tamada
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tatsuma
authors.initials: T
authors.lastname: Okazaki
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Koarai
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Sugiura
authors.affiliation: Department of Medical Genetics, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Niihori
authors.affiliation: Department of Medical Genetics, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Medical Genetics, Tohoku University Graduate School of Medicine, Sendai, Japan.|National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Research Division for Development of Anti-Infective Agents, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nukiwa
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ichinose
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt
keywords: Epidermal growth factor receptor; exome; familial lung cancer; human MET protein; missense mutation