title: Development of lung adenocarcinomas with exclusive dependence on oncogene fusions.
abstract: This report delivers a comprehensive genetic alteration profile of lung adenocarcinomas (LADC) driven by ALK, RET, and ROS1 oncogene fusions. These tumors are difficult to study because of their rarity. Each drives only a low percentage of LADCs. Whole-exome sequencing and copy-number variation analyses were performed on a Japanese LADC cohort (n = 200) enriched in patients with fusions (n = 31, 15.5%), followed by deep resequencing for validation. The driver fusion cases showed a distinct profile with smaller numbers of nonsynonymous mutations in cancer-related genes or truncating mutations in SWI/SNF chromatin remodeling complex genes than in other LADCs (P < 0.0001). This lower mutation rate was independent of age, gender, smoking status, pathologic stage, and tumor differentiation (P < 0.0001) and was validated in nine fusion-positive cases from a U.S. LADCs cohort (n = 230). In conclusion, our findings indicate that LADCs with ALK, RET, and ROS1 fusions develop exclusively via their dependence on these oncogene fusions. The presence of such few alterations beyond the fusions supports the use of monotherapy with tyrosine kinase inhibitors targeting the fusion products in fusion-positive LADCs.
authors: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors: Motonobu
authors: M
authors: Saito
authors: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors: Yoko
authors: Y
authors: Shimada
authors: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors: Kouya
authors: K
authors: Shiraishi
authors: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors: Hiromi
authors: H
authors: Sakamoto
authors: Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors: Koji
authors: K
authors: Tsuta
authors: Solution Development Department, New Project Development Division, Hitachi Government & Public Sector Systems, Ltd., Tokyo, Japan.
authors: Hirohiko
authors: H
authors: Totsuka
authors: Science Solutions Division, Mizuho Information and Research Institute Inc., Tokyo, Japan.
authors: Suenori
authors: S
authors: Chiku
authors: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors: Hitoshi
authors: H
authors: Ichikawa
authors: Department of Bioinformatics, National Cancer Center Research Institute, Tokyo, Japan.
authors: Mamoru
authors: M
authors: Kato
authors: Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors: Shun-Ichi
authors: S
authors: Watanabe
authors: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors: Teruhiko
authors: T
authors: Yoshida
authors: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. Cancer Genome Biology Group, Institute of Predictive and Personalized Medicine of Cancer, Barcelona, Spain.
authors: Jun
authors: J
authors: Yokota
authors: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. tkkohno@ncc.go.jp.
authors: Takashi
authors: T
authors: Kohno
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D056915:DNA Copy Number Variations / Q000235:genetics; D059472:Exome; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D050596:Oncogene Fusion / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D011518:Proto-Oncogene Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases