Frequent Germline and Somatic Single Nucleotide Variants in the Promoter Region of the Ribosomal RNA Gene in Japanese Lung Adenocarcinoma Patients

Cells

Atsushi Shiga¹  Norikazu Hara²  Akinori Miyashita²  Takeshi Ikeuchi²  Peter Schraml³  Keiko Horiuchi⁴  Kenji Daigo⁴  Takao Hamakubo⁴  Tomoki Sekiya⁵  Kosuke Ichikawa⁵  Satoshi Watanabe⁵  Toshiaki Kikuchi⁵  Aya Ohtsubo⁵  Hiroshi Kagamu⁵  Tadahiro Nagaoka⁶  Shujiro Okuda⁷  Ayako Sato⁸  Tatsuya Abé⁸  Teiichi Motoyama⁸  Shuhei Kondo⁸  Jun-Ichi Tanuma⁹  Hajime Umezu^1,10  Masanori Tsuchida^1,11  Seijiro Sato^1,11  Riuko Ohashi^1,12  Yoichi Ajioka^1,12  Masashi Kishi^1,13 

[1] Department of Clinical Laboratory, Niigata Cancer Center hospital, Niigata 951-8560, Japan;Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata 951-8510, Japan;Department of Pathology and Molecular Pathology, University of Zurich and University Hospital Zurich, CH-8091 Zurich, Switzerland;Department of Protein-Protein Interaction Research, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Kanagawa 211-8533, Japan;Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan;Division for Therapies against Intractable Diseases, Institute for Comprehensive Medical Science, Fujita Health University, Aichi 470-1192, Japan;Division of Bioinformatics, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan;Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan;Division of Oral Pathology, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8514, Japan;Division of Pathology, Niigata University Medical & Dental Hospital, Niigata 951-8520, Japan;Division of Thoracic and Cardiovascular Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan;Histopathology Core Facility, Niigata University Faculty of Medicine, Niigata 951-8510, Japan;Neuroscience Laboratory, Research Institute, Nozaki Tokushukai Hospital, Osaka 574-0074, Japan;

关键词: lung adenocarcinoma;    rDNA;    ribosome biogenesis;    single nucleotide variant;    prognosis;   

DOI  :  10.3390/cells9112409

来源: DOAJ

【 摘 要 】

Ribosomal RNA (rRNA), the most abundant non-coding RNA species, is a major component of the ribosome. Impaired ribosome biogenesis causes the dysfunction of protein synthesis and diseases called “ribosomopathies,” including genetic disorders with cancer risk. However, the potential role of rRNA gene (rDNA) alterations in cancer is unknown. We investigated germline and somatic single-nucleotide variants (SNVs) in the rDNA promoter region (positions −248 to +100, relative to the transcription start site) in 82 lung adenocarcinomas (LUAC). Twenty-nine tumors (35.4%) carried germline SNVs, and eight tumors (9.8%) harbored somatic SNVs. Interestingly, the presence of germline SNVs between positions +1 and +100 (n = 12; 14.6%) was associated with significantly shorter recurrence-free survival (RFS) and overall survival (OS) by univariate analysis (p < 0.05, respectively), and was an independent prognostic factor for RFS and OS by multivariate analysis. LUAC cell line PC9, carrying rDNA promoter SNV at position +49, showed significantly higher ribosome biogenesis than H1650 cells without SNV. Upon nucleolar stress induced by actinomycin D, PC9 retained significantly higher ribosome biogenesis than H1650. These results highlight the possible functional role of SNVs at specific sites of the rDNA promoter region in ribosome biogenesis, the progression of LUAC, and their potential prognostic value.

【 授权许可】

Unknown