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

• Main Authors: Riuko Ohashi, Hajime Umezu, Ayako Sato, Tatsuya Abé, Shuhei Kondo, Kenji Daigo, Seijiro Sato, Norikazu Hara, Akinori Miyashita, Takeshi Ikeuchi, Teiichi Motoyama, Masashi Kishi, Tadahiro Nagaoka, Keiko Horiuchi, Atsushi Shiga, Shujiro Okuda, Tomoki Sekiya, Aya Ohtsubo, Kosuke Ichikawa, Hiroshi Kagamu, Toshiaki Kikuchi, Satoshi Watanabe, Jun-Ichi Tanuma, Peter Schraml, Takao Hamakubo, Masanori Tsuchida, Yoichi Ajioka
• Format: Article
• Language: English
• Published: MDPI AG 2020-11-01
• Series: Cells
• Subjects: lung adenocarcinoma; rDNA; ribosome biogenesis; single nucleotide variant; prognosis
• Online Access: https://www.mdpi.com/2073-4409/9/11/2409

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 (<i>n</i> = 12; 14.6%) was associated with significantly shorter recurrence-free survival (RFS) and overall survival (OS) by univariate analysis (<i>p</i> < 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.