TY - JOUR
T1 - Frequent germline and somatic single nucleotide variants in the promoter region of the ribosomal rna gene in japanese lung adenocarcinoma patients
AU - Ohashi, Riuko
AU - Umezu, Hajime
AU - Sato, Ayako
AU - Abé, Tatsuya
AU - Kondo, Shuhei
AU - Daigo, Kenji
AU - Sato, Seijiro
AU - Hara, Norikazu
AU - Miyashita, Akinori
AU - Ikeuchi, Takeshi
AU - Motoyama, Teiichi
AU - Kishi, Masashi
AU - Nagaoka, Tadahiro
AU - Horiuchi, Keiko
AU - Shiga, Atsushi
AU - Okuda, Shujiro
AU - Sekiya, Tomoki
AU - Ohtsubo, Aya
AU - Ichikawa, Kosuke
AU - Kagamu, Hiroshi
AU - Kikuchi, Toshiaki
AU - Watanabe, Satoshi
AU - Tanuma, Jun Ichi
AU - Schraml, Peter
AU - Hamakubo, Takao
AU - Tsuchida, Masanori
AU - Ajioka, Yoichi
N1 - Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/11
Y1 - 2020/11
N2 - 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.
AB - 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.
KW - Lung adenocarcinoma
KW - Prognosis
KW - RDNA
KW - Ribosome biogenesis
KW - Single nucleotide variant
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U2 - 10.3390/cells9112409
DO - 10.3390/cells9112409
M3 - Article
C2 - 33153169
AN - SCOPUS:85095758252
SN - 2073-4409
VL - 9
SP - 1
EP - 22
JO - Cells
JF - Cells
IS - 11
M1 - 2409
ER -