Clinical Significance of Detecting Somatic Gene Mutations in Surgically Resected Adenosquamous Cell Carcinoma of the Lung in Japanese Patients

Abstract Background Emerging evidence confirms that lncRNAs (long non-coding RNAs) are potential biomarkers that play vital roles in tumors. ZNF582-AS1 is a novel lncRNA that serves as a potential prognostic marker of cancers. However, the specific clinical significance and molecular mechanism of ZNF582-AS1 in ccRCC (clear cell renal cell carcinoma) are unclear. Methods Expression level and clinical significance of ZNF582-AS1 were determined by TCGA-KIRC data and qRT-PCR results of 62 ccRCCs. DNA methylation status of ZNF582-AS1 promoter was examined by MSP, MassARRAY methylation and demethylation analysis. Gain-of-function experiments were conducted to investigate the biological roles of ZNF582-AS1 in the phenotype of ccRCC. The subcellular localization of ZNF582-AS1 was detected by RNA FISH. iTRAQ, RNA pull-down and RIP-qRT-PCR were used to identify the downstream targets of ZNF582-AS1. rRNA MeRIP-seq and MeRIP-qRT-PCR were utilized to examine the N(6)-methyladenosine modification status. Western blot and immunohistochemistry assays were used to determine the protein expression level. Results ZNF582-AS1 was downregulated in ccRCC, and decreased ZNF582-AS1 expression was significantly correlated with advanced tumor stage, higher pathological stage, distant metastasis and poor prognosis. Decreased ZNF582-AS1 expression was caused by DNA methylation at the CpG islands within its promoter. ZNF582-AS1 overexpression inhibited cell proliferative, migratory and invasive ability, and increased cell apoptotic rate in vitro and in vivo. Mechanistically, we found that ZNF582-AS1 overexpression suppressed the N(6)-methyladenosine modification of MT-RNR1 by reducing rRNA adenine N(6)-methyltransferase A8K0B9 protein level, resulting in the decrease of MT-RNR1 expression, followed by the inhibition of MT-CO2 protein expression. Furthermore, MT-RNR1 overexpression reversed the decreased MT-CO2 expression and phenotype inhibition of ccRCC induced by increased ZNF582-AS1 expression. Conclusions This study demonstrates for the first time that ZNF582-AS1 functions as a tumor suppressor gene in ccRCC and ZNF582-AS1 may serve as a potential biomarker and therapeutic target of ccRCC.

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Whole exome sequencing and deep sequencing of esophageal squamous cell carcinoma and adenocarcinoma in Japanese patients using the Japanese version of the Genome Atlas, JCGA

Esophagus ◽

10.1007/s10388-021-00835-z ◽

2021 ◽

Author(s):

Eisuke Booka ◽

Yasuhiro Tsubosa ◽

Tomoya Yokota ◽

Shuhei Mayanagi ◽

Kenjiro Ishii ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Cancer ◽

Cell Carcinoma ◽

Squamous Cell ◽

Somatic Mutations ◽

Molecular Targets ◽

Japanese Version ◽

Japanese Patients ◽

Genetic Alterations ◽

Genome Atlas

Abstract Background Recent comprehensive mutation analyses have revealed a relatively small number of driver mutations in esophageal cancer, implicating a limited number of molecular targets, most of which are also implicated in squamous cell carcinoma. Methods In this study, we investigated genetic alterations in 44 esophageal squamous cell carcinomas (ESCC) and 8 adenocarcinomas (EAC) from Japanese patients as potential molecular targets, based on data from the Japanese version of The Genome Atlas (JCGA). Results Esophageal cancer was characterized by TP53 somatic mutations in ESCC (39/44, 88.6%) and EAC (5/8, 62.5%). In addition to TP53 mutations, somatic mutations in NFE2L2 (16/44, 36.4%), CDKN2A (7/44, 15.9%), and KMT2D (7/44, 15.9%) were more frequently detected in ESCC than in EAC. WRN-truncated type mutations that lead to genomic instability correlate with EAC, but not ESCC. ESCC samples were enriched in ALDH2-associated mutational signature 16 as well as the APOBEC signature. Patients with FAT2 mutations had significantly poorer overall survival compared with those with wild-type status at FAT2 (p < 0.05). Patients with EP300 or PTPRD mutations also had poor progression-free survival compared with respective wild-types (p < 0.05 or p < 0.001). Conclusions These findings may facilitate future precision medicine approaches based on genomic profiling in ESCC and EAC.

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