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The ribosomal protein gene RPL5 is a haploinsufficient tumor suppressor in multiple cancer types
Laura Fancello1, Kim R Kampen1, Isabel J F Hofman1
1KU Leuven-University of Leuven, Department of Oncology, LKI-Leuven Cancer Institute, Leuven, Belgium.
Abstract:
For many years, defects in the ribosome have been associated to cancer. Recently, somatic mutations and deletions affecting ribosomal protein genes were identified in a few leukemias and solid tumor types. However, systematic analysis of all 81 known ribosomal protein genes across cancer types is lacking. We screened mutation and copy number data of respectively 4926 and 7322 samples from 16 cancer types and identified six altered genes (RPL5, RPL11, RPL23A, RPS5, RPS20 and RPSA). RPL5 was located at a significant peak of heterozygous deletion or mutated in 11% of glioblastoma, 28% of melanoma and 34% of breast cancer samples. Moreover, patients with low RPL5 expression displayed worse overall survival in glioblastoma and in one breast cancer cohort. RPL5 knockdown in breast cancer cell lines enhanced G2/M cell cycle progression and accelerated tumor progression in a xenograft mouse model. Interestingly, our data suggest that the tumor suppressor role of RPL5 is not only mediated by its known function as TP53 or c-MYC regulator. In conclusion, RPL5 heterozygous inactivation occurs at high incidence (11-34%) in multiple tumor types, currently representing the most common somatic ribosomal protein defect in cancer, and we demonstrate a tumor suppressor role for RPL5 in breast cancer.
Insights
Ribosome defects are linked to cancer. This study found RPL5 gene inactivation in 11-34% of glioblastoma, melanoma, and breast cancers, revealing its role as a tumor suppressor.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ribosome defects have long been associated with cancer development.
- Recent findings link somatic mutations in ribosomal protein genes to specific leukemias and solid tumors.
- A comprehensive analysis of all ribosomal protein genes across diverse cancer types was previously lacking.
Purpose of the Study:
- To systematically screen all 81 known ribosomal protein genes for mutations and copy number alterations across 16 cancer types.
- To identify specific ribosomal protein genes frequently altered in cancer.
- To investigate the functional role and clinical significance of altered ribosomal protein genes, particularly RPL5, in cancer.
Main Methods:
- Screening of mutation and copy number data from 4926 and 7322 samples across 16 cancer types.
- Identification of significantly altered ribosomal protein genes.
- Analysis of RPL5 expression levels and their correlation with patient survival.
- Functional studies involving RPL5 knockdown in breast cancer cell lines and xenograft mouse models.
Main Results:
- Six ribosomal protein genes (RPL5, RPL11, RPL23A, RPS5, RPS20, RPSA) were identified as altered.
- RPL5 showed significant heterozygous deletions or mutations in 11% of glioblastoma, 28% of melanoma, and 34% of breast cancer samples.
- Low RPL5 expression correlated with worse overall survival in glioblastoma and some breast cancer cohorts.
- RPL5 knockdown accelerated tumor progression in mice and enhanced cell cycle progression in breast cancer cells.
- Evidence suggests RPL5 acts as a tumor suppressor, potentially through mechanisms beyond TP53 or c-MYC regulation.
Conclusions:
- Heterozygous inactivation of RPL5 occurs frequently (11-34%) in multiple cancer types, representing the most common somatic ribosomal protein defect found to date.
- RPL5 functions as a tumor suppressor in breast cancer.
- These findings highlight the critical role of ribosomal protein gene integrity in cancer and identify RPL5 as a potential therapeutic target.
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