The ribosomal protein gene RPL5 is a haploinsufficient tumor suppressor in multiple cancer types

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.

How Ribosomes Translate Cancer

“…In T-cell acute lymphoblastic leukemia (T-ALL), 2% of patients carry heterozygous inactivating mutations in RPL5 (8). Moreover, RPL5 is located at a significant peak of heterozygous deletion, and it is deleted or mutated in 11% of glioblastoma, 28% of melanoma, 34% of breast cancer and ≥20% of multiple myeloma tumors (11,12). A haploinsufficient tumor suppressor role for RPL5 is further supported by the observation that a 50% knock-down of RPL5 in breast cancer cell lines enhances G2/M cell cycle progression and accelerates tumor progression in a xenograft mouse model (12).…”

“…Moreover, RPL5 is located at a significant peak of heterozygous deletion, and it is deleted or mutated in 11% of glioblastoma, 28% of melanoma, 34% of breast cancer and ≥20% of multiple myeloma tumors (11,12). A haploinsufficient tumor suppressor role for RPL5 is further supported by the observation that a 50% knock-down of RPL5 in breast cancer cell lines enhances G2/M cell cycle progression and accelerates tumor progression in a xenograft mouse model (12). Of therapeutic relevance, in the context of multiple myeloma, patients with low RPL5 expression have poor prognoses which can be overcome by including the proteasome inhibitor bortezomib in the treatment regimen (11).…”

“…Rare somatic mutations in relapse T-ALL patients have been described, and 1.4% of melanoma cases show mutations (12,97). Besides displaying a DBA phenotype, heterozygous Rpl11 knock-out mice present increased susceptibility to radiation-induced lymphomagenesis (98), making this mouse the only model fully recapitulating DBA to date, including its cancer predisposition.…”

Osteosarcoma: Molecular Pathogenesis and iPSC Modeling

“…The dysregulation of specific RPs has also been noted in cancers [89]. For instance, RPL5 heterozygous mutations or deletions are found in 11% of glioblastomas, 28% of melanomas and 34% of breast cancer patients [95]. Besides being the most common RP mutation in cancer, RPL5 mutations also lead to craniofacial anomalies [96].…”

Low frequency mutations in ribosomal proteins RPL10 and RPL5 in multiple myeloma

“…RPL5 is mutated in 11-34% of glioblastoma, melanoma and breast cancer samples, and 10-20% of chronic lymphocytic leukemia samples have RPS15 mutations. 4,5,6 The plasma cell malignancy multiple myeloma (MM) is an attractive candidate for harboring RP mutations: initial genome sequencing revealed that half of the patients carry mutations in genes that may be functionally linked to protein translation, and we recently described that RPL5 is in a 58 kb minimal deleted region on 1p22 that is deleted in ≥20% of MM cases. …”