Altered patterns of global protein synthesis and translational fidelity in RPS15-mutated chronic lymphocytic leukemia

Bretones, Gabriel; Álvarez, Marina Rodríguez; Arango, Javier R.; Rodrı́guez, David; Nadeu, Ferran; Prado, Miguel A.; Valdés-Mas, Rafael; Puente, Diana; Paulo, João A.; Delgado, Julio; Villamor, Neus; López‐Guillermo, Armando; Finley, Daniel; Gygi, Steven P.; Campo, Elı́as; Quesada, Vı́ctor; López-Otı́n, Carlos

doi:10.1182/blood-2017-09-804401

Cited by 52 publications

(54 citation statements)

References 66 publications

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“…30,31 Moreover, mutations in RPS15 at highly conserved sites resulting in gain of function have been identified as one of the drivers of chronic lymphocytic leukemia and have been associated with aggressive phenotype and shorter survival. 32,33 Finally, of the three known DNA areas used in this study (variables X 1 – X 3 ), only one corresponds to a protein-coding gene, namely, RPS15 . According to the results of our transcriptomic analysis, which will be presented in a future study, RPS15 was significantly and highly overexpressed in the tumor cells compared with the normal ones.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide DNA Methylation Model for the Diagnosis of Prostate Cancer

Nikas¹,

Nikas

2019

ACS Omega

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Prostate cancer is the most prevalent and the second most lethal malignancy among males in the United States of America. Its diagnosis is almost entirely predicated upon histopathological analysis of the biopsied tissue, and it is associated with a substantial average error. Using genome-wide DNA methylation data derived from 469 prostatic tumor tissue samples and 50 normal prostatic tissue samples and interrogating over 485 000 CpG sites per sample (spanning across gene promoters, CpG islands, shores, shelves, gene bodies, and intergenic and other areas), we were able to develop a mathematical model that classified with a high accuracy (overall sensitivity = 95.31% and overall specificity = 94.00%) tumor tissue versus normal tissue. The methylation β values of five CpG sites, corresponding to the genes LINC01091, RPS15, SNORA10, and two unknown DNA areas in chromosome 1, provided the input to the model. The model was validated with unknown samples, as well as with a sixfold cross-validation and a leave-one-out cross-validation. This study presents a novel genomic model based on genome-wide DNA methylation analysis of biopsied prostatic tissue that could aid in the diagnosis of prostate cancer and help advance the transition to genomic medicine.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide DNA Methylation Model for the Diagnosis of Prostate Cancer

Nikas¹,

Nikas

2019

ACS Omega

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“…HIST1H3B, SMARCB1, and SETBP1 are involved in epigenetic regulation and their mutations can alter gene expression patterns [ 50 , 51 ]. Mutations of EIF1AX and RPS15 are likely to perturb translation events [ 52 , 53 ]. However, SRSF2, which is responsible for orchestrating splicing events, can also have a global influence on cellular states [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Ancient Evolutionary Origin of Intrinsically Disordered Cancer Risk Regions

2020

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Cancer is a heterogeneous genetic disease that alters the proper functioning of proteins involved in key regulatory processes such as cell cycle, DNA repair, survival, or apoptosis. Mutations often accumulate in hot-spots regions, highlighting critical functional modules within these proteins that need to be altered, amplified, or abolished for tumor formation. Recent evidence suggests that these mutational hotspots can correspond not only to globular domains, but also to intrinsically disordered regions (IDRs), which play a significant role in a subset of cancer types. IDRs have distinct functional properties that originate from their inherent flexibility. Generally, they correspond to more recent evolutionary inventions and show larger sequence variations across species. In this work, we analyzed the evolutionary origin of disordered regions that are specifically targeted in cancer. Surprisingly, the majority of these disordered cancer risk regions showed remarkable conservation with ancient evolutionary origin, stemming from the earliest multicellular animals or even beyond. Nevertheless, we encountered several examples where the mutated region emerged at a later stage compared with the origin of the gene family. We also showed the cancer risk regions become quickly fixated after their emergence, but evolution continues to tinker with their genes with novel regulatory elements introduced even at the level of humans. Our concise analysis provides a much clearer picture of the emergence of key regulatory elements in proteins and highlights the importance of taking into account the modular organisation of proteins for the analyses of evolutionary origin.

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“…HIST1H3B, SMARCB1 and SETBP1 are involved in epigenetic regulation and their mutations can alter gene expression patterns [44,45] . Mutations of EIF1AX and RPS15 are likely to perturb translation events [46,47] . However, SRSF2, which is responsible for orchestrating splicing events, can also have a global influence on cellular states [48] .…”

Section: Discussionmentioning

confidence: 99%

Ancient evolutionary origin of intrinsically disordered cancer risk regions

Pajkos

Zeke

Dosztányi

2020

Preprint

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Cancer is a heterogeneous genetic disease that alters the proper functioning of proteins involved in key regulatory processes such as cell cycle, DNA repair, survival or apoptosis. Mutations often accumulate in hot-spots regions, highlighting critical functional modules within these proteins that need to be altered, amplified or abolished for tumor formation. Recent evidence suggests that these mutational hotspots can not only correspond to globular domains but also to intrinsically disordered regions (IDRs), which play a significant role in a subset of cancer types. IDRs have distinct functional properties that originate from their inherent flexibility. Generally, they correspond to more recent evolutionary inventions and show larger sequence variations across species. In this work we analyzed the evolutionary origin of disordered regions that are specifically targeted in cancer. Surprisingly, the majority of these disordered cancer risk regions showed remarkable conservation with ancient evolutionary origin, stemming from the earliest multicellular animals or even beyond. Nevertheless, we encountered several examples, where the mutated region emerged at a later stage compared to the origin of the gene family. We also showed the cancer risk regions become quickly fixated after their emergence, but evolution continues to tinker with their genes with novel regulatory elements introduced even at the level of humans. Our concise analysis provides a much clearer picture of the emergence of key regulatory elements in proteins and highlights the importance of taking into account the modular organisation of proteins for the analyses of evolutionary origin.

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Altered patterns of global protein synthesis and translational fidelity in RPS15-mutated chronic lymphocytic leukemia

Cited by 52 publications

References 66 publications

Genome-Wide DNA Methylation Model for the Diagnosis of Prostate Cancer

Genome-Wide DNA Methylation Model for the Diagnosis of Prostate Cancer

Ancient Evolutionary Origin of Intrinsically Disordered Cancer Risk Regions

Ancient evolutionary origin of intrinsically disordered cancer risk regions

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