Reboot: a straightforward approach to identify genes and splicing isoforms associated with cancer patient prognosis

Santos, Felipe R. C. dos; Guardia, Gabriela D. A.; Santos, Fernanda Oliveira; O’Hara, Daniel T.; Galante, Pedro A. F.

doi:10.1093/narcan/zcab024

Cited by 8 publications

(11 citation statements)

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“…Having confirmed the high and distinct expression of retro-miRs in cancer, we sought to check whether these miRNAs have prognostic values to overall survival in cancer patients. To assess this, we used Reboot [32], an algorithm to find gene signatures (including miRNAs) associated with cancer patient prognosis. Using this strategy in approximately 8 thousand samples from 10 cancer types presenting overall survival (OS), we found two signatures with prognostic values, a signature with two retro-miRs (Figure 6A-B) in Liver Hepatocellular Carcinoma (LICH) and another with three retro-miRs with prognostic value in Stomach Adenocarcinoma (STAD), Figure 6C-D.…”

Section: Resultsmentioning

confidence: 99%

Retro-miRs: Novel and functional miRNAs originated from mRNA retrotransposition

Mercuri

Conceicao

Guardia

et al. 2023

Preprint

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Reverse transcribed gene copies, or retrocopies, have emerged as a major source of evolutionary novelties. MicroRNAs (miRNAs) are small, highly conserved RNAs molecules among species that serve as key post-transcriptional regulators of gene expression. The birth and subsequent evolution of miRNAs have been addressed, but not fully. In this study, we carried out a comprehensive investigation of miRNAs origination through retroduplicated mRNA sequences (retrocopies). We identified 17 retroduplicated miRNAs (retro-miRs) that emerged from mRNAs retrocopies. Four of these retro-miRs had de novo origination within retrocopied sequences, while 13 retro-miRNAs were located within exon regions and were duplicated along with their host mRNAs. We found that retro-miRs are primates specific, including 5 retro-miRs conserved among all primates and two human-specific retro-miRs. All of the retro-miRs were expressed and had predicted and experimentally validated target genes, with the exception of miR-10527. Notably, the target genes of retro-miRs are involved in key biological processes, such as metabolic processes, cell signaling and regulation of neurotransmitters in the central nervous system. Additionally, we found that these retro-miRs have a potential oncogenic role in cancer, targeting key cancer genes and being overexpressed in several cancer types, including Liver Hepatocellular Carcinoma and Stomach Adenocarcinoma. Our findings demonstrate that mRNAs retrotransposition is a key mechanism for the generation of novel miRNAs (retro-miRs) in primates. These retro-miRs are expressed, conserved, have target genes with important cellular functions, and play roles in cancer.

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Section: Resultsmentioning

confidence: 99%

Retro-miRs: Novel and functional miRNAs originated from mRNA retrotransposition

Mercuri

Conceicao

Guardia

et al. 2023

Preprint

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“…For a TMB ≥10 mut/Mb cutoff (N = 488), we assessed OS regarding the mutational status of each gene mutation found in at least 5 patients (N = 392). For all genes exhibiting a correlation with survival considering a standard alpha-error level ( p < 0.05), a Cox multivariate analysis was also conducted using Reboot [ 10 ]. The adjustment variables included sex, median age, microsatellite instability (MSI) status, TMB under or above the median TMB of the cohort (20 mut/Mb), and tumor histology (non-small cell lung cancer (NSCLC), melanoma, bladder cancer, and colorectal cancer).…”

Section: Methodsmentioning

confidence: 99%

Interplay between Tumor Mutational Burden and Mutational Profile and Its Effect on Overall Survival: A Pilot Study of Metastatic Patients Treated with Immune Checkpoint Inhibitors

Xavier

Lopes

Awni

et al. 2022

Cancers

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Purpose: Solid tumors harboring tumor mutational burden (TMB) ≥10 mutations per megabase (mut/Mb) received agnostic approval for pembrolizumab. This work aims to analyze the somatic mutational profile’s influence on the outcomes of patients with TMB-high tumors treated with immune checkpoint inhibitors (ICIs). Methods: This post-hoc analysis evaluated clinical and molecular features of patients with solid tumors treated with ICIs that could be either monoclonal antibody directed against programmed cell death protein-1 or monoclonal antibody directed against programmed cell death ligand 1 (anti-PD-1/anti-PD-L1), monoclonal antibody directed against cytotoxic T lymphocyte-associated antigen (anti-CTLA-4) or a combined treatment regimen including one anti-PD-1/anti-PD-L1 and one anti-CTLA-4 (ICIs combination). We performed OS analysis for TMB thresholds of ≥10, ≥20, and <10 mut/Mb. We assessed OS according to the mutational profile for a TMB ≥ 10 mut/Mb cutoff. For genes correlated with OS at the univariate assessment, we conducted a Cox multivariate analysis adjusted by median TMB, sex, age, microsatellite instability (MSI), and histology. Results: A total of 1661 patients were investigated; 488 with a TMB ≥10 mut/Mb (29.4%). The median OS was 42 months for TMB ≥10 or 20 mut/Mb, and 15 months for TMB <10 mut/Mb (p < 0.005). Among TMB ≥10 mut/Mb patients, mutations in E2F3 or STK11 correlated with worse OS, and mutations in NTRK3, PTPRD, RNF43, TENT5C, TET1, or ZFHX3 with better OS. These associations were confirmed with univariate and multivariate analyses (p < 0.05). Melanoma histology and TMB above the median endowed patients with better OS (p < 0.05), while MSI status, age, and gender did not have a statistically significant effect on OS. Conclusion: Combining TMB and mutation profiles in key cancer genes can better qualify patients for ICI treatment and predict their OS.

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“…For a TMB ≥ 10mut/Mb cutoff (N = 488), we assessed OS regarding the mutational status of each gene mutation found in at least 5 patients (N = 392). For all genes exhibiting a correlation with survival considering a standard alpha-error level (P < 0.05), a Cox multivariate analysis was also conducted using Reboot 10 . The adjustment variables included sex, median age, microsatellite instability (MSI) status, TMB under or above the median TMB of the cohort (20 mut/Mb), and histology (non-small cell lung cancer (NSCLC), melanoma, bladder cancer, and colorectal cancer).…”

Section: Methodsmentioning

confidence: 99%

Interplay between Tumor Mutational Burden and Mutational Profile and its effect on overall survival: A Post Hoc Analysis of Metastatic Patients Treated with Immune Checkpoint Inhibitors

Xavier

Guardia

Lopes

et al. 2022

Preprint

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Importance: Tumor mutational burden (TMB) greater than or equal to 10 mutations per megabase (mut/Mb) has received agnostic FDA approval for pembrolizumab. However, this TMB cut-off alone is not a complete predictor of overall survival (OS) in patients treated with immune checkpoint inhibitors (ICIs). Objective. To analyze the influence of the molecular profile in patients with TMB ≥ 10mut/Mb treated with ICIs. Design, Setting, and Participants. This post-hoc analysis evaluated the clinical and molecular features of tumor-normal pairs from 1,661 patients with solid tumors sequenced using the MSK-IMPACT assay and treated with ICIs. Main Outcomes and Measures. We performed OS analysis and compared the results for TMB thresholds of ≥ 10, ≥ 20, and < 10 mut/Mb. For a TMB ≥ 10mut/Mb, we assessed OS according to mutational status. For all genes exhibiting a correlation with OS (P < 0.05), we conducted a Cox multivariate analysis stratified by median TMB, sex, median age, microsatellite instability (MSI) status, and histology. Results. After a maximum follow-up of 80 months, a total of 1,661 patients were investigated, and survival to ICIs increased with higher TMB cut-offs. The median OS was 42 months for TMB ≥ 10 or 20mut/Mb, and 15 months for TMB < 10 mut/Mb (P < 0.005). Patients harboring a TMB ≥ 10 (N=488, 29%) were further stratified by their somatic mutation profile in key cancer genes. When only genes with n ≥ 5 mutations were considered, mutations in E2F3 or STK11 were correlated with worse OS, and those with mutations in NTRK3, PTPRD, RNF43, TENT5C, TET1 or ZFHX3 were correlated with better OS in TMB-high patients receiving ICIs compared to wild-type patients. These associations were confirmed by univariate and multivariate analyses (P < 0.05). MSI status and clinical features, including age, sex, and histology (except for melanoma), failed to predict outcomes to ICIs in patients with high TMB. Conclusion and relevance. The findings suggest that combining TMB information and mutation profiles in key cancer genes can be used to better qualify patients for ICI treatment and predict their OS.

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Reboot: a straightforward approach to identify genes and splicing isoforms associated with cancer patient prognosis

Cited by 8 publications

References 93 publications

Retro-miRs: Novel and functional miRNAs originated from mRNA retrotransposition

Retro-miRs: Novel and functional miRNAs originated from mRNA retrotransposition

Interplay between Tumor Mutational Burden and Mutational Profile and Its Effect on Overall Survival: A Pilot Study of Metastatic Patients Treated with Immune Checkpoint Inhibitors

Interplay between Tumor Mutational Burden and Mutational Profile and its effect on overall survival: A Post Hoc Analysis of Metastatic Patients Treated with Immune Checkpoint Inhibitors

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