Endoplasmic reticulum ribosome-binding protein 1, RRBP1, promotes progression of colorectal cancer and predicts an unfavourable prognosis

Pan, Yun-long; Cao, Fuao; Guo, Aijiang; Chang, Wenjun; Chen, X; Ma, Wei; Gao, Xu; Guo, Shu; Fu, Chuangang; Zhu, Jiaqi

doi:10.1038/bjc.2015.260

Cited by 45 publications

(59 citation statements)

References 41 publications

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“…These biologic roles likely account for the distinctive cytoplasmic and perinuclear ALK localization in EIMS with RRBP1-ALK fusions. RRBP1 overexpression has been implicated as a marker of poor prognosis in breast and colorectal cancer [19,20], but the IMT studies reported here are the first demonstration of an RRBP1 oncogenic mechanism. RRBP1-ALK retained the N-terminal RRBP1 coiled-coil domain (Figure 2 and Figure 3), and hence is one of various ALK fusion oncoproteins, such as TPM3-ALK [21], in which a coiled-coil fusion partner dictates ALK oncogenic activation.…”

Section: Discussionmentioning

confidence: 95%

ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma

et al. 2016

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ALK oncogenic activation mechanisms were characterized in four conventional spindle-cell inflammatory myofibroblastic tumours (IMT) and five atypical IMT, each of which had ALK genomic perturbations. Constitutively activated ALK oncoproteins were purified by ALK immunoprecipitation and electrophoresis, and were characterized by mass spectrometry. The four conventional IMT had TPM3/4-ALK fusions (two cases) or DCTN1-ALK fusions (two cases), whereas two atypical spindle-cell IMT had TFG-ALK and TPM3-ALK fusion in one case each, and three epithelioid inflammatory myofibroblastic sarcomas had RANBP2-ALK fusions in two cases, and a novel RRBP1-ALK fusion in one case. The epithelioid inflammatory myofibroblastic sarcoma with RRBP1-ALK fusion had cytoplasmic ALK expression with perinuclear accentuation, different from the nuclear membranous ALK localization in epithelioid inflammatory myofibroblastic sarcomas with RANBP2-ALK fusions. Evaluation of three additional uncharacterized epithelioid inflammatory myofibroblastic sarcomas with ALK cytoplasmic/perinuclear- accentuation expression demonstrated RRBP1-ALK fusion in two cases. These studies show that atypical spindle-cell IMT can utilize the same ALK fusion mechanisms described previously in conventional IMT, whereas in clinically aggressive epithelioid inflammatory myofibroblastic sarcoma we identify a novel recurrent ALK oncogenic mechanism, resulting from fusion with the RRBP1 gene.

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Section: Discussionmentioning

confidence: 95%

ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma

et al. 2016

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“…This protein functions in post-translational processing of proteins secreted from the endoplasmic reticulum 41 and has been implicated in cell autophagy 42,43 . While these mutations have not been previously described for RRBP1, overexpression of this gene has been reported in other solid tumors, including breast and colorectal adenocarcinomas 44,45 . In non-metastatic colorectal cancer, high expression of RRBP1 has been described as a poor prognostic biomarker 44 .…”

Section: Discussionmentioning

confidence: 79%

“…While these mutations have not been previously described for RRBP1, overexpression of this gene has been reported in other solid tumors, including breast and colorectal adenocarcinomas 44,45 . In non-metastatic colorectal cancer, high expression of RRBP1 has been described as a poor prognostic biomarker 44 . While no effect on metastatic survival was noted in this population of patients with metastatic SCCA based on RRBP1 mutation status, our findings of this gene warrants further evaluation in future studies for anal cancer.…”

Section: Discussionmentioning

confidence: 79%

Comprehensive Genomic Profiling of Metastatic Squamous Cell Carcinoma of the Anal Canal

Morris

Rao

Pickering

et al. 2017

Molecular Cancer Research

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Squamous cell carcinoma of the anal canal (SCCA) is a rare gastrointestinal malignancy with an increasing annual incidence globally. The majority of cases are linked to prior infection with the human papillomavirus (HPV). For patients with metastatic SCCA, no consensus standard treatment exists. Identification of relevant targeted agents as novel therapeutic approaches for metastatic SCCA has been limited by a lack of comprehensive molecular profiling. For our study we performed whole-exome sequencing on tumor-normal pairs from 24 patients with metastatic SCCA. Tumor tissue from 17 additional patients was analyzed using a 263-gene panel as a validation cohort. Gene expression profiling was performed on available frozen tissue to assess for differential expression patterns. Based on these findings, patient-derived xenograft (PDX) models of SCCA were generated to test targeted therapies against PI3K and EGFR. Despite a low mutation burden, mutations in PIK3CA, MLL2, and MLL3 were among the most commonly mutated genes. An association between TP53 mutations and HPV-negative SCCA tumors was observed. Gene expression analysis suggested distinct tumor subpopulations harboring PIK3CA mutations and for which HPV had integrated into the host genome. In vivo studies demonstrated improvement with anti-EGFR treatment. Gene mutation frequencies, tumor mutation burden, and gene expression patterns for metastatic SCCA appear similar to other HPV-associated malignancies. Here we report the first comprehensive genomic characterization for patients with metastatic SCCA which provides further rationale for the integration of SCCA into the development of novel targeted therapies across HPV-related cancers.

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“…expression [41]. The up-regulation of FRMD4A was reported in human head and neck squamous cell carcinoma (HNSCC) and correlated with increased risks of relapse [42].…”

Section: Resultsmentioning

confidence: 99%

Two-Step Mixed Model Approach to Analyzing Differential Alternative RNA Splicing

Luo¹,

Kang²,

Li³

et al. 2020

Preprint

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18Changes in gene expression can correlate with poor disease outcomes in two ways: through changes in 19 relative transcript levels or through alternative RNA splicing leading to changes in relative abundance of 20 individual transcript isoforms. The objective of this research is to develop new statistical methods in 21 detecting and analyzing both differentially expressed and spliced isoforms, which appropriately account for 22 the dependence between isoforms and multiple testing corrections for the multi-dimensional structure of at 23 both the gene-and isoform-level. We developed a linear mixed effects model-based approach for analyzing 24 the complex alternative RNA splicing regulation patterns detected by whole-transcriptome RNA-25 sequencing technologies. This approach thoroughly characterizes and differentiates three types of genes 26 related to alternative RNA splicing events with distinct differential expression/splicing patterns. We applied 27 the concept of appropriately controlling for the gene-level overall false discovery rate (OFDR) in this multi-28 dimensional alternative RNA splicing analysis utilizing a two-step hierarchical hypothesis testing 29 framework. In the initial screening test we identify genes that have differentially expressed or spliced 30 isoforms; in the subsequent confirmatory testing stage we examine only the isoforms for genes that have 31 passed the screening tests. Comparisons with other methods through application to a whole transcriptome 32 RNA-Seq study of adenoid cystic carcinoma and extensive simulation studies have demonstrated the 33 advantages and improved performances of our method. Our proposed method appropriately controls the 34 gene-level OFDR, maintains statistical power, and is flexible to incorporate advanced experimental designs. 35

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Endoplasmic reticulum ribosome-binding protein 1, RRBP1, promotes progression of colorectal cancer and predicts an unfavourable prognosis

Cited by 45 publications

References 41 publications

ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma

ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma

Comprehensive Genomic Profiling of Metastatic Squamous Cell Carcinoma of the Anal Canal

Two-Step Mixed Model Approach to Analyzing Differential Alternative RNA Splicing

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