The presence of Y674/Y675 phosphorylated NTRK1 via TP53 repression of PTPN6 expression as a potential prognostic marker in neuroblastoma

Youssef, Gehad; Gillett, Cheryl; Rampling, Dyanne; Chagtai, Tasnim; Virasami, Alex; Barton, Jack; Edwards, David I.; Sebire, Neil J.; Anderson, John; Montano, Ximena

doi:10.1016/j.humpath.2018.12.003

Cited by 8 publications

(14 citation statements)

References 33 publications

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“…For the NTRK1-TP53-PTPN6 module, samples with TP53 and PTPN6 z-scores < 0 and NTRK1 z-scores > 0 were considered as having the presence of the module whereas samples with TP53 and PTPN6 z-scores > 0 and NTRK1 z-scores < 0 were considered as having absence of the module. This approach is consistent with published studies characterising this module [ 10 ].…”

Section: Methodssupporting

confidence: 92%

“…We have demonstrated that the tumour suppressor TP53 represses expression of the phosphatase PTPN6, resulting in activation of NTRK1 [ 9 ]. Furthermore, we have shown that this type of NTRK1-activation is independently and significantly associated with 5-year relapse free survival (RFS) of children with neuroblastoma including patients with high-risk type tumours [ 10 ]. This module is independently associated with RFS in the presence of MYCN- amplification, SCA and histology status.…”

Section: Introductionmentioning

confidence: 99%

“…This module is independently associated with RFS in the presence of MYCN- amplification, SCA and histology status. Therefore, suggesting that together NTRK1, wild-type TP53 and low levels of PTPN6 expression could be a predictive biomarker of good prognosis for neuroblastoma [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Analysis of SARS-CoV-2 infection associated cell entry proteins ACE2, CD147, PPIA, and PPIB in datasets from non SARS-CoV-2 infected neuroblastoma patients, as potential prognostic and infection biomarkers in neuroblastoma

Bergsneider

Bailey

Ahmed

et al. 2021

Biochemistry and Biophysics Reports

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SARS-CoV-2 viral contagion has given rise to a worldwide pandemic. Although most children experience minor symptoms from SARS-CoV-2 infection, some have severe complications including Multisystem Inflammatory Syndrome in Children. Neuroblastoma patients may be at higher risk of severe infection as treatment requires immunocompromising chemotherapy and SARS-CoV-2 has demonstrated tropism for nervous cells. To date, there is no sufficient epidemiological data on neuroblastoma patients with SARS-CoV-2. Therefore, we evaluated datasets of non-SARS-CoV-2 infected neuroblastoma patients to assess for key genes involved with SARS-CoV-2 infection as possible neuroblastoma prognostic and infection biomarkers. We hypothesized that ACE2, CD147, PPIA and PPIB, which are associated with viral-cell entry, are potential biomarkers for poor prognosis neuroblastoma and SARS-CoV-2 infection. We have analysed three publicly available neuroblastoma gene expression datasets to understand the specific molecular susceptibilities that high-risk neuroblastoma patients have to the virus. Gene Expression Omnibus (GEO) GSE49711 and GEO GSE62564 are the microarray and RNA-Seq data, respectively, from 498 neuroblastoma samples published as part of the Sequencing Quality Control initiative. TARGET, contains microarray data from 249 samples and is part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. ACE2, CD147, PPIA and PPIB were identified through their involvement in both SARS-CoV-2 infection and cancer pathogenesis. In-depth statistical analysis using Kaplan-Meier, differential gene expression, and Cox multivariate regression analysis, demonstrated that overexpression of ACE2, CD147, PPIA and PPIB is significantly associated with poor-prognosis neuroblastoma samples. These results were seen in the presence of amplified MYCN , unfavourable tumour histology and in patients older than 18 months of age. Previously, we have shown that high levels of the nerve growth factor receptor NTRK1 together with low levels of the phosphatase PTPN6 and TP53 are associated with increased relapse-free survival of neuroblastoma patients. Interestingly, low levels of expression of ACE2, CD147, PPIA and PPIB are associated with this NTRK1-PTPN6-TP53 module, suggesting that low expression levels of these genes are associated with good prognosis. These findings have implications for clinical care and therapeutic treatment. The upregulation of ACE2, CD147, PPIA and PPIB in poor-prognosis neuroblastoma samples suggests that these patients may be at higher risk of severe SARS-CoV-2 infection. Importantly, our findings reveal ACE2, CD147, PPIA and PPIB as potential biomarkers and therapeutic targets for neuroblastoma.

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Section: Methodssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Analysis of SARS-CoV-2 infection associated cell entry proteins ACE2, CD147, PPIA, and PPIB in datasets from non SARS-CoV-2 infected neuroblastoma patients, as potential prognostic and infection biomarkers in neuroblastoma

Bergsneider

Bailey

Ahmed

et al. 2021

Biochemistry and Biophysics Reports

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“…Similar to gene fusion, the aberrant expression of NTRKs gene is a critical event in cancers. NTRK1 promoted proliferation and metastasis of cancer cells and lead to poor prognosis in multiple cancers [14][15][16][17][18], while it suppressed cell proliferation in neuroblastoma [19]. NTRK2 was shown to serve as an oncogene in multiple cancers [20][21][22][23], and its increased expression was associated with poor outcome [24,25].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer

et al. 2021

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Background Neurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers. We aimed to investigate the methylation and expression profiles and prognostic value of NTRKs gene in colorectal cancer (CRC). Methods An analysis of DNA methylation and expression profiles in CRC patients was performed to explore the critical methylations within NTRKs genes. The methylation marker was validated in a retrospectively collected cohort of 229 CRC patients and tested in other tumor types from TCGA. DNA methylation status was determined by quantitative methylation-specific PCR (QMSP). Results The profiles in six CRC cohorts showed that NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression. We identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC. NTRK3 promoter methylation showed independently predictive value for survival outcome in the validation cohort (P = 0.004, HR 2.688, 95% CI [1.355, 5.333]). Based on this, a nomogram predicting survival outcome was developed with a C-index of 0.705. Furthermore, the addition of NTRK3 promoter methylation improved the performance of currently-used prognostic model (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64, P = 0.032). Finally, NTRK3 promoter methylation also predicted survival in other tumors, including pancreatic cancer, glioblastoma and stomach adenocarcinoma. Conclusions This study highlights the essential value of NTRK3 methylation in prognostic evaluation and the potential to improve current prognostic models in CRC and other tumors.

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“…Similar to gene fusion, the aberrant expression of NTRKs gene is a critical event in cancers. NTRK1 promoted proliferation and metastasis of cancer cells and lead to poor prognosis in multiple cancers (13)(14)(15)(16)(17), while it suppressed cell proliferation in neuroblastoma (18). NTRK2 was shown to serve as an oncogene in multiple cancers (19)(20)(21)(22), and its increased expression was associated with poor outcome (23,24).…”

Section: Introductionmentioning

confidence: 99%

Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer

Chen

Huang

Luo

et al. 2020

Preprint

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Background: Neurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers. We aimed to investigate the methylation and expression profiles and prognostic value of NTRKs gene in colorectal cancer (CRC).Methods: An analysis of DNA methylation and expression profiles in CRC patients was performed to explore the critical methylations within NTRKs genes. The methylation marker was validated in a retrospectively collected cohort of 229 CRC patients and tested in other tumor types from TCGA. DNA methylation status was determined by quantitative methylation-specific PCR (QMSP).Results: The profiles in six CRC cohorts showed that NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression. We identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC. NTRK3 promoter methylation showed independently predictive value for survival outcome in the validation cohort (P = 0.004, HR = 2.688, 95% CI = [1.355, 5.333]). Based on this, a nomogram predicting survival outcome was developed with a C-index of 0.705. Furthermore, the addition of NTRK3 promoter methylation improved the performance of currently-used prognostic model (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64, P = 0.032). Finally, NTRK3 promoter methylation also predicted survival in other tumors, including pancreatic cancer, glioblastoma and stomach adenocarcinoma.Conclusions: This study highlights the essential value of NTRK3 methylation to evaluate prognosis risk, improve current prognostic models and the potential to guide treatment in CRC and other tumors.

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The presence of Y674/Y675 phosphorylated NTRK1 via TP53 repression of PTPN6 expression as a potential prognostic marker in neuroblastoma

Cited by 8 publications

References 33 publications

Analysis of SARS-CoV-2 infection associated cell entry proteins ACE2, CD147, PPIA, and PPIB in datasets from non SARS-CoV-2 infected neuroblastoma patients, as potential prognostic and infection biomarkers in neuroblastoma

Analysis of SARS-CoV-2 infection associated cell entry proteins ACE2, CD147, PPIA, and PPIB in datasets from non SARS-CoV-2 infected neuroblastoma patients, as potential prognostic and infection biomarkers in neuroblastoma

Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer

Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer

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