A multi-step classifier addressing cohort heterogeneity improves performance of prognostic biomarkers in three cancer types

Patrick, Ellis; Schramm, Sarah-Jane; Ormerod, John T.; Scolyer, Richard A.; Mann, Graham J.; Mueller, S.; Yang, Yee Hwa

doi:10.18632/oncotarget.13203

Cited by 10 publications

(11 citation statements)

References 19 publications

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“…Mechanistically, this blockade would disrupt bi-directional cross-talk between the melanoma cells and stromal fibroblasts which allow the tumors to amplify a drug-resistant niche. Genomic studies have clearly demonstrated the evolution of genetic heterogeneity in melanoma in the course of tumor progression and metastasis formation ( 41 , 42 ). The tumor microenvironment seems to participate in the tumor evolution by the formation of a suitable cellular ecosystem supporting its progression ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

Microenvironment‑driven resistance to B‑Raf inhibition in a melanoma patient is accompanied by broad changes of gene methylation and expression in distal fibroblasts

et al. 2018

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The incidence of malignant melanoma is rapidly increasing and current medicine is offering only limited options for treatment of the advanced disease. For B-Raf mutated melanomas, treatment with mutation-specific drug inhibitors may be used. Unfortunately, tumors frequently acquire resistance to the treatment. Tumor microenvironment, namely cancer-associated fibroblasts, largely influence this acquired resistance. In the present study, fibroblasts were isolated from a patient suffering from acrolentiginous melanoma (Breslow, 4.0 mm; Clark, IV; B-Raf V600E mutated). The present study focused on the expression of structural and functional markers of fibroblast activation in melanoma-associated fibroblasts (MAFs; isolated prior to therapy initiation) as well as in autologous control fibroblasts (ACFs) of the same patient isolated during B-Raf inhibitor therapy, yet before clinical progression of the disease. Analysis of gene transcription was also performed, as well as DNA methylation status analysis at the genomic scale of both isolates. MAFs were positive for smooth muscle actin (SMA), which is a marker of myofibroblasts and the hallmark of cancer stoma. Surprisingly, ACF isolated from the distant uninvolved skin of the same patient also exhibited strong SMA expression. A similar phenotype was also observed in control dermal fibroblasts (CDFs; from different donors) exclusively following stimulation by transforming growth factor (TGF)-β1. Immunohistochemistry confirmed that melanoma cells potently produce TGF-β1. Significant differences were also identified in gene transcription and in DNA methylation status at the genomic scale. Upregulation of SMA was observed in ACF cells at the protein and transcriptional levels. The present results support recent experimental findings that tumor microenvironment is driving resistance to B-Raf inhibition in patients with melanoma. Such an activated microenvironment may be viable for the growth of circulating melanoma cells.

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Section: Discussionmentioning

confidence: 99%

Microenvironment‑driven resistance to B‑Raf inhibition in a melanoma patient is accompanied by broad changes of gene methylation and expression in distal fibroblasts

et al. 2018

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“…These studies have however identified similar GO categories of interest for prognostic impact, for example related to immune response and proliferation. A strategy to overcome the problem with tumor heterogeneity could be to use a combination of different prognostic variables, including clinicopathological variables, to better predict clinical outcome [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Presence of immune cells, low tumor proliferation and wild type BRAF mutation status is associated with a favourable clinical outcome in stage III cutaneous melanoma

et al. 2017

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BackgroundThe variable prognosis in stage III cutaneous melanoma is partially due to unknown prognostic factors. Improved prognostic tools are required to define patients with an increased risk of developing metastatic disease who might benefit from adjuvant therapies. The aim was to examine if cellular immune markers in association with tumor proliferation rate and BRAF mutation status have an impact on prognosis in stage III melanoma.MethodsWe have used two sets of case series with stage III disease: 23 patients with short survival (≤ 13 months) and 19 patients with long survival (≥ 60 months). Lymph node metastases were analyzed for Ki67, CD8 and FOXP3 protein expression using immunohistochemistry. BRAF mutation status was analyzed in a previous study on the same samples.ResultsLow tumor proliferation rate was significantly associated with a better prognosis (p = 0.013). Presence of FOXP3+ T cells was not correlated to adverse clinical outcome. A highly significant trend for a longer survival was found in the presence of an increasing number of markers; CD8+ and FOXP3+ T cells, low tumor proliferation and BRAF wildtype status (p = 0.003). Presence of at least three of these four markers was found to be an independent favorable prognostic factor (OR 19.4, 95% CI 1.9-197, p = 0.012), when adjusting for ulceration and number of lymph node metastases. Proliferation alone remained significant in multivariate analyses (OR 26.1, 95% CI 2.0-344, p = 0.013) but with a wider confidence interval. This panel still remained independent when also adjusting for a previously identified prognostic glycolytic-pigment panel.ConclusionsWe have demonstrated that presence of immune cells in association with tumor proliferation and BRAF mutation status may further contribute to identify stage III melanoma patients with high risk of relapse.

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“…Similar concepts of identifying cohort heterogeneity to improve prediction performance have been developed in other omics settings and for other diseases 28,29 . However, simple adaptations of methodologies developed for other omics platforms remain challenging as these do not account for the hierarchical taxonomic structure observed in the study of the diet-microbiome-host interaction.…”

Section: Introductionmentioning

confidence: 95%

NEMoE: A nutrition aware regularized mixture of experts model addressing diet-cohort heterogeneity of gut microbiota in Parkinson’s disease

Xu¹,

Lubomski

Holmes

et al. 2021

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The microbiome plays a fundamental role in human health and diet is one of the strongest modulators of the gut microbiome. However, interactions between microbiota and host health are complex and diverse. Understanding the interplay between diet, the microbiome and health state could enable the design of personalized intervention strategies and improve the health and wellbeing of affected individuals. A common approach to this is to divide the study population into smaller cohorts based on dietary preferences in the hope of identifying specific microbial signatures. However, classification of patients based solely on diet is unlikely to reflect the microbiome-host health relationship or the taxonomic microbiome makeup. To this end, we present a novel approach, the Nutrition-Ecotype Mixture of Experts (NEMoE) model, for establishing associations between gut microbiota and health state that accounts for diet-specific cohort variability using a regularized mixture of experts model framework with an integrated parameter sharing strategy to ensure data driven diet-cohort identification consistency across taxonomic levels. The success of our approach was demonstrated through a series of simulation studies, in which NEMoE showed robustness with regard to parameter selection and varying degrees of data heterogeneity. Further application to real-world microbiome data from a Parkinson’s disease cohort revealed that NEMoE is capable of not only improving predictive performance for Parkinson’s Disease but also for identifying diet-specific microbiome markers of disease. Our results indicate that NEMoE can be used to uncover diet-specific relationships between nutritional-ecotype and patient health and to contextualize precision nutrition for different diseases.

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A multi-step classifier addressing cohort heterogeneity improves performance of prognostic biomarkers in three cancer types

Cited by 10 publications

References 19 publications

Microenvironment‑driven resistance to B‑Raf inhibition in a melanoma patient is accompanied by broad changes of gene methylation and expression in distal fibroblasts

Microenvironment‑driven resistance to B‑Raf inhibition in a melanoma patient is accompanied by broad changes of gene methylation and expression in distal fibroblasts

Presence of immune cells, low tumor proliferation and wild type BRAF mutation status is associated with a favourable clinical outcome in stage III cutaneous melanoma

NEMoE: A nutrition aware regularized mixture of experts model addressing diet-cohort heterogeneity of gut microbiota in Parkinson’s disease

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