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Machine learning analysis identifies genes differentiating triple negative breast cancers.

ABSTRACT: Triple negative breast cancer (TNBC) is one of the most aggressive form of breast cancer (BC) with the highest mortality due to high rate of relapse, resistance, and lack of an effective treatment. Various molecular approaches have been used to target TNBC but with little success. Here, using machine learning algorithms, we analyzed the available BC data from the Cancer Genome Atlas Network (TCGA) and have identified two potential genes, TBC1D9 (TBC1 domain family member 9) and MFGE8 (Milk Fat Globule-EGF Factor 8 Protein), that could successfully differentiate TNBC from non-TNBC, irrespective of their heterogeneity. TBC1D9 is under-expressed in TNBC as compared to non-TNBC patients, while MFGE8 is over-expressed. Overexpression of TBC1D9 has a better prognosis whereas overexpression of MFGE8 correlates with a poor prognosis. Protein-protein interaction analysis by affinity purification mass spectrometry (AP-MS) and proximity biotinylation (BioID) experiments identified a role for TBC1D9 in maintaining cellular integrity, whereas MFGE8 would be involved in various tumor survival processes. These promising genes could serve as biomarkers for TNBC and deserve further investigation as they have the potential to be developed as therapeutic targets for TNBC.

SUBMITTER: Kothari C

PROVIDER: S-EPMC7320018 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Machine learning analysis identifies genes differentiating triple negative breast cancers.

Kothari Charu C Osseni Mazid Abiodoun MA Agbo Lynda L Ouellette Geneviève G Déraspe Maxime M Laviolette François F Corbeil Jacques J Lambert Jean-Philippe JP Diorio Caroline C Durocher Francine F

Scientific reports 20200626 1

Triple negative breast cancer (TNBC) is one of the most aggressive form of breast cancer (BC) with the highest mortality due to high rate of relapse, resistance, and lack of an effective treatment. Various molecular approaches have been used to target TNBC but with little success. Here, using machine learning algorithms, we analyzed the available BC data from the Cancer Genome Atlas Network (TCGA) and have identified two potential genes, TBC1D9 (TBC1 domain family member 9) and MFGE8 (Milk Fat G ...[more]

PMID: 32591639

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Project description:BackgroundNeoadjuvant chemotherapy (NAC) is the standard treatment for early-stage triple negative breast cancer (TNBC). The primary endpoint of NAC is a pathological complete response (pCR). NAC results in pCR in only 30-40% of TNBC patients. Tumor-infiltrating lymphocytes (TILs), Ki67 and phosphohistone H3 (pH3) are a few known biomarkers to predict NAC response. Currently, systematic evaluation of the combined value of these biomarkers in predicting NAC response is lacking. In this study, the predictive value of markers derived from H&E and IHC stained biopsy tissue was comprehensively evaluated using a supervised machine learning (ML)-based approach. Identifying predictive biomarkers could help guide therapeutic decisions by enabling precise stratification of TNBC patients into responders and partial or non-responders.MethodsSerial sections from core needle biopsies (n = 76) were stained with H&E and immunohistochemically for the Ki67 and pH3 markers, followed by whole-slide image (WSI) generation. The serial section stains in H&E stain, Ki67 and pH3 markers formed WSI triplets for each patient. The resulting WSI triplets were co-registered with H&E WSIs serving as the reference. Separate mask region-based CNN (MRCNN) models were trained with annotated H&E, Ki67 and pH3 images for detecting tumor cells, stromal and intratumoral TILs (sTILs and tTILs), Ki67+, and pH3+ cells. Top image patches with a high density of cells of interest were identified as hotspots. Best classifiers for NAC response prediction were identified by training multiple ML models and evaluating their performance by accuracy, area under curve, and confusion matrix analyses.ResultsHighest prediction accuracy was achieved when hotspot regions were identified by tTIL counts and each hotspot was represented by measures of tTILs, sTILs, tumor cells, Ki67+, and pH3+ features. Regardless of the hotspot selection metric, a complementary use of multiple histological features (tTILs, sTILs) and molecular biomarkers (Ki67 and pH3) resulted in top ranked performance at the patient level.ConclusionsOverall, our results emphasize that prediction models for NAC response should be based on biomarkers in combination rather than in isolation. Our study provides compelling evidence to support the use of ML-based models to predict NAC response in patients with TNBC.

Project description:BackgroundImmune checkpoint blockade (ICB) has been approved for the treatment of triple-negative breast cancer (TNBC), since it significantly improved the progression-free survival (PFS). However, only about 10% of TNBC patients could achieve the complete response (CR) to ICB because of the low response rate and potential adverse reactions to ICB.MethodsOpen datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were downloaded to perform an unsupervised clustering analysis to identify the immune subtype according to the expression profiles. The prognosis, enriched pathways, and the ICB indicators were compared between immune subtypes. Afterward, samples from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset were used to validate the correlation of immune subtype with prognosis. Data from patients who received ICB were selected to validate the correlation of the immune subtype with ICB response. Machine learning models were used to build a visual web server to predict the immune subtype of TNBC patients requiring ICB.ResultsA total of eight open datasets including 931 TNBC samples were used for the unsupervised clustering. Two novel immune subtypes (referred to as S1 and S2) were identified among TNBC patients. Compared with S2, S1 was associated with higher immune scores, higher levels of immune cells, and a better prognosis for immunotherapy. In the validation dataset, subtype 1 samples had a better prognosis than sub type 2 samples, no matter in overall survival (OS) (p = 0.00036) or relapse-free survival (RFS) (p = 0.0022). Bioinformatics analysis identified 11 hub genes (LCK, IL2RG, CD3G, STAT1, CD247, IL2RB, CD3D, IRF1, OAS2, IRF4, and IFNG) related to the immune subtype. A robust machine learning model based on random forest algorithm was established by 11 hub genes, and it performed reasonably well with area Under the Curve of the receiver operating characteristic (AUC) values = 0.76. An open and free web server based on the random forest model, named as triple-negative breast cancer immune subtype (TNBCIS), was developed and is available from https://immunotypes.shinyapps.io/TNBCIS/.ConclusionTNBC open datasets allowed us to stratify samples into distinct immunotherapy response subgroups according to gene expression profiles. Based on two novel subtypes, candidates for ICB with a higher response rate and better prognosis could be selected by using the free visual online web server that we designed.

Project description:BackgroundPathological complete response (pCR) is associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, only 30-40% of TNBC patients treated with neoadjuvant chemotherapy (NAC) show pCR, while the remaining 60-70% show residual disease (RD). The role of the tumor microenvironment in NAC response in patients with TNBC remains unclear. In this study, we developed a machine learning-based two-step pipeline to distinguish between various histological components in hematoxylin and eosin (H&E)-stained whole slide images (WSIs) of TNBC tissue biopsies and to identify histological features that can predict NAC response.MethodsH&E-stained WSIs of treatment-naïve biopsies from 85 patients (51 with pCR and 34 with RD) of the model development cohort and 79 patients (41 with pCR and 38 with RD) of the validation cohort were separated through a stratified eightfold cross-validation strategy for the first step and leave-one-out cross-validation strategy for the second step. A tile-level histology label prediction pipeline and four machine-learning classifiers were used to analyze 468,043 tiles of WSIs. The best-trained classifier used 55 texture features from each tile to produce a probability profile during testing. The predicted histology classes were used to generate a histology classification map of the spatial distributions of different tissue regions. A patient-level NAC response prediction pipeline was trained with features derived from paired histology classification maps. The top graph-based features capturing the relevant spatial information across the different histological classes were provided to the radial basis function kernel support vector machine (rbfSVM) classifier for NAC treatment response prediction.ResultsThe tile-level prediction pipeline achieved 86.72% accuracy for histology class classification, while the patient-level pipeline achieved 83.53% NAC response (pCR vs. RD) prediction accuracy of the model development cohort. The model was validated with an independent cohort with tile histology validation accuracy of 83.59% and NAC prediction accuracy of 81.01%. The histological class pairs with the strongest NAC response predictive ability were tumor and tumor tumor-infiltrating lymphocytes for pCR and microvessel density and polyploid giant cancer cells for RD.ConclusionOur machine learning pipeline can robustly identify clinically relevant histological classes that predict NAC response in TNBC patients and may help guide patient selection for NAC treatment.

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Machine learning analysis identifies genes differentiating triple negative breast cancers.

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Machine learning analysis identifies genes differentiating triple negative breast cancers.

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