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      Identifying Methylation Pattern and Genes Associated with Breast Cancer Subtypes

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          Abstract

          Breast cancer is regarded worldwide as a severe human disease. Various genetic variations, including hereditary and somatic mutations, contribute to the initiation and progression of this disease. The diagnostic parameters of breast cancer are not limited to the conventional protein content and can include newly discovered genetic variants and even genetic modification patterns such as methylation and microRNA. In addition, breast cancer detection extends to detailed breast cancer stratifications to provide subtype-specific indications for further personalized treatment. One genome-wide expression–methylation quantitative trait loci analysis confirmed that different breast cancer subtypes have various methylation patterns. However, recognizing clinically applied (methylation) biomarkers is difficult due to the large number of differentially methylated genes. In this study, we attempted to re-screen a small group of functional biomarkers for the identification and distinction of different breast cancer subtypes with advanced machine learning methods. The findings may contribute to biomarker identification for different breast cancer subtypes and provide a new perspective for differential pathogenesis in breast cancer subtypes.

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          Most cited references107

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          MicroRNAs: New Biomarkers for Diagnosis, Prognosis, Therapy Prediction and Therapeutic Tools for Breast Cancer

          Dysregulation of microRNAs (miRNAs) is involved in the initiation and progression of several human cancers, including breast cancer (BC), as strong evidence has been found that miRNAs can act as oncogenes or tumor suppressor genes. This review presents the state of the art on the role of miRNAs in the diagnosis, prognosis, and therapy of BC. Based on the results obtained in the last decade, some miRNAs are emerging as biomarkers of BC for diagnosis (i.e., miR-9, miR-10b, and miR-17-5p), prognosis (i.e., miR-148a and miR-335), and prediction of therapeutic outcomes (i.e., miR-30c, miR-187, and miR-339-5p) and have important roles in the control of BC hallmark functions such as invasion, metastasis, proliferation, resting death, apoptosis, and genomic instability. Other miRNAs are of interest as new, easily accessible, affordable, non-invasive tools for the personalized management of patients with BC because they are circulating in body fluids (e.g., miR-155 and miR-210). In particular, circulating multiple miRNA profiles are showing better diagnostic and prognostic performance as well as better sensitivity than individual miRNAs in BC. New miRNA-based drugs are also promising therapy for BC (e.g., miR-9, miR-21, miR34a, miR145, and miR150), and other miRNAs are showing a fundamental role in modulation of the response to other non-miRNA treatments, being able to increase their efficacy (e.g., miR-21, miR34a, miR195, miR200c, and miR203 in combination with chemotherapy).
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            A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer.

            To compare clinical, immunohistochemical (IHC), and gene expression models of prognosis applicable to formalin-fixed, paraffin-embedded blocks in a large series of estrogen receptor (ER)-positive breast cancers from patients uniformly treated with adjuvant tamoxifen. Quantitative real-time reverse transcription-PCR (qRT-PCR) assays for 50 genes identifying intrinsic breast cancer subtypes were completed on 786 specimens linked to clinical (median follow-up, 11.7 years) and IHC [ER, progesterone receptor (PR), HER2, and Ki67] data. Performance of predefined intrinsic subtype and risk-of-relapse scores was assessed using multivariable Cox models and Kaplan-Meier analysis. Harrell's C-index was used to compare fixed models trained in independent data sets, including proliferation signatures. Despite clinical ER positivity, 10% of cases were assigned to nonluminal subtypes. qRT-PCR signatures for proliferation genes gave more prognostic information than clinical assays for hormone receptors or Ki67. In Cox models incorporating standard prognostic variables, hazard ratios for breast cancer disease-specific survival over the first 5 years of follow-up, relative to the most common luminal A subtype, are 1.99 [95% confidence interval (CI), 1.09-3.64] for luminal B, 3.65 (95% CI, 1.64-8.16) for HER2-enriched subtype, and 17.71 (95% CI, 1.71-183.33) for the basal-like subtype. For node-negative disease, PAM50 qRT-PCR-based risk assignment weighted for tumor size and proliferation identifies a group with >95% 10-year survival without chemotherapy. In node-positive disease, PAM50-based prognostic models were also superior. The PAM50 gene expression test for intrinsic biological subtype can be applied to large series of formalin-fixed, paraffin-embedded breast cancers, and gives more prognostic information than clinical factors and IHC using standard cut points. ©2010 AACR.
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              A study of cross-validation and bootstrap for accuracy estimation and model selection in

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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                31 August 2019
                September 2019
                : 20
                : 17
                : 4269
                Affiliations
                [1 ]School of Life Sciences, Shanghai University, Shanghai 200444, China
                [2 ]College of Information Engineering, Shanghai Maritime University, Shanghai 201306, China
                [3 ]Shanghai Key Laboratory of PMMP, East China Normal University, Shanghai 200241, China
                [4 ]Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China
                [5 ]Institute of Image Processing and Pattern Recognition, Shanghai Jiao Tong University, and Key Laboratory of System Control and Information Processing, Ministry of Education of China, Shanghai 200240, China
                [6 ]IDLab, Department for Electronics and Information Systems, Ghent University, 9000 Ghent, Belgium
                [7 ]Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
                Author notes
                [* ]Correspondence: tohuangtao@ 123456126.com (T.H.); cai_yud@ 123456126.com (Y.-D.C.); Tel.: +86-21-5492-3269 (T.H.); +86-21-6613-6132 (Y.-D.C.)
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-3068-1583
                https://orcid.org/0000-0002-0295-3994
                https://orcid.org/0000-0003-1975-9693
                https://orcid.org/0000-0001-5664-7979
                Article
                ijms-20-04269
                10.3390/ijms20174269
                6747348
                31480430
                06c99473-1ab0-44c6-afa1-ac40356da4cc
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 01 August 2019
                : 29 August 2019
                Categories
                Article

                Molecular biology
                breast cancer,subtype,methylation,pattern,multi-class classification
                Molecular biology
                breast cancer, subtype, methylation, pattern, multi-class classification

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