title: Integrative genomic and transcriptomic analysis for pinpointing recurrent alterations of plant homeodomain genes and their clinical significance in breast cancer.
abstract: A wide range of the epigenetic effectors that regulate chromatin modification, gene expression, genomic stability, and DNA repair contain structurally conserved domains called plant homeodomain (PHD) fingers. Alternations of several PHD finger-containing proteins (PHFs) due to genomic amplification, mutations, deletions, and translocations have been linked directly to various types of cancer. However, little is known about the genomic landscape and the clinical significance of PHFs in breast cancer. Hence, we performed a large-scale genomic and transcriptomic analysis of 98 PHF genes in breast cancer using TCGA and METABRIC datasets and correlated the recurrent alterations with clinicopathological features and survival of patients. Different subtypes of breast cancer had different patterns of copy number and expression for each PHF. We identified a subset of PHF genes that was recurrently altered with high prevalence, including PYGO2 (pygopus family PHD finger 2), ZMYND8 (zinc finger, MYND-type containing 8), ASXL1 (additional sex combs like 1) and CHD3 (chromodomain helicase DNA binding protein 3). Copy number increase and overexpression of ZMYND8 were more prevalent in Luminal B subtypes and were significantly associated with shorter survival of breast cancer patients. ZMYND8 was also involved in a positive feedback circuit of the estrogen receptor (ER) pathway, and the expression of ZMYND8 was repressed by the bromodomain and extra terminal (BET) inhibitor in breast cancer. Our findings suggest a promising avenue for future research-to focus on a subset of PHFs to better understand the molecular mechanisms and to identify therapeutic targets in breast cancer.
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.|College of Basic Medicine, Jilin University, Changchun, China.
authors.forename: Huimei
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Lanxin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Shan
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Chu
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.|Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors.forename: Zeng-Quan
authors.initials: ZQ
authors.lastname: Yang
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D053208:Kaplan-Meier Estimate; D010802:Phylogeny; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C493258:PHF11 protein, human; C000588559:PHF20L1 protein, human; C523053:PHF23 protein, human; D014157:Transcription Factors
keywords: breast cancer; copy number alteration; histone modification; plant homeodomain