Genetic alterations of histone lysine methyltransferases and their significance in breast cancer.

Lanxin Liu,Zeng-Quan Yang,Hui Liu,Sarah Kimball,Andreana Holowatyj

doi:10.18632/oncotarget.2967

Abstract

Histone lysine methyltransferases (HMTs), a large class of enzymes that catalyze site-specific methylation of lysine residues on histones and other proteins, play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of HMTs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of approximately 50 HMTs in breast cancer and identified associations among recurrent copy number alterations, mutations, gene expression, and clinical outcome. We identified 12 HMTs with the highest frequency of genetic alterations, including 8 with high-level amplification, 2 with putative homozygous deletion, and 2 with somatic mutation. Different subtypes of breast cancer have different patterns of copy number and expression for each HMT gene. In addition, chromosome 1q contains four HMTs that are concurrently or independently amplified or overexpressed in breast cancer. Copy number or mRNA expression of several HMTs was significantly associated with basal-like breast cancer and shorter patient survival. Integrative analysis identified 8 HMTs (SETDB1, SMYD3, ASH1L, SMYD2, WHSC1L1, SUV420H1, SETDB2, and KMT2C) that are dysregulated by genetic alterations, classifying them as candidate therapeutic targets. Together, our findings provide a strong foundation for further mechanistic research and therapeutic options using HMTs to treat breast cancer.

Highlights

Breast cancer is the most common cancer among women worldwide, with 1.3 million women diagnosed each year and about 500,000 deaths per year from the disease
Histone lysine methyltransferases (HMTs) copy number and expression are associated with breast cancer patient survival To investigate the clinical relevance of genetic alterations of HMTs in breast cancer, we examined the relationship between HMT copy number, mRNA expression, and overall patient survival in 770 of 958 breast cancer samples for which detailed survival data were available
We discovered that deletion of KMT2C was significantly associated with shorter survival, and amp/gain of this gene was significantly associated with longer survival, compared with patients who had no change in copy number (Figure 6A)

Summary

Introduction

Breast cancer is the most common cancer among women worldwide, with 1.3 million women diagnosed each year and about 500,000 deaths per year from the disease. Five intrinsic molecular subtypes of human breast cancer include Luminal A, Luminal B, human epidermal growth factor receptor 2 (HER2/ ERBB2)-positive, basal-like, and normal-like breast cancer [2, 3]. Basal-like breast cancer is especially aggressive as it includes tumors that lack ER, progesterone receptor (PR), and HER2 expression ( the name “triple-negative”) [5, 6]. These characteristics render conventional therapies ineffective and lead to poor prognosis. By understanding the genetic and epigenetic abnormalities that are associated with the different types of breast cancer, we can identify new subtype-specific targets for therapy

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