Journal of Cancer Therapy, 2012, 3, 797-809 http://dx.doi.org/10.4236/jct.2012.325101 Published Online October 2012 (http://www.SciRP.org/journal/jct) 797 Novel Methods in the Study of the Breast Cancer Genome: Towards a Better Understanding of the Disease of Breast Cancer Jian Li 1,2* , Xue Lin 1* , Nils Brünner 3 , Huanming Yang 2# , Lars Bolund 1,2# 1 Department of Biomedicine, University of Aarhus, Aarhus, Denmark; 2 BGI, Shenzhen, China; 3 Department of Veterinary Pathobi- ology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark. Email: # yanghm@genomics.org.cn, # bolund@hum-gen.au.dk Received August 15 th , 2012; revised September 17 th , 2012; accepted September 29 th , 2012 ABSTRACT Rapidly developing sequencing technologies and bioinformatic approaches have provided us with an unprecedented instrument allowing for an unbiased and exhaustive characterization of the cancer genome in genetic, epigenetic and transcriptomic dimensions. This review introduces recent exciting findings and new methodologies in genomic breast cancer research. With this development, cancer genome research will illuminate new delicate interactions between mo- lecular networks and thereby unravel the underlying biological mechanisms for cancer initiation and progression. It also holds promise for providing a molecular clock for the estimation of the temporal processes of tumorigenesis. These methods in combination with single cell sequencing will make it possible to construct a family tree elucidating the evo- lutionary lineage relationships between cell populations at single-cell resolution. The anticipated rapid progress in ge- nomic breast cancer research should lead to an enhanced understanding of breast cancer biology and guide us towards novel ways to ultimately prevent and cure breast cancer. Keywords: Breast Cancer Genome; Massively Parallel Sequencing; Pathway-Oriented Analysis; Mitochondrial Genome; Temporal Order of Aberrations; Single Cell Sequencing; Microbiome 1. Introduction Breast cancer is the second most commonly diagnosed cancer and seriously threatens women health [1]. As a complex disease, both genetics and environmental causes are implicated in the tumorigenesis of breast cancer. The catalogue of inherited or somatic mutations accumulated in a cancer genome encompasses substitutions of nucleo- tides, insertions and deletions, translocations and other chromosomal rearrangements as well as copy number changes [2]. Many efforts have been spent in the last decade to identify the spectrum of genes associated with breast cancer [3]. Genes, such as BRCA1 and BRCA2, with high penetrance mutations are involved in approxi- mately 70% of breast cancers in high-risk families. How- ever, they only account for a minority of all breast cancer cases [4]. In general, <10% of breast cancer cases are thought to be hereditary in a Mendelian fashion and usu- ally a somatic “second hit” in the homologous normal allele is required for disease development. Thus, to identify low penetrance susceptibility gene variants (inherited or somatically acquired) has become an area of interest in breast cancer research. Genome- wide association studies (GWAS) are commonly used for the search for correlations between disease incidence and genetics. GWAS routinely encompasses tens of thousands of patient samples and scans the full length of the ge- nomes [5]. GWAS have identified 25 genetic loci associ- ated with breast cancer risk [5]. Still, to date, GWAS can only account for 9% - 10% of breast cancers [5]. Even when considering all types of genetic studies, some 70% of breast cancer cases remain unexplained [5,6]. It has become obvious that genetic factors only account for part of the phenotypic variance [7]. Breast cancer develop- ment represents a multiple-step process and the risk in- creases with age. Environmental degenerative factors no doubt play an important role in breast cancer tumori- genesis. Epigenetic changes, including somatically ac- quired (and sometimes germ line transmitted) chemical modifications of DNA (without DNA sequence changes) as well as DNA binding small RNAs and proteins (e.g. histones), bridge the gap between genetics and the envi- ronment significantly improving our understanding of the * These two authors (Jian Li and Xue Lin) equally contributed to this work. # Corresponding authors. Copyright © 2012 SciRes. JCT