Literature review
Cancer is a group of more than 200 distinct diseases involving abnormal proliferation of cells with the potential to invade or metastasize to other normal tissues and organs [1].
Since 2010, cancer has been the leading cause of death in China with an estimated 4.29 million new cases and 2.81 million deaths in the year 2015 alone [2]. To effectively diag-nose and treat cancer, better understanding of the disease is required. The last century has witnessed a tremendous advance in our knowledge of cancer, and an emerging consensus is that cancer is a disease of the genome.
1.1 Cancer is a disease of the genome
More than a century ago, seminal studies on the development of doubly fertilized sea urchin eggs by Theodor Boveri led to the hypothesis that cancer is caused by chromoso-mal abnorchromoso-malities [3], in other words, cancer is “a disease of the genome”[4, 5]. At the beginning of the 20th century, cancer causing chemicals were discovered, however, their cellular targets have not yet been identified [6]. The discovery of DNA as the genetic material of inheritance [7] and the determination of its structure by Watson and Crick [8]
indicated that DNA was the cellular target for chemical carcinogens and that these agents generate mutations leading to cancer [6]. The role of genetic mutations in human cancer was confirmed by the discovery of translocation between chromosomes 9 and 22 (known as the “Philadelphia chromosome”) in chronic myeloid leukemia [9–11]. The discovery of the Philadelphia chromosome in almost all cases of a specific human cancer strongly supported Boveri’s hypothesis that a critical genetic alteration in a single cell could give rise to a tumor [12]. Advances in molecular techniques later allowed the identification of
critical genes involved in the Philadelphia chromosome: v-abl Abelson murine leukemia viral oncogene homolog (ABL) on chromosome 9 and breakpoint cluster region (BCR) on chromosome 22 [13]. The idea that cancer is a disease of an altered genome attracted wider attention following the discovery that transfer of total genomic DNA from tumor cells into other cells was sufficient to cause transformation [14, 15]. Cloning and char-acterization of the specific DNA segment responsible for the transformation led to the identification of the first oncogene—HRAS, followed by the discovery of the exact point mutation (G >T substitution) in codon 12 resulting in a glycine to valine substitution [16–18]. These landmark findings launched a new era of molecular cancer genetics re-search that continues to date: identification of mutated genes causally implicated in the development of human cancer (cancer genes) [4, 19].
1.1.1 Cancer genes: oncogenes and tumor suppressor genes
A major aim of cancer studies is to search for genes that are implicated in tumor ini-tiation and development. Based on whether mutations are dominant or recessive at the cellular level, cancer genes can be divided into oncogenes (dominant mutation, a single altered allele is sufficient to initiate cancer) and tumor suppressor genes (TSGs) (recessive mutation, both alleles need to be changed)[19].
The protein products of oncogenes include transcription factors, chromatin remodelers, growth factors, growth factor receptors, signal transducers, and apoptosis regulators [20].
Oncogenes are altered in ways that render them permanently active or active when they are not supposed to [21]. Oncogene activation can be achieved by chromosomal translo-cations, gene amplifitranslo-cations, intragenic mutations, or by changes in methylation [21]. A common translocation event in Burkitt’s lymphoma is a well-characterized example of oncogene activation. Translocations juxtapose MYC oncogene to the enhancer elements in the immunoglobulin loci on chromosomes 14q, 22q and 2p, thereby leading to tran-scriptional deregulation of MYC gene [22]. MYC protein, a transcription factor, plays an important role in cell cycle progression and cellular transformation. Amplification of ERBB2gene was found in some breast cancers, and is associated with poor clinical out-come [23]. Oncogene gain-of-function mutations often involve critical regulatory regions leading to continuously increased activity of the mutated protein. For example, the most common mutations ofBRAFgene, amino acid change of a valine to a glutamate at codon 599, results in elevated kinase activity and transformation capability [24].
1.1. CANCER IS A DISEASE OF THE GENOME TSGs normally act to inhibit inappropriate cell growth and division, stimulate apopto-sis, and repair DNA [25]. In many tumors, these genes are lost or inactivated by genetic or epigenetic alterations, including non-synonymous mutations, insertion or deletions of variable sizes, and epigenetic silencing [21]. Although for some TSGs haploinsufficiency (loss of only one allele) may contribute to carcinogenesis [26], mutation or loss of both al-leles is generally required to facilitate tumor progression [21]. The first tumor suppressor geneRB1was identified by studies of the genetic mechanisms underlying retinoblastoma, a rare childhood retinal tumor. Besides the inherited mutation in an allele ofRB1gene, a retinoblastoma patient normally has an additional mutation event or loss of heterozygosity (LOH) to inactivate the other allele [27]. Among TSGs, DNA repair genes are particularly important in prohibiting tumor development. These genes are responsible for correcting DNA mistakes during normal DNA replication or those induced by mutagens [21]. When these genes are inactivated, mutation rate will be elevated in other genes. Typical exam-ples includeBRCA1in breast and ovary cancers, andRECQL4in bone tumors.
1.1.2 A consistent cancer hallmark—genome instability
Although there are significant differences between cancer types, there are also properties shared by most if not all cancers. These properties, referred to as “cancer hallmarks”, in-clude but are not limited to self-sufficiency in growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis [28]. Genome instability is a consistent characteristic cru-cial to the acquisition of the hallmarks of cancer [29], and plays important roles in tumor initiation and progression. Genome instability is typically subdivided into three cate-gories: nucleotide instability, microsatellite instability and chromosomal instability [30].
Nucleotide instability is characterized by increased frequencies of base-pair mutations and small insertions and deletions. Microsatellite instability, which refers to the expan-sion and contraction of oligonucleotide repeats in microsatellites, is the consequence of impaired mismatch repair genes. Chromosomal instability, the most prevalent form of genome instability, refers to the changes in the structure and number of chromosomes in cancer cells compared with normal ones. Several mechanisms have been proposed to explain the source of genome instability: defects in DNA repair and mitotic checkpoint genes [30], telomere dysfunction [31], centrosome abnormality and replication stress [32].