Genes and cancer
Cancer is a genetic disease that is triggered by altered genes. Cancer cells showed a deregulation of their gene profiles, that may caused the completely loss of cell homeostasis control, allowing cancer cells to reproduce without restraint and eventually to spread into neighboring tissues. Most cancers have roots in normal tissue cells that acquire random mutations, either as a mistake when cells are going through cell division or in response to injuries from environmental agents such as radiation or chemicals. Several hereditary factors can also increase the chance of cancer-causing mutations, including the activation of oncogenes or the inhibition of tumor suppressor genes.
Figure 1. Cancer development and progression is a complex process that involves a host of functional and genetic abnormalities. Tumors arise from uncontrolled cell division based on the loss of balance between cell division and cell differentiation. Defective cell cycle control mechanisms can lead to uncontrolled cell proliferation generating a tumor.
The role of a given gene in cancer progression may vary tremendously, depending on the stage and type of cancer involved. For this reason, a genome-wide scale profile of tumors from various tissues and at different stages, may be important to understand tumor progression and treatment success. In particular, microarray or real-time RT-PCR tecniques, can be useful in the classification or prognosis of various types of cancer.
Resistance to drugs is a major problem in cancer chemotherapy. Cancer cells, during cancer progression, may acquire a resistant phenotype, leading to their survival to cancer treatment (Figure 2).
Figure 2. Cancer actively defends itself through the activation of trans-membrane proteins that export chemotherapeutic agents such as to reduce the overall efficacy of therapeutics and lead to reduced survival rates in cancer patients.
Various cellular mechanisms of drug resistance have been identified in cultured tumor cell lines selected for growth in the presence of sub-lethal concentrations of various anticancer drugs. They involve drug transport and detoxification, qualitative or quantitative alterations of the drug target, repair of drug-induced DNA lesions, and alterations in signaling or execution of apoptosis.
Gene expression profile data may be useful also to explore the relationships between gene expression and sensitivity to several anticancer drugs. In numerous studies, researchers have used microarray technique, to identify genes governing tumor chemo-sensitivity. Some clinical studies have also been carried out to investigate whether tumor gene expression patterns could predict clinical response to chemotherapy. Results of these studies are encouraging, indicating that individualization of drug treatment based on multigenic response-predictive markers could be feasible.
The cancer signature challenge
As described before, gene signature profile may function as a prognostic tool, functional to understand the specific state/grade of a disease with accuracy that may facilitates selection of treatments.
The Trust Sanger Institute, one of the leader in the Human Genome Project, focused its interest on understanding the role of genetics in health and disease. In particular, they were able to develop different projects, focused on cancer research, as the Cancer Genome Project .
The Cancer Genome Project started in 2004 and its goal is to uncover the basis of genetic and infectious disease. In particular, the aim of this project was to identify sequence variants/mutations critical in the development of human cancers.
Using the human genome sequence and high throughput mutation detection techniques, they want to identify somatically acquired sequence variants/mutations and consequently detect genes critical in the development of human cancers. Moreover, they look forward to the discover of germline mutations in non-neoplastic human genetic diseases through genome-wide mutation detection approaches.
All the data derived from the Cancer Genome Project are collected in the COSMIC cancer database (Trust Sanger Institute).
The COSMIC cancer database, arose from the necessity to collect and document all the acquired genetic mutations from hundreds of thousands of human cancer sample. In particular, COSMIC is designed to store and display somatic mutation information and related details.
The database collects information from two major sources. Firstly, mutations in known cancer genes are collected from the literature. Secondly, data for inclusion in the database is collected from whole genome re-sequencing studies of cancer samples derived from the Cancer Genome Project.
|Cancer Cell Line Project|
|Genomics of Drug Sensitivity|
|CGP Trace and Genotype Archive|
|CGP Resequencing Studies|
|Cancer Gene Census|
Table 1. Structure of the COSMIC database.
Another interesting project, based on high throughput data analysis, is the Cancer Genome Atlas.
TCGA (started in 2005) is a project born to catalogue genetic mutations responsible for cancer, using genome analysis techniques. The National Cancer Institute and the National Human Genome Research Institute have selected the laboratories involved in this project. The goal of TCGA is to provide systematic, comprehensive genomic characterization and sequence analysis of three types of human cancers, glioblastoma multiforme, lung, and ovarian cancer.
All these large scale projects, involving about 350 different types of tumor, have identified ~130,000 mutations in ~3000 genes that resulted mutated in cancer. The majority occurred in 319 genes of which 286 were tumour supressor genes and 33 oncogenes.
Gene signature databases and projects
Molecular Signatures Database - GSEA | MSigDB
COSMIC cancer database
Cancer Genome Project
Cancer Genome Atlas
MicroRNAs (miRNAs) are a class of small noncoding RNAs of 19–23 nucleotides that derive from a 70-nucleotide precursor and function as post-transcriptional regulators of gene expression by either promoting degradation of target mRNAs or repressing their translation.
miRNAs were firstly described as gene expression regulators in Caenorhabditis elegans, and subsequently identified also as an abundant class of RNAs in plants, animals, and DNA viruses. About 3% of human genes encode for miRNAs and about 40–50% of mammalian mRNAs are thought to be regulated by miRNAs at the translational level. Based on their potential to target hundreds of different mRNAs, miRNAs may finely coordinate the transcriptome expression in the cell.
The functional consequence of miRNA action implicates a tight regulation of cellular development and differentiation by a complex and dynamic mechanism. Therefore alterations of miRNA pattern can lead to pathogenic consequences. In particular, miRNAs play a key role in different biological processes, including development, cell proliferation, differentiation, and apoptosis. Accordingly, altered miRNA expression is likely to contribute to human disease, including cancer.
Moreover, miRNAs have been described as potential regulators of self renewal, plasticity and differentiation potential of many stem cell types including mesenchymal stem cells.
This supports the theory that miRNA patterns may be used as signatures to define and track different cell populations.
MicroRNA Signature and cancer
With the advent of miRNA expression profiles, significant efforts have been made to correlate miRNA expressions with tumor prognosis.
Since one miRNA can regulate hundreds of downstream genes, the information gained from miRNA profiling may be complementary to that from the expression profiling of protein-coding genes. Moreover, recent reports even suggest that the expression profiling of miRNAs may be a more accurate method of classifying cancer subtype than using the expression profiles of protein-coding genes.
The miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours. Different reports demonstrated a general downregulation of miRNAs in tumors compared with normal tissues. Moreover, researchers have speculate that the abnormalities in miRNA expression showed in cancer, may similarly contribute to the generation or maintenance of ‘cancer stem cells’, recently proposed to be responsible for cancerous growth in both leukaemias and solid tumors.
All the studies focus on miRNA signature in pathological states as cancer, support different ideas:
* MiRNA profiling offers a new diagnostic tool for different types of cancer at different differentiation states, even for cancers of unknown origin.
- MiRNA profiling can be used for prognosis.
- Anti-miRNA oligonucleotides, antisense oligonucleotides and locked nucleic acid-modifier miRNAs or 'antagomirs' offer the ability to target specifically in vivo miRNAs.
- MiRNA-based gene therapy targeting deregulated miRNAs will be the future tool for cancer treatment.
- Using data from miRNA profiling and knowledge of familial history of a certain disease will help in developing miRNA-based personalized therapy.
miRNA signature databases