ClinOmicsTrailbc 1.0
A visual analytics tool for breast cancer treatment stratification using multi-omics data
Biological background
The flow of genetic and regulatory information. This model is commonly used to explain how genotype and phenotype of a cell are related to each other. Basically, it can be seen as a model with different layers of regulation that finally lead to the expression of proteins or functional RNAs. The current state of those layers in a cell can be measured by various types of experiments. Each of those layers can help to depict which cellular processes are deregulated in comparison to a healthy cell. In the following, changes that are known to influence cellular behavior will be outlined. Additionally, examples of important genetic and epigenetic aberrations with known implications in breast cancer are given. Clicking on a respective panel heading will (de-)collapse the corresponding description.
Carcinogenesis is a multi-step process in which cells gradually evolve until they reach a certain state of malignancy. Despite the fact that during tumor progression different alterations occur, it is presumed that cancer cells still have several deregulations in common, which are involved in key regulatory cellular processes. These characteristics are well-known as the Hallmarks of Cancer proposed by Hanahan and Weinberg [1].
Healthy tissue is in a state known as homeostasis, which means that a balance between cell death and regeneration is persistently maintained. However, cancer cells manage to sustain chronic proliferation by a considerable amount of different mechanisms including increased expression of growth factor receptors or permanent activation of signaling pathways downstream of the respective receptors.
In order to maintain chronic proliferation, cancer cells must also ensure a stable supply of nutrients and offer possibilities to discard waste. These needs are often addressed by the sprouting of new blood and lymph vessels.
Another barrier to chronic proliferation is the negative regulation of proliferation by apoptosis-inducing mechanisms, often associated with tumor suppressors. Examples for such tumor suppressors are the tumor protein P53 (TP53) and the retinoblastoma protein (RB). TP53 can for example activate apoptosis in cases of high intracellular stress. One function of RB is to decide whether a cell enters the growth-and-division cycle or not. Another growth suppressing mechanism is contact inhibition. Connected to the evasion of growth suppression is the hallmark capability of resistance to cell death. For instance, the programmed cell death is initiated by increased levels of DNA damage, which for example can occur if a cell has undergone too many growth-and-division cycles leading to the depletion of chromosomal ends. Cancer cells manage to circumvent this procedure by gaining replicative immortality. It can be attained by the reactivation of telomerases that add suitable segments to the end of the chromosomes.
After the gain of many new properties and the loss of others, tumors can reach higher grades of malignancy by managing to invade other tissues or forming metastases. For this purpose, cancer cells loose their cell-cell contacts or develop cell-cell contact structures associated with mobility. More recently it has been stated that altered energy metabolism, which also supports chronic proliferation, and evasion of immune system destruction play key roles in carcinogenesis.
Hanahan and Weinberg name two enabling characteristics for the tumorigenic phenotypes described above. One of them is tumor-promoting inflammation. Inflammatory cells can have a positive effect on the growth of tumors by supplying molecules that stimulate cells to proliferate, and hence tumor growth is promoted. Those inflammatory cells are part of what Hanahan and Weinberg refer to as tumor microenvironment. The second enabling characteristic is the instability of the genome. Direct or indirect changes of the (epi)genome have many effects on the state of a cell, and thus tumor progression can be seen as a succession of changes to the encoding material.
Genomic alterations play an important role in genetic diversity, but they can also contribute to the manifestation of several diseases [2]. One classification of genomic alterations can be done by means of their size. Basically, large scale changes like numerical or structural aberrations of chromosomes or chromosome arms can be distinguished from changes only affecting a few nucleotides. One prominent large scale structural change is denoted as copy number variation (CNV). This term refers to changes in the genome that encompass more than 1 kb [3] and includes insertions, deletions and duplications of genomic regions. An example for a typical CNV in breast cancer is the amplification of the HER2 gene [4] , an epidermal growth factor receptor that stimulates proliferation. On a smaller scale, several point mutations in BRCA1, a tumor suppressor that is involved in repairing damaged DNA, are known to increase cancer susceptibility [5].
Not only the plain genetic code and its alterations are known to play an important role in tumorigenesis. Epigenetic alterations such as histone modifications or methylation pattern changes influence the packing of the DNA, and hence gene expression [6] [7]. Generally, a more tight packing of the DNA leads to a lower transcription rate. The nucleosome is the smallest unit of packed DNA. It consists of eight histones around which DNA is wrapped. Changes of the N-terminal tails of histones influence the accessibility of DNA and are also known to be linked to the deactivating methylation of the DNA in promoter regions [8]. CpG-islands are CpG-rich regions in the genome mostly associated with promoters. But CpG-rich regions can also be found in intergenic regions or gene bodies. Recent studies suggest that opposed to methylation of CpGs in promoter regions, methylation of gene bodies does not stop transcription or might even stimulate elongation. A typical example for hypermethylation of CpGs in promoter regions in breast cancer is RASSF1 [9]. RASSF1 is a tumor suppressor involved in apoptosis. Its expression is often repressed by hypermethylation of CpGs in the respective promoter region.
The formerly mentioned alterations change the abundance or the functionality of the transcribed genes. The abundance of transcribed genes in a cell at a particular point in time is called transcriptome and comprises various types of RNA: mRNAs that are translated into proteins, rRNAs that are part of the ribosomes that execute translation, tRNAs that are donors for the correct amino acid during translation and diverse other RNAs with distinct biological functions.
As already mentioned above, properly processed mRNAs can be translated into proteins. Nevertheless, not all transcripts are translated into proteins as they can be degraded before translation starts. Furthermore, they often need to be modified before they are in an active form. An example for an activating posttranslational modification is the phosphorylation of activator proteins like AKT, which is involved in many signaling pathways, e.g. the PI3K-AKT-mTOR-pathway. As proteins largely influence the phenotype of a cell, it is of importance to also measure their abundance and current activity.
Bibliography
- Hallmarks of cancer: the next generation Cell Elsevier
- Structural variation in the human genome Nature Reviews Genetics Nature Publishing Group
- Copy number variations and cancer Genome medicine BioMed Central
- HER2 expression in breast cancer primary tumours and corresponding metastases. Original data and literature review British journal of cancer Nature Publishing Group
- Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE JNCI: Journal of the National Cancer Institute Oxford University Press
- Functions of DNA methylation: islands, start sites, gene bodies and beyond Nature Reviews Genetics Nature Publishing Group
- Computational epigenetics Bioinformatics Oxford University Press
- Histone H2A. Z and DNA methylation are mutually antagonistic chromatin marks Nature Nature Publishing Group
- Ras uses the novel tumor suppressor RASSF1 as an effector to mediate apoptosis Journal of Biological Chemistry ASBMB