Mack et al studied subtypes of three ependymoma(same histopathology) brain tumors and found that one subtype carries an intrachromosomal translocation that creates a new tumor-driving gene, another lacks tumor-driving mutations but has aberrant epigenetic modifications, and a third shows neither gene mutations nor epigenetic aberrations. There were three genotype but one cancer phenotype. Similarly Martincorena and colleagues found thousands of mutations in cancer-relevant genes, including cancer-driver genes, in normal eyelid epidermis .(multiple cancer genotypes but no cancer phenotype).
In disparate classes of biological systems, there are more genotypes than phenotypes. Where sufficient information exists to enumerate these phenotypes, there are exponentially more genotypes than phenotypes, as a function of the number of system parts. This means that any one phenotype typically has many genotypes that form it.
In a brief, cancer is the decision of the cell to choose the innovative/adaptive phenotype and understanding the genotype does not mean understanding cancer.
References
1. Mack, S. C., Witt, H., Piro, R. M., Gu, L., Zuyderduyn, S., Stütz, A. M., et al. (2014). Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506, 445–450.
2. Martincorena, I., Roshan, A., Gerstung, M., Ellis, P., Van Loo, P., McLaren, S., et al. (2015). High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886.
Hi Mesut,
One potential cause of tumor #3 not appearing to be driven by standard genetic mutations nor epi-mutations is that these studies rarely examine miRNA genes which are read and regulated by the same mechanisms as messenger RNA. Alterations at these sites can then "buffer" gene expression and affect phenotype without direct gene mutation nor inappropriate epigenetic modification.
Of course phenotype is a plastic phenomena, and there are many papers where
tissue cells bearing genetic mutations or epi-mutations continue to present a normal phenotype due to the interaction with the micro-environment that provides phenotype stabilizing signals, both mechanical and chemical. The problem is that the plasticity of phenotype allows these cells to become "stem cell like" due to rare combinations of events. Mutations, and epimutations in cells going through a normal developmental pathway usually do not result in a metastatic tumor because terminal differentiation and environmental interactions prevent this.
We now understand that in liver all brain specific genes are complexed/compacted into a form that is unreadable, the same being true of the brain, where liver specific genes are made unavailable to transcription (but not absolutely). However, each tissue cell can have differences in the expression of these tissue specific genes along with the degree of expression of "house keeping genes needed in most cell types" resulting in cells with different gene expression being close enough in phenotype to be regarded as having the same phenotype, e.g, liver cells.
Thus, this is not just a phenomena of Cancer, but occurs throughout the body to provide tissue cells the ability to function in unique ways, even if only slightly different from each other, i.e., there is no direct correlation between phenotype and genotype and each cancer cell within a category may and likely does have it's own miRNA, epigenetic and genetic defects (lets not forget about the role of long noncoding RNA in defining developmental pathways as well, which is also often aberrant) but is still regarded as having the same phenotype.
Best Regards,
Randall
no - your conclusion is much too simple because you just classify the phenotype differently - with a different degree of detail than the genotype:
1) the genotype you measure in detail in the terms of the numbers of mutations...
2) the genotype you just classify by what?
a) that it is a certain cell-typ originating from
b) that the morphology of the cell
c) that you can stain it with this or that
d) that you have how many cellular markers...
??? already how many parameters? how many combinations?
in consequence: the question is, whether your classification scheme is reflecting fine enough the different phenotypes which might exist...
now in terms of a phase transition in the form of differentiation, of course this is a cumulated effect => it could mean
a) different fine-grained phenotype with multiple fine-leveled genotypes
a) same overall phenotype with multiple fine-leveled genotypes
b) same overall phenotype with same overall genotype
==> in reality you always have a mixture of this...
BUT in the end genotype will also and only produce one detailed phenotype - why? because the phenotype is always entangled inseparably from your genotype.
that some details of a genotype are perhaps levelled-off in a phenotype might be one thing in a static view, but very likely might not during the evolution (although it could)...
For sure, with the worse genotype you can imagine inside a cell, if it induces no replication anomalies, no phenotype changes, it's not a cancer, but you know the process from promotion, initiation, in situ carcinoma, local spread, distant metastasis, could be based in same genotype, but have different apperances.
Biological events are better followed, tracked, filmed, than photographed or dissected. Tahnks. Regards. Gesund +
Dear Matthias;
I am asking again: genotype? or phenotype?
If ,understanding cancer genotype is understanding cancer, why we can't solve the cancer mystery?(please look -Cancer Genome Anatomy Project)
Second question: phenotype-first approach or genotype first approach: which is the best way to understand cancer? or an alternative approach? what is yours?
Somatic mutant clones colonize the human esophagus with age
Iñigo Martincorena1,*,†, et. al.
Science 23 Nov 2018: Vol. 362, Issue 6417, pp. 911-917 DOI: 10.1126/science.aau3879
The mutational burden of aging
As people age, they accumulate somatic mutations in healthy cells. About 25% of cells in normal, sun-exposed skin harbor cancer driver mutations. What about tissues not exposed to powerful mutagens like ultraviolet light? Martincorena et al. performed targeted gene sequencing of normal esophageal epithelium from nine human donors of varying age (see the Perspective by Chanock). The mutation rate was lower in esophagus than in skin, but there was a strong positive selection of clones carrying mutations in 14 cancer-associated genes. By middle age, more than half of the esophageal epithelium was colonized by mutant clones. Interestingly, mutations in the cancer driver gene NOTCH1 were more common in normal esophageal epithelium than in esophageal cancer.
Science, this issue p. 911; see also p. 893
Abstract
The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter. In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with NOTCH1 and TP53 mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of NOTCH1 mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and aging.
Hi Mesut,
Here is the thing, genotype and phenotype are like ying and yang. Genotypic alterations are an essential component of cancer cell phenotype and the fact that somatic cells can harbor "cancer related" mutations and yet predominantly continue to function within their tissue Milieu demonstrates that a mutated genotype is often not sufficient for the generation of metastatic cancers. There is a large body of literature showing the stabilizing effect of the cellular environment on otherwise mutated cells which continue their tissue specific function (phenotype).
BUT
We now know that the whole genome is transcribed and that aberrant epi-mutations, i.e., changes in histone modification and subsequently DNA methylation that affect the accessibility of genes to the transcriptional machinery independent of DNA sequence is also an essential step in oncogenesis in almost all cancers. This includes epimutations occur at both protein coding and noncoding RNA loci, including miRNA genes which together with actual DNA mutations can then alter cell phenotype towards uncontrolled cell division and enhanced cell mobility producing metastatic cancer.
Often the contribution of these non-genotype factors are enough to sway phenotype from functional to pathological.
This older paper explains the role of miRNA epimutaion in oncogenesis quite well.
Article A microRNA DNA methylation signature for human cancer metastasis
From my perspective then, phenotype is a combination of gene and regulatory RNA expression altered by mutation, epimutation, and the regulatory factors both physical and chemical within the tissues cellular milieu. Together these factors dictate whether a cell continues to function within the "normal" range of phenotypic variation or becomes phenotypically pathological.
The situation is more complex than simply which is most important because phenoype and genotype are interrelated, the ying to the others yang and are modified by so many intrinsic and external factors.
This is recent, and seems addressing your question:
The paradox of mutations and cancer
Gene mutation is not sole reason of cancer. If cell/genome compensate the genetic mutation (genome is not a pack of genes, gene is a part of the genome, topology gene networks etc. are other important parts of the genome concept) homeostasis continues (low entropy) If not, genome seeks for a new solution for adaptation (to reduce entropy-disequilibrium/ chaotic search).
I think that, genome, entropy, adaptation terms can explain Martincorenas findings.
I emphatically agree, Mesut!
That is the explaination at a more grand level.
It takes a reversal of entropy and the expenditure of massive amounts of energy for a "tissue" cell with all the "genetic" mutations necessary for malignant transformation to undergo epithelial to mesenchymal transition, or to re-sort the relative distribution of silencing and enhancing histone modifying complexes in order to gain "cancer stem cell like" properties. Even when a cell is really messed up and has no way of undergoing apoptosis or senescence, it is alot "easier" for it to follow the differntiation to death pattern of its tissue-mates than it is to declare anarchy against the body and spread wildly.
If you consider that 'ESMO Glossary on Molecular Biology' includes just the names of genes, enzymes, or its products, that each page includes tenths of different names, and that the booklet has hundreds of pages, you'll begin to build a mental image of the issue 'genotype-phenotype'.
The first time I watched a 'Kinome', the memory of 'The head of Gorgon' came to my mind.
Hard task!
Regards. Salut +
Cancer is chronic, genetic disease, with all the evolutionary aspects, selection, progression, transformation. We will learn more about cancer, but it always reminds us to treat individuals, rather than statistics. And with such a personalized appr, will “ cure” cancer before goes in a non return cycle.
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