ABOUT GENOME

Epithelial cells form a monolayer connected to adjacent epithelial cells through tight junctions. They have microcilia on the upper side, having a completely different function than the lateral side and basement. It is called the polarity of the cell. Due to these characteristics, epithelial cells perform their own tasks, such as absorbing and excreting substances into and out of our bodies.

Therefore, an epithelial cell must have an appropriate shape and must properly place various devices made of proteins within the cell. In addition, it is necessary to have a proper surrounding structure to perform the tasks by exchanging information with neighboring cells, such as fibroblasts, adipocytes, vascular endothelial cells, and nerve cells.

Tissues are completed through differentiation during the human embryonic developmental stage. However, they cannot retain the same shape and function without maintenance and repair after that.

Modern large-scale buildings and residential facilities are not simply physical structures. Instead, they have various functions specialized according to their use; such buildings have complex control systems for maintenance and repair. If the control systems fail to function, they will gradually become slumped and lose their original function.

Of course, a large number of mutations can make some differences because the repair function for DNA damage does not work perfectly. However, mutation is one of the many phenomena that cancer causes.

It is questionable whether the structural difference in some proteins can explain how all functions of normal cells are transformed in cancer cells.

Suppose the genome lost the ability to operate the proteome. The proteome would respond to changes in the environment inside and outside the cell, and the programs embedded in the genome would not work.

In cancer, therefore, 1) the cell loses its characteristics, 2) the proteome responds only to the microenvironment, 3) the proteomic system, which must stop cell division in response to DNA damage and repairs the damage, fails to function, and 4) uncontrolled cell division only appears. Eventually, a large number of mutations are bound to occur.

The pattern in gene relations increases the probability that the genome dwells in some transcriptional states. This lowers the entropy of the mRNA and drives the proteome toward a specific direction.

There is little difference between normal tissue samples because the characteristics of the cells are determined by the programs encoded in the DNA. Therefore, the entropy calculated with mRNA expression data obtained from several normal samples is low.

The only difference for each normal sample is the microenvironment; it functions solely as a ‘parameter’ of the programs encoded in the DNA. Because what determines the cell’s characteristics is encoded in the DNA, it is robust to the changes in the microenvironment. Therefore, in normal tissue, the effect of the microenvironment on the genome is mostly trivial.

The proteome has no room for embedding complex programs. When the programs in the DNA fail in operation, the genome depends on the proteome, and the patterns of gene relations become disordered. Therefore, the probability dwelling in each transcriptional state is no longer biased in cancer samples, and the entropy increases.

In cancer cells, the genome loses the ability to operate the proteome. The cancer genome becomes a passive device that produces mRNAs at the request of the proteome to replenish lacking or damaged proteins.

The microenvironment of cells has no program to play a role of a buffer. Unlike the normal genome, the cancer genome is directly affected by the microenvironment on its transcriptional state.

Therefore, along with an increase in entropy, the deviation from the normal state has a direction dependent on the microenvironment, and it is inevitably different for each sample. This is why personalized medicine is necessary for cancer treatment.

A good cancer treatment guideline can be determined when individual patients’ direction and degree of variation are specified. However, information obtained directly from the gene expression profiles of individual patients is minimal. Gene mutations may show some characteristics of individual cancer patients as a result of cancer, but too many variables are involved.

For personalized cancer treatment, the pattern in the breakdown of the functional system must be presented in precise numerical terms: the direction and degree to which the function of the genome in normal tissue is disrupted in cancer. Therefore, it is essential to make the functional state of the normal genome show first.

The degree to which each function of the normal genome is destroyed in an individual cancer patient is a key measure of personalized diagnosis.

For example, it is well known that estrogen receptor modulators are effective in the treatment of breast cancer patients with estrogen receptor (ER+). However, the drugs are not effective for all ER+ patients in practice.

A drug will have little effect if its drug target is included in a severely disrupted part of the patient’s genomic functional system.

Most cancer treatments have followed standard treatment guidelines depending on the diagnosis and stage of progression. However, cancer is a disease that originates from the functional transformation of the genomic system. The direction of the functional transformation is different for each patient, even with the same diagnosis.

We calculate the contribution of each gene to the functional transformation of the cancer genome from the normal genome and present it as a therapeutic target candidate.

COVID19 vaccines show that mRNAs and inhibitory RNAs can be used as cancer treatments. The RNAs are effective at the laboratory level, but finding the right target RNA for each patient will be the most critical issue among the tens of thousands of RNAs.

We hack into the genome’s function at the mRNA level to present the most effective therapeutic target.