Possible relationship between the somatic mutations and the formation of cancers

. Cancer is one of the most life-threatening diseases and has been studied for more than 3 thousand years (earliest records of cancer research is 1500BC). But there are still insufficient number of efficient treatments for cancer. This is a review started with introducing the cancer and somatic mutations by explaining the hallmarks of cancer, followed by, the discussion of few types of mutations, which may be potential targets regarding to the therapeutic treatments. Also, some potential targets related to those mutations are listed, such as, pRb proteins with its two subunits (p130 and p107), reverse transcriptase telomerase (TERT), shelterin complex and so on. The statement “cancer is caused by accumulation of somatic mutations” can be supported by the positive correlation between cancer and age. In addition, some mutations, which have contribution on increasing mutation frequencies, has been proved to be the factors of cancer. For example, xeroderma pigmentosum, mutations on DNA MMR rep air and BRCA1 and BRCA2 mutations. This overview of the relationship between cancer and those somatic mutations, which may provide potentials for further cancer treatments.


Introduction
The earliest recorded case of cancer was discovered from ancient Egypt in 1500BC, and evidence suggests that there is no treatment. (Sudhakar, 2009) As the technology developing, different types of cancer start to be found and the definition of cancer starts to be clarified. Cancer is classified in different ways. The simplest classification is according to the position where cancer grows on, e.g., breast cancer, lung cancer. Scientists found that most types of cancer are caused by mutations. (Ponder, 2001) Therefore, modern technology starts to classify cancer according to their genetic differences by FS methods. (Alhenawi et al., 2021) From this classification, targets are easier to be determinate. Thus, treatments which focus on specific mutated proteins can be applied on a group of patients rather than one patient. Cancer is a group of cells grows uncontrollably in a certain section. (Sporn, 1996) There are six hallmarks of cancer that has been discussed in 2000. (Hanahan and Weinberg, 2000) These hallmarks are self-sufficiency in growth signals; insensitivity to anti-growth signals; tissue invasion and metastasis; limitless replicative potential; sustained angiogenesis and evading apoptosis. This suggests that to form a cancer, the growth and anti-growth signals are functional abnormally. For cancer grow uncontrollably, there are multiple ways to keep cell dividing. But in general, these mechanisms lead to the cells lost controlling of cell cycles by mistakes in signals. (Golias et al., 2004) Also, telomerase is continuing to produce telomere repeats to let cell replicate without limit. In addition, apoptosis must be defective, so abnormal cells cannot kill themselves. Somatic mutations are mutations which occurs after body development. Multiple factors lead to this type of mutations. For examples, radiations are one of the most obvious factors of somatic mutations. (Balmain, 2020) Somatic mutations might also occur during the cell divisions and some somatic mutations taken pace spontaneously. (Martincorena and Campbell, 2015) Those somatic mutations change the DNA sequence. Sometimes, somatic mutations may occur on some important positions (e.g., DNA region coding for growth signals and anti-growth signals receptors, telomere section or DNA region coding for telomerase, etc.) and lead to the cancer.

Somatic mutations related to cancer
There are some examples of the somatic mutations which contribute for the cancer formation. Firstly, the insensitivity of anti-growth signals of cells may be caused by the genetic interruption on retinoblastoma protein (pRb) pathway. In the normal cells, during G1 phase, nearly all antigrowth signals are controlled by retinoblastoma protein (pRb) and its two relatives, p107 and p130. (Wang et al., 2019) The combination of oncogene c-MYC and transforming growth factor TGF-alpha causes the loss of RB1 gene. This affects the pRb proteins with their two subunits and E2F family members thus the pathway is interrupted. (Di Fiore et al., 2013) Failure of antigrowth signals transmission leads cells dividing uncontrollably. Excess telomeres raise the limitless replicative potentials of cells. The length of telomere DNA is maintained by the reverse transcriptase telomerase (TERT). (Kelland, 2007) Mutations taken place on regulator proteins of TERT would leads to the raise of limitless replicative potentials. (Autexier, 2006) The regulator proteins are called multiprotein telomere complex, shelterin in shorts. Shelterin compound has six subunits (TRF1, TRF2, POT1, TPP1, TIN2 and Rap1), which is found at certain interstitial telomeric sequences. TRF1 and TRF2 would bind and interact with telomeres. POT1 is a protein connected TRF1 and TRF2 with TPP1 and TIN2. Rap1 only attaches with TRF2 and regulates several genes next to itself which act as a transcriptional coregulator.(Schmutz and de Lange, 2016) (Schmutz and de Lange, 2016). In cancer cells, a mutation may take place on TRF1 causes the negatively regulated telomere length. Therefore, telomere lengths loss the ability of stopping DNA replicates which may facilitate the growth of cells without a limit. (Martínez and Blasco, 2010) Epigenetic silencing of death receptors and caspase-8 genes may lead to evasion of apoptosis. There are two signalling pathways of apoptosis, one is the death receptor (extrinsic) pathway and the other one is the mitochondrial (intrinsic) pathway. Epigenetic silencing of death receptors, overexpression of FLIP or epigenetic silencing of caspase-8 may occur and lead to pathway defection. Down the intrinsic pathway, overexpression of Bcl-2 proteins (anti-apoptotic proteins), Bax mutations or epigenetic silencing of Apaf-1 causes pathway failure. These mutations activate the anti-apoptosis mechanisms. (Fulda, 2009) Furthermore, oncogene MYC may be able to trigger apoptosis. High levels of MYC gene triggers robust apoptosis, which might be a potential for cancer treatment by increasing the MYC gene levels. (McMahon, 2014)

Factors lead to those somatic mutations
Cancer is a genetic disease, which means that cancer is caused by the genetic information damaging. ( (Figure 1) The accumulation of cancer often is affected by nonfunctional DNA repair system. To explain this idea more clearly, some examples are used to introduce these suggestions. When UV radiation hits the DNA strand, it may lead to certain mutations called TT-cyclobutane pyrimidine dimer. If this molecule is not repaired in time, these types of mutation may be accumulated in the cells.
There is a disease called xeroderma pigmentosum (XP) affects the DNA repair mechanisms, which may contribute to the mutations accumulations and therefore increases the chance of getting cancer.

Conclusion
Discussing the relationship between the somatic mutations and the cancer origins, some examples were used in this review. Those examples were analysed, and few possible targets were suggested. The fighting with cancer still needs effort and there is still a long way to end. This overview only suggested few ideas of the treatment of cancers, but none of them can really 'solve the problem'. In my point of view, the combination of different treatments should be taken place to deal with cancer due to large number of mutations. The targets suggested above can only stop or 'kill'cancer cells in some extent, but the repairment of those healthy tissues are still the problems regarding to the cancer treatments. In addition, the types of cancer are varied. This even increases the difficulty of cancer treatment. For example, treatment for xeroderma pigmentosum can only dealing with certain types of skin cancers, and treatments for BRCA1/BRCA2 are only functions for few cancers and especially for breast cancer. From those starting points, more types of cancer treatments may be discovered. Then, combining those treatments may increase the possibility to treat the cancer properly.