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A study on cancer a dna altering disease

This article has been cited by other articles in PMC. Abstract Cancer is the most challenging disease of our time with increasing numbers of new cases each year, worldwide.

Great achievements have been reached in cancer research through deep sequencing which helped define druggable targets.


However, the still-evolving targeted therapy suffers resistance suggesting that DNA mutations considered as drivers may not have a role in tumor initiation. The present work discusses the role of DNA mutations as drivers and passengers in cancer initiation and development.

First, it is important to discern the role of these DNA mutations as initiating events causing cancer or as contributors crucial for the development of a tumor once it has initiated. Second, breast cancer shown here illustrates how identification of DNA mutations in cancerous cells has influenced our approach for anti-cancer drug design. The cancer trilogy we have reached and described as: To design more effective cancer drugs with durable and positive outcome, future cancer research needs to move beyond the sequencing era and explore changes which are taking place in cancer cells at levels other than the DNA.

Evolutionary constraints may be acting as a barrier to preserve the human species from being transformed and, for that matter, all multi-cellular species which can incur cancer. Furthermore, mutations in the DNA do occur and for a multitude of reasons but without necessarily causing cancer. New directions will draw themselves when more focus is given to the event responsible for the switch of a cell from normalcy to malignancy.

Until then, targeted therapy will certainly continue to improve the outcome of patients; however, it is unlikely to eradicate breast a study on cancer a dna altering disease depicted here.

The number of drugs designed to treat cancer is also increasing [ 1 ], but without achieving the intended goal of curing cancer. Moreover, accumulated evidence shows that cancer therapy today has come to what looks like an endless battle as new drugs seem only to lead to new paths of resistance. Resistance mechanisms so far identified include, among others, drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition and epithelial—mesenchymal transition [ 2 ].

The obvious question here is whether we are battling cancer from the right front. No doubt, cancer is a complicated disease and, no doubt, enormous progress has been made in cancer research that has shed light on almost every biological aspect of this disease.

  • In 2018, a CRISPR trial for sickle cell anemia , another inherited blood disorder caused by a mutation that deforms the red blood cells, is planned in the U;
  • All 10 studied cases showed a long trunk with multiple branches where half of the mutations mapped to the trunk and the other half mapped to the branches [ 72 ].

The cancer genome sequencing project allowed the discovery of oncogenic mutations and gave valuable insights into the genomics of cancer. Moreover, the establishment of the Cancer Genome Atlas TCGA [ 3 ] is the most important scientific advance of the century and analysis of cancer genomes continues to supply valuable information with clinical and therapeutic implications.

  • There researchers take immune cells — called T cells — from cancer patients and use CRISPR to stop these cells from producing a protein called PD-1 program cell death-1;
  • However, cancer cells exploit this protective mechanism to evade the body defense system.

Cataloging genetic mutations responsible for cancer, TCGA project, which begun in 2005, used several techniques to provide a large, statistically significant data set for further discovery. Today, whether searching to understand the pathogenesis of tumor development such as in lung squamous cell carcinoma [ 4 ] or in oropharyngeal carcinomas [ 5 ], consulting TGCA for that end is of paramount importance. All this progress is still, however, not enough because we are not yet done with cancer.

Shrinking a a study on cancer a dna altering disease is one thing, but preventing the rising of transformed cancerous cells which form tumors is another thing totally different. Shrinking a tumor translates into a symptom-oriented treatment while preventing the rise of cancerous cells translates into a cure of cancer. This original work discusses the role of DNA mutations as drivers and passengers in cancer initiation and development.

It is deemed important to discern the role of these DNA mutations and whether they are the cause that initiates cancer or arise as a consequence of tumor formation and contribute to the growth and the development of the tumor once it had initiated. This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors. As technology made more progress with large-scale genome sequencing techniques, the Cancer Genome Anatomy Project CGAP set new goals to determine gene expression profiles of cancerous, precancerous and normal tissues [ 6 ].

The objective behind sequencing cancer genomes is to look for driver mutations, which increase the mutation rate in the cell, leading to a more rapid evolution of the tumor and metastases formation [ 7 ].

CRISPR-Edited Cells Linked to Cancer Risk in 2 Studies

The rationale behind a mutated gene as causal in cancer is based on the observation that the number and pattern of mutations in affected genes were found to be very unlikely the result of chance [ 8 ]. Therefore, mutational data obtained through sequencing can be used to identify candidate cancer genes that are most likely to be the drivers. Moreover, it is reasonable to suggest that genes that are mutated more frequently than predicted by chance are more likely the drivers [ 9 ].

Some of the identified mutations are called passengers as they do not drive progression to metastatic disease [ 10 ], whereas others called genetic drivers [ 1112 ] are considered crucial for cancer cell survival and growth. Although it is difficult to determine driver mutations from DNA sequences alone, drivers tend to be the most commonly shared mutations between tumors and cluster around known oncogenes and also tend to be non-silent [ 14 ], whereas passenger mutations are randomly distributed throughout the genome.

Clones bearing driver mutations are assumed to be positively selected in the evolution of neoplasia to invasive and advanced a study on cancer a dna altering disease [ 10 ].

The sequencing of cancer genomes has thus helped identify specific and unique changes in cancer patients and based on this information, a personalized therapeutic strategy [ 1516 ] became possible. Additionally, while genome sequencing can provide important information on patients with rare or novel tumor types, translating such information into clinical treatment strategy is often complicated [ 1516 ].

Moreover, malignancies are known to have a spectrum of gene mutations which can affect several metabolic pathways, complicating the task further. Cancer patients may not be able to afford the costs of personalized therapy while others may lack access to such treatment option. Nonetheless, it is important to highlight the benefits of the sequencing data and mutation cataloging in clinics.

In lung cancer, the discovery of the anaplastic lymphoma kinase gene ALK rearrangements and the subsequent development of crizotinib, an oral tyrosine kinase inhibitor targeting ALK for a selected ALK-positive patient group, is an example of such a successful biomarker-driven drug development [ 17 ]. The authors have concluded that crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer NSCLC with ALK rearrangement [ 17 ].

Three generations of epidermal growth factor receptor tyrosine kinase inhibitors EGFR-TKIs have thus far been developed reviewed in [ 20 ]. The question which remains to be answered is how to overcome resistance and recurrence phenomena in targeted and personalized medicine?

CRISPR concerns

This resistance barrier is perhaps teaching us to take a major turn in cancer research and redefine the etiology of cancer in order to redefine its treatment. The Driver—Passenger Point of View One of the first sequencing studies estimated that individual colorectal cancers contain about 100 non-synonymous mutations and that as many as 20 of the mutated genes in individual cancers might play a causal role in the neoplastic process [ 23 ]. Data from this study also showed that the mutational patterns among colorectal cancers from different patients are diverse.

In another sequencing study, it has been estimated that the average tumor carries around 80 somatic mutations, fewer than 15 of which are expected to be drivers [ 9 ].

More recent studies have shown that an average cancer of the breast or the colon can harbor about 60—70 protein-altering mutations, of which 3 or 4 may be driver mutations while the remaining may be passenger mutations [ 13 ], and that at least 125 mutated driver genes have been identified among 3284 sequenced tumor genomes.

Another study conducted by Ding et al. From the driver—passenger point of view, mutations in the BRAF gene, mainly the V600E mutation, are considered a driver leading to constitutive activation of the MAP kinase pathway and increase in growth signals [ 28 ].

These observations clearly show that drivers are many and diverse and the main question here is how to conquer cancer with these many mutations in a single type of cancer? How many drivers can we target at once in a given patient without increasing toxicity?

  1. Additionally, while genome sequencing can provide important information on patients with rare or novel tumor types, translating such information into clinical treatment strategy is often complicated [ 15 , 16 ]. Shrinking a tumor translates into a symptom-oriented treatment while preventing the rise of cancerous cells translates into a cure of cancer.
  2. The ex vivo approach has also been used in China to test treatments against an array of human cancers. As stated by Gonzalez-Angulo et al.
  3. However, the still-evolving targeted therapy suffers resistance suggesting that DNA mutations considered as drivers may not have a role in tumor initiation. The aim is to explore the theoretical advantage of using two HER2 targeted agents for more complete blockade of the HER2 signaling pathway.
  4. However, this may not be the rule in cancer as cancer cells are thought to not follow universal laws governing cell division [ 33 ], but can take advantage of any shortcuts available, adapting to their microenvironment and resulting, as a consequence, in tumor heterogeneity. An important finding in mouse model experiments failed to show CIN as a driver in transformation.

Most importantly, though, is what really needs to be targeted in cancer? The end product, i. DNA mutations which shape each tumor can go on endlessly and can change according to their microenvironment, including in the presence of chemotherapeutic drugs and radiation. Running after genes that are mutated in cancer cells may mean running in the same direction with cancer cells, but not in the opposite direction, as it should be in order to stop their proliferation. To stop cancer growth, we should go in the opposite direction, come face-to-face and neutralize the entity behind the establishment of these DNA mutations in cancerous cells.

On the other hand, it has been suggested that the failure of current cancer therapies may be the result of the used drugs not targeting what really causes cancer [ 33 ]. Also, in the hypothetical settings where the cause of cancer is still unknown and remains to be identified [ 33 ], what is, then, the role of these DNA mutations in cancer genesis?

Do any of these mutations in driver genes cause the switch from normalcy to malignancy? There is no evidence that such is the case and none of the identified driver DNA mutation causes the switch of a cell from normalcy to malignancy.

There is, however, ample evidence showing that these identified DNA mutations together contribute to the rising of cancer. The prevalent idea is that a large number of mutations, each associated with a small fitness advantage, drive tumor progression [ 34 ].

On the other hand, an important finding showed more passengers hills than drivers mountains shaping cancer landscapes at least in breast and colon cancers, and passenger rates vary considerably from tumor to tumor [ 9 ]. Moreover, studies on myelomas suggested that there are multiple genes, each mutated in a small proportion of tumors that can alter the same signal transduction pathway [ 3536 ].

Based on these observations, the number of potential drivers, spreading to include a diverse range of genes, appears large enough to qualify as the driving cause in one and the same disease. Furthermore, it is not clear how to separate a driver from a passenger a study on cancer a dna altering disease mutation [ 13 ]. While these DNA mutations may explain how cancer progresses, they do not explain how it starts. The important question to ask is not how cancer progresses but instead how cancer starts.

If the focus is on the tumor and how to shrink it then these DNA mutations in driver genes are indeed important to consider for the design of anti-cancer drugs. However, if we seek long-lasting outcomes in cancer treatment, then the focus should shift from the tumor, formed by a mass of heterogeneous cancerous cells, to the level of a single cancerous cell.

  • What makes a cancerous cell create those tools, use them intelligently to defy our inhibiting strategies is what needs more attention;
  • Indeed, the resistance of normal cells to CRISPR editing actually makes it more appealing for cancer treatment since there would be less potential collateral damage to normal tissues — a conclusion that is supported by research in our lab;
  • However, after a variable period of time, progression occurs [ 100 ];
  • Blocking the PARP pathway used by cancerous cells could translate in an increase in the aggressiveness of the tumors treated with PARPi as they become more skilled, should these tumors resort to an error-prone repair pathway.

Putting more emphasis on tumor growth has led us to design drugs aimed at shrinking those tumors while we lost from sight what really causes a normal cell to become cancerous in the first place. Looking thus from a different angle, these DNA mutations a study on cancer a dna altering disease be interpreted as consequences of transformation but not the cause of it.

Once a normal cell has switched to a cancerous cell, symptoms of that transformation are seen in the form of a number of DNA mutations we came to call drivers and passengers. Each major mutation or set of mutations may indicate the path taken by different cancerous cells on their way to invasion and metastases.

Following this line of reasoning, there should be no driver or passenger gene mutation per se, as mutations seen in cancer may be the result of that cellular modification catalyzing the switch from normalcy to malignancy that has yet to be identified [ 33 ].

Therefore, the observed mutations in cancer cells may occur to fulfill the malignant character and complete the reprogramming [ 33 ] process during transformation. On the other hand, mutations can occur in the human genome without causing cancer. Another reason to question the idea of driver mutations, i. In a study conducted by Poynter JN et al. The study showed evidence of the up-regulation of the mitogen-activated protein kinase pathway in a large percentage of melanocytic lesions, but these mutations have been suggested to be not sufficient for malignant transformation.

The authors suggested that BRAF mutations contribute to benign melanocytic hyperplasia, but are likely to contribute to invasive melanoma only in conjunction with other mutations [ 40 ]. A more recent study in melanoma, however, showed that BRAF and NRAS co-mutations are not mutually exclusive and that the co-existence of BRAF and NRAS driver mutations in the same melanoma cells resulted in heterogeneity of resistance in response to targeted therapy that was not observed in non-targeted therapy [ 41 ].

Inherited DNA Mutations and Cancer If somatic mutations in driver genes do not fully qualify to directly cause cancer, how about germ line mutations?

DNA Mutations May Not Be the Cause of Cancer

If the cause of cancer was in the DNA, one should expect a direct effect of the inherited driver mutation s to cause cancer and this should not be limited to a predisposition to develop cancer.

In the light of this work, predisposition in the presence of a germ line mutation means that the ground is fertile to drive transformation but not to initiate it.

Therefore, the presence of a germ line mutation alone is unlikely to cause cancer and limits its effect on predisposition to cancer but is unable by itself to switch a cell from normalcy to malignancy. In this line of reasoning, individuals with germ line mutations in DNA repair genes cannot develop cancer unless exposed to UV radiation [ 4243 ].

Moreover, the effect of inherited mutations should be systematic and not limited to one organ only, such as the skin in the case of melanoma. Is not the inherited driver mutation present in each and every cell of the body? Or do we assume that each organ has its own specific driver DNA mutation in order to develop its own cancer? It has been suggested that tissue specificity of inherited mutations in BRCA1, for example, may result from BRCA1 being evolutionarily recruited to suppress cancer in breast and ovarian tissues, but not for such a role in the non-susceptible tissues [ 44 ].

Based on such tissue functional specialization, the yet unidentified cancer-causing entity acts accordingly to hijack the major metabolic pathway in that specific tissue, rerouting it towards transformation.

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However, this may not be the rule in cancer as cancer cells are thought to not follow universal laws governing cell division [ 33 ], but can take advantage of any shortcuts available, adapting to their microenvironment and resulting, as a consequence, in tumor heterogeneity. It is important to note that several genes with germ line mutations that cause cancer predisposition have been reported to show very few, if any, somatic mutations in sporadic cancers of the same type, such as BRCA1 and BRCA2 in breast cancer [ 4546 ].

It has also been suggested that genes predisposing to cancer, when inherited in mutant forms in the germ line, stimulate tumorigenesis in indirect ways but do not confer an increase in selective growth advantage [ 13 ]. Therefore, none of these inherited mutations turns on tumorigenesis and causes cancer directly, even when the gene is qualified as a driver as opposed to a passenger gene.