GENE PATHWAYS IN CANCER: BEGINNING, ENDING AND THE ACTORS OF THE STORY

GENE PATHWAYS IN CANCER: BEGINNING, ENDING AND THE ACTORS OF THE STORY

Mirza Jawad Ul-Hasnain^{* 1, 2}, Tehreem Anwar ¹, Bakhtawar Afzal ², Hafiz Muhammad Talha Malik ^{2, 3} and Syed Hassan Abbas ²

Department of Bioinformatics ¹, Virtual University, Lahore, Pakistan.

Department of Biosciences ², COMSATS Institute of Information and Technology, Islamabad, Pakistan.

Jamilul Rehman Center for Genome Research ³, PCMD (ICCBS), University of Karachi, Karachi, Pakistan.

ABSTRACT: The advancements of cancer research if put in a nutshell can be described as: “Cancer is a genetic disease.” From the past two decades, several actors for cancer are identified, their mutations are characterized, and the pathways they control are described. Intricate relations among JAK-STAT, TGF-B, MAPK, Ras, Wnt, Notch, and Hedgehog signaling pathway have a vital role in apoptosis, survival, proliferation, and differentiation. Dysregulation of these pathways due to driver mutations are often found involved in the growth of cancer. The purpose of this review is to enlighten the advancement in these areas of cancer, specify where there is room for research, and provide a potential base for future research.

Keywords: Cancer, Pathways, Tumorigenesis, Proliferation, Apoptosis, Oncogenes

INTRODUCTION: Information we already have: Cancer, a term that relates to the abnormal growth of any living physical entity that resides inside the body ¹. The entity can be a vessel, a tissue, or even a cell ². The term cancer is further divided into several major types, namely, the proliferation of cells, angiogenesis, vascular genesis, carcinogenesis, leukemia and lymphomas ³. Several cancer hallmarks have been stamped for the recognition, working behaviour of cancerous cells and prevention protocols ⁴. Some of them are known to sustain proliferative signaling or enabling replicative immortality evading over the growth

Suppressors, even inducing angiogenesis ultimately resisting cell death, activating invasion and metastasis ⁵.In the case of developing an understanding of the intense behavior of the cancer-causing genes, gene pathway analysis is mandatorily important before the gene networks ⁶.

Based on the occurring frequency 20 genes are very vital in cancer study ^{7, 8}: TP53, XRCC1, PTGS2, EGFR, AKT1, TERT, VEGFA, TGFB1, mTOR, PTEN, MMP2, GSTM1, CXCR4, CTNNB1, CDH1, MYC, ABCB1, CDKN1A, ABCG2 and CCND1 Table 1. Prescribed network analysis shows that linkage of MYC, PTGS2, VEGFA, CXCR4, ABCB1, ABCG2, XRCC1, and GSTM1 genes are only hypothetically reported while rest 12 genes show experimental support in their network linkages. A panel of these 8 genes can be characterized experimentally using different assays including invasion assay ⁹, proliferation assay ¹⁰, adhesion assay ^11, and migration assays ⁹.

 TABLE 1: LIST OF EXPERIMENTALLY CONNECTED AND HYPOTHETICAL GENES IN PRESCRIBED NETWORK

 Three types of genes, in the result of alterations, are accountable for the process of tumorigenesis; oncogenes, the tumor-suppressor genes, and the genes responsible for stability ¹². Single gene faults cannot tend to be alone responsible for causing cancer, unlike other diseases where single gene mutation can be a cause including cystic fibrosis or muscular dystrophy. Cells have several defenses that safeguard them from adverse effects of tumor responsible genes, and cancer only develop when multiple genes have mutations and alterations ¹³. So, in this sense, we can say mutations in genes are cancer responsible, not cancer causing.

The mutations in tumor suppressor genes are somehow different from that occurring in oncogenes. Mutations lead to the reduction of gene product activity ¹⁴. Such activations can be caused by several factors including truncated proteins as a result of mutations, the essentially required mutated crucial residues, epigenetic silencing or indels of various sizes. We can think of mutations of tumor suppressor genes to be malfunction brake in a vehicle where the vehicle continues to move even if the vehicle driver is attempting to engross it. The cancer repressor genes can employ a specific benefit on the cell when only one of the two alleles is dysfunctional, and the other is functional ¹⁵. But, alterations in both paternal and maternal alleles are needed to deliberate that selective advantage ¹⁶.

Oncogenes mutations render them active in conditions under which wild type genes are not ¹⁷. Activations of oncogenes can be due to alterations of several different types including translocations in chromosomes, amplification of genes or even from some intragenic mutations that lead to alter the important residues responsible for normal gene functioning ¹². For instance, alteration of valine to glutamate at codon 599 in BRAF gene leads to activation of kinase domain loop ¹⁸. Active BRAF kinase leads to aberrant growth by the process of phosphorylating the targets present downstream, including the kinase regulated by extracellular signals ¹⁹. Oncogene mutation is like an accelerator stuck in an automobile; the car does not stop moving even if the driver has removed his foot from it.

Stability genes have an opposite mechanism of mutations from tumor suppressor genes and oncogenes. All the repair mechanisms considering mismatch, base-excision, and nucleotide-excision repairs are included in this class of genes ^{20, 21, 22}. These genes are responsible for keeping alterations to a minimum, so their inactivation can lead to a very high mutation rate ²³. Same as in the case of cancer suppressor genes, both the maternal alleles and paternal alleles are required to be activated. In term of automobile analogy, we can think of stability genes as mechanics, and faulty genes are more like an incompetent mechanic. The mutations occurring in these three types of genes can be both somatic or germline. Examples of Inherited syndromes associated with these kinds of mutations are also listed in Table 2.

Major Pathways and Genes Involved in them: Research from the past decade shows that the number of pathways is way less than that of genes. The notion being very common for researchers that there is a collection of many such diverse types of genes that, when altered, produce similar or nearly similar phenotypes. So, it is preferred to study pathways rather than genes, and the same strategy is followed in this review.

TABLE 2: MOST OCCURRING GENES, RELATED SYNDROMES AND HEREDITARY PATTERNS, PATHWAYS (SINGLE PATHWAY SELECTED IS THE BEST GUESS MADE), HEREDITARY TUMOR TYPES IN WHICH THEY ARE PRESENT AND GROWTH FACTORS THEY ACTIVATE ARE LISTED

Receptor Tyrosine Kinase RTK Pathway: In human cancers at codon number 599 if a mutation occurs to change valine to glutamate in BRAF gene leads to activation of kinase domain loop¹⁸ known to be regulated by the process of Ser601 and Thr598 phosphorylation ⁵⁵. This advocates that substitution of glutamate to valine at codon number 599 impersonates a phosphate group. That is why this substitution constitutively activates the enzyme even when signals are not present that would, in a normal situation, phosphorylating the adjacently existing serine or threonine residues. This activation of the BRAF kinase domain is ultimately followed by phosphorylation of certain downstream entities ¹⁹ such as extracellular signal-regulated kinase (ERK) that leads to abnormal growth Fig. 1.

FIG. 1: RECEPTOR TYROSINE KINASE (RTK) PATHWAY. ‘GPG’ denotes growth-promoting-genes-which means, genes that enhance cell growth or proliferation or hinder the speed of cell arrest or death. Diamonds and adjacent textboxes indicate PPIs. T-bars indicate transcriptional repression. ⁺P represent covalently attached phosphate groups.

RB Pathway: Phase shift from the resting phase to replicating stage of the cell cycle (i.e., from G0 or G1 phase to S phase), is sometimes directly controlled by some cancer genes Fig. 2. Proteins which are the result of such genes are as heterogenous as Rb (transcription factor), cdk4, cyclin D1 (which cooperates with and activate cdk4) and p16 (which cooperates with and constrain cdk4) ^{56, 57, 58}. Mutation activates the genes (oncogenes) that code for cyclin D1 and cdk4 while inactivating the genes (tumor suppressor) that code for p16 and Rb ⁵⁹.

Additionally, with studying of functional systems through modeling, convincing proves has also been established by the comprehensive study of individual tumors illustrating that these under discussion four genes have roles in a common human cancer pathway ⁶⁰. Research has found out that the mutations that occur in this pathway follow the rule of exclusivity, meaning that only one of these gene mutations causes tumor, provided that functional consequences of each mutation were analogous ^{56, 57, 58, 59, 60, 61}.

P53 Pathway: TP53 gene that encodes P53 protein ⁶² is a transcription factor which generally functions to restrict cell growth, and when induction of cellular stress takes place, cell death is stimulated by p53 ^{63, 64}. Missense point mutation is the most usual way that disrupts the p53 pathway that hinders its ability to bind with its specific allied recognition sequence ⁶⁵. Several other triggers can also achieve the same effect such as MDM2 geneamplification⁶⁶ and DNA tumor virus’s infection, which inactivates the pathway by inhibiting products such as E6 protein that binds to p53 pathway ⁶⁷ Fig. 3.

 APC Pathway: APC gene is a tumor suppressor gene whose mutation causes β-catenin to accumulate, which then bind to T cell factor-4. Transcriptional activation of some unknown genes is activated by this binding of β-catenin to Tcf-4. c-MYC oncogene being the target gene identified in this signaling pathway, where wild type APC downregulates its expression and is activated by β-catenin. The effects are mediated by the Tcf-4 binding sites that are present in c-MYC promoter ^{65, 66}.

PI3K Pathway: Epidermal Growth Factors Receptor, abbreviated as EGFR is a transmembrane glycoprotein and is a member of Superfamily, a tyrosine kinase receptor ⁶⁸. An EGRF signaling pathway is a key pathway that is discussed for the survival, differentiation, proliferation, and growth regulation in mammalians cells ⁶⁹. The role of Akt1 with EGRF during the cellular response to any oxidant quibble/injury was investigated in this approach. It was known that PI3k phosphorylates and activates Akt1, upregulating for the evading apoptosis process but in normal conditions ⁷⁰. We found that EGFR signaling provokes the apoptosis activity by suppressing Akt1 and the de-phosphorylation of EGFR resulting in the expression of the Akt1 and the survival of the cell growth and the raised Akt activity advises defense against oxidative stress-induced apoptosis ⁷¹.

PI3k/AKT1 and MTOR and Antagonistic Behaviour of PTEN: The mammalian target of rapamycin mTOR, is known to be a key gene in the evading apoptosis mechanism ⁷² but when required participates as a usual process in normal cell life. It plays the role of downstream effector in PI3k/AKT1 pathway ⁷³. A mTOR signaling pathway is activated by PI3k-Akt signaling k2 pathway activated by the Cytokine-cytokine receptor interaction on the ECM ⁷⁴. As a finding of studies, we know that PI3k. AKT/mTOR pathway is a signaling pathway that intracellularly plays a vital role in cell cycle regulation ⁷⁵. This pathway is directly responsible for the proliferation, cellular quiescence, cancer, and even the longevity ⁷⁶. Activation of PI3K from the signals coming from the ECM phosphorylates and activates the AKT, confining it in the plasma membrane. AKT has many pathways, for example, inhibition of p27 ⁷⁷, activation of CREB ⁷⁸, activating Ptdlns-3ps ⁷⁹, confining of FOXO in the cytoplasm ⁸⁰, activating mTOR which can further affect the transcription of p70 or 4EBP1 ⁸¹. These pathways are disturbed by numerous factors, which influence to harvest cancer. These factors include PTEN, HB9 and GSK3B, etc ^{82, 83, 84}.

SMAD Pathway: Transforming growth factor (TGFβ) is a key gene involved in this pathway that targets SMAD proteins and some other proteins those results in dysregulations ^{84, 85}. TGFβ has a broad number of activities including stimulation of cell proliferation ⁸⁵, context-specific inhibition ⁸⁶, extracellular matrix ECM production and degradation ⁸⁷, mediating the cell responses that occur in defense of an injury ⁸⁸ and direction of carcinogenesis ⁸⁹. Following several phosphorylation and activation events, TGFβ acts on SMAD proteins, and a complex is formed which acts as a transcriptional regulator of target genes ⁹⁰. We have discussed only pathways so far. Within these pathways, some genes are very important when we talk about cancer. Their importance and role in the pathways mentioned above are discussed in detail below.

FIG. 6: SMAD PATHWAY. SIGNS AS EXPLAINED IN FIG. 1.

Akt1 and CTNNB1: Talking of Akt and CTNNB1 interaction we found that CTNNB1 (beta-catenin 1) is a key gene and main effector in the Wnt signaling pathway in stem cells as well as embryonic cell development and tumorgenesis mechanism ⁹¹. Beta-catenin signaling pathway includes the adhesion of the cells onto the ECM, whereas, a mutation in beta-catenin results in invasion and metastasis ⁵. Wnt signaling pathways comprises of a group of signal transduction passageways made up of those proteins that allow the signals to pass inside from the cell surface via receptors located on cell surface ⁹². Akt (protein kinase B or PKB) present in Wnt like PI3K-Akt pathway for the transduction of the signals to promote the growth and survival when receiving the extracellular signals. Mostly Akt makes beta-catenin to get phosphorylated results in 14-2- 3zeta binding and stabilizes the CTNNB1 for the development of stem cells ⁹³.

Akt1 and PTEN: PTEN (Phosphatase and tensin homolog) is a significant gene in humans. Its mutation can cause many cancers in Homo sapiens. Its lost copy has reported 70% of the prostate cancer cases ⁹⁴. It is known to be a tumor suppressor gene ⁹⁵ and has always been under consideration in cancer biology. Akt signal transduction pathway is reported as in an equilibrium that is altered by mutated tumor suppressor genes like PTEN and causes not to go the apoptosis process, which leads to cancer ⁹⁶.

Akt1, TERT, Tp53, and MDM2: Telomerase reverse transcriptase TERT, is a catalytic part of a telomerase unit of an enzyme ⁹⁷. The addition of telomere repeats is made possible by telomerase, as TTAGGG and comprises of a protein subunit for the reverse transcription activity being a reverse transcriptase ⁹⁸. The telomere is a region which stops the cell division after a certain time ⁹⁹ and undergoes apoptosis process while TERT elongates the telomere region by adding repeated units making a cell immortal ¹⁰⁰. Tp53 is known as a tumor suppressor as its function is to go for the apoptosis mechanism in case of the DNA damage or breakdown ^{95, 96, 97, 98, 99, 100, 101}.

Mouse double minute 2 homolog, MDM2 is a regulator attached to tp53 which controls tp53 whether to allow it to go for apoptosis or not in normal condition ¹⁰². If any DNA damage happens, tp53 sends a signal to MDM2 to get suppressed so that tp53 can be up-regulated and apoptosis process can be gone through. But due to the mutation in tp53 suppression, ofMDM2 is disabled, and no apoptosis occurs, which results in cancer. This mutated tp53 enhances TERT activity and cause oncogenesis and in this downstream TERT suppress Akt1 to increase tumor genesis and reduced evading apoptosis ^{94, 96, 97, 98, 99, 100, 101, 102, 103}. TERT regulates CTNNB1 via BRG1 too¹⁰⁴.

AKt1 and VEGFA: Vascular endothelial growth factor VEGF is a signal protein that stimulates the processes which are integral for differentiation and proliferation of the cells, namely, angiogenesis and vascular genesis ¹⁰⁵. But the excessive angiogenesis and vascular genesis cause tumor and cancer. But as we know that the normal function of PI3-Akt1 is to go for the cell destruction via mTOR signaling pathway when DNA abnormality occurs but in a normal manner ¹⁰⁶. At normal condition phosphorylation of AKT1 helps in the phosphorylation of VEGFA-R for the VEGFA mediated as activation but when a mutation in VEGF cause tumorigenesis by the excessive angiogenesis Akt1 down regulates VEGFA to suppress tumor ^{68, 107}.

CTNNB1 and CDH1: E-cadherin or CDH1 is a key protein playing an integral role in cellular adhesion, and a decreased expression of this protein increases angiogenesis and cell invasiveness ¹⁰⁸. β-catenin is an essential constituent of the signaling pathway of Wnt ¹⁰⁹ and gets combined with CDH1and the complex of these two proteins stabilize the cellular adhesiveness ¹¹⁰.

EGFR and CTNNB1 and CDH1: EGFR (Epidermal growth factor receptor) which inhibits Akt1 ¹¹¹ from apoptosis upregulates CTNNB1 for the cellular adhesion supported by the Wnt pathway where CTNNB1 makes a complex with CDH1 ¹¹². EGRF and CTNNB1 both regulate each other to decrease invasion and metastasis. But CDH1 downregulates the overexpression of EGFR to avoid cancer ¹¹³. Where interaction of nuclear PTEN (Phosphatase and tensin homolog) with APC indorses APC connotation with CDH1, and thus boosts the activity of cancer-suppression of APC-CDH1 complex ¹¹⁴. PTEN also suppresses CTNNB1 and down-regulates its activity of cellular adhesion to increase the invasion and metastasis ¹¹⁵.

MMP2/TGFB1/Tp53 Downstream: TGFB1 (Transforming growth factor beta1) is involved in certain essential cellular activities and functions like apoptosis, cell growth, and cell differentiation in both adults and embryo ¹¹⁶. There is another significant gene MMP2 (Matrix metalloproteinase-2), which makes the breakdown of the ECM (extracellular matrix) in normal physiological conditions such as in reproduction or development of embryo ¹¹⁷.

The mutation in MMP2 causes metastasis as the ECM rapidly destroys and allows the cells to get out from it and spread apart ¹¹⁸. We investigated from the literature that mutated MMP2 downregulates TGFB1 for the sustained angiogenesis process via VEGF signaling pathway. We also examined that there is a positive correlation between betweenTp53 and TGFB1 ¹¹⁶.

Tp53 and XRCC1: TP53 and X-ray repair cross-complementing protein 1 abbreviated as XRCC1, a DNA fixing and a tumor suppressor, respectively, underwrite to cancer progression ^{119, 120}. Whereas, the TP53 gene somehow may root the distinction in vulnerability to cancer, giving rise to clues about the progression of the disease. It’s known that most of the genes that play their parts in DNA repair, such asXRCC1, are carrying the genetic metastasis which ultimately becomes the reason of changes in the DNA repairing ability and also change the exposure of the body to several fatal tumors, such as breast cancer ^{121, 122}.

CTNNB1 and PTGS2/COX-2: Cytoplasmic beta-catenin is found to be linked with COX-2 overexpression for cell-cell adhesion ¹²³. Besides its function in cell adhesion and Wnt signaling pathway, an explicit RNA motif at 3’UTR of mRNA of COX-2 is recognized by β-catenin, and it interacts with HuR in the case of colon cancer ¹²⁴.

PKM/AKT, PTEN, MDM2, Tp53, mTOR and TERT Linkage: By the phosphorylation of PKM/KT via PDK1 starting from the activation of PI3K, PTEN acts as a suppressor of the Akt1 pathways here. PKB/Akt supports the cell growth by inhibition of apoptosis activating MDM2 which can stop Tp53 ¹²⁵ and then mTOR which on its behalf when victimized by any mutation causes tumor growth ¹²⁶ which enhances TERT to elongate the telomere end sizes leading to tumors and cancer formation ^{4, 104, 126}.

Tp53 and PTGS2/COX-2: The DNA damage induction by nitrogen and oxygen species activates Tp53, which in return musters NF-kappa-B to stimulate COX-2, ultimately following by consequences that are anti-apoptotic and cause the expansion of cells in the inflammatory precursor lesions ¹²⁷. The oncogenic stress that occurs due to initiation of growth-stimulating kinases upregulates COX-2 promoter being independent of NF-kappa-B and p53, working together with mutation of TP53 leading to the promoted tumor development ¹²⁸.

Information that is needed To Know:

The Initiation: A mutation in the gatekeeping pathway initiates tumorigenesis in stem cell or the descendants of it that are partially differentiated, also known as a replication-competent cell that leads it to some growth factor activation ¹²⁹. Gatekeeping pathways are identified in some cancers like RB1, NF1, and APC in the eye, colon, and nervous system cancers, respectively ¹³⁰. However, the gatekeeper is not known in most of the cases. For example, if we talk about bladder, prostate, breast, lung or brain cancer, they can either be initiated by only one gatekeeping pathway or by any one of several gatekeeping pathways ^{131, 132, 133}. Several gatekeeping pathways and gatekeepers are recognized through the study of several uncommon families with particular types of cancer pre-disposition ¹⁶.

In the future, other families may also provide insights into the nature of gatekeeping pathways. The prediction is, however, that identification of novel gatekeeping genes will be through sequence identification of major cancer genome portion and more brute force approaches ¹³⁴. As central clues about pathogenesis and biology of cancer are provided by identification of gatekeeping mutations, so they are of fundamental importance in therapeutic and diagnostic strategies, and research on this subject should be prioritized ¹³⁵.

The Actors: It seems that to achieve malignant status, cancer cells must gather several mutations in replication-competent cells. Cancer prevalence will be minimal if such mutations have to simultaneously occur in a single cell ¹³⁶. According to existing dogma, these mutations prevail slowly with time, where each mutation is producing expansion clonally creating a new substrate for the upcoming mutations ¹³⁷. Are only normal mutations, along with clonal expansion, adequate for causing cancer or genetic instability is fundamental in the prevalence of cancer? This is a hotly debated issue ^{138, 139} but some facts are clarified through the research of the last ten years.

Firstly, the mutation rate is not very high in most of the cancers ¹⁴⁰. Typically, mutations in cancer cells are less than 1 megabase of DNA just like the probability of mutation in a normal cell which has conceded overpopulation bottlenecks and generations ¹⁴¹. Secondly, genetic instability has a contribution to cancer prevalence as hereditary cancers, which are caused by flaws of tumor genes ¹⁴¹ Table 1.

In nonhereditary tumors, these facts argue against the common role of NER, BER, or MMR. However, another type of instability, namely Chromosomal instability CIN happens more in the prevailing types of cancers, and this instability is not determined at the nucleotide level, instead of at gross chromosomal level ¹⁴². Although a small number of cases are studied for the actual rate of chromosomal changes, in nearly all solid tumors, aneuploidy, which is the result of chromosomal changes is observed ¹⁴³. Loss of heterozygosity is observed as chromosomal losses occur at the molecular level. 25% to 30% alleles exist in normal cells are lost due to chromosomal losses in cancer, and sometimes the sells lose over 75% of its alleles ¹⁴². Both classic and modern studies confirm these facts ^{144, 145}.

Such chromosomal losses can be beneficial for cancer cells allowing them to cause cancer by eliminating tumor suppressor gene and production of variants. The fundamental processes underlying CIN and aneuploidy in tumors are still largely needed to identify, but some candidate genes pathways and genes are proposed such as those involved in telomere crisis, centrosomes or cell cycle checkpoints ^{137, 146, 147, 148, 149, 150}. Telomerase is potentially important in the incidence of most cancers, which are age-dependent ^{148, 151}. The identification of molecular processes responsible for the genetic instabilities is an important area of study as these instabilities seems to be playing a pivotal role to cancer development and may lie the production of increased chemotherapeutic agents resistance ^{136, 138}.

The Finishing: Most of the variations in cancer genes happen initially in the disease progression and are not recognized to be particularly linked with the change over the stage of the disease ¹⁵², although variations in tumor genes listed in Table 1 are significant sponsors of cancer. Satellite lesions and seeding in other organs is the final stage that is majorly responsible for neoplastic deaths ¹⁵³. Early tumors can be excised by surgery, but lesions that are widely spread cannot be removed, and sometimes a milestone to be achieved in terms of treatment.

Some processes involved in early metastasis have been well studied till now such as the production of matrix-degrading protease and increased cell motility ¹⁵⁴, through genetic changes responsible for bringing cells to this stage are still not identified. Evolution of cancer cells does not halt just as macroevolution never halts and new alternatives are always being creating with greater ability to metastasize and invade cells. As explained above, the evolution itself is caused by hereditary genetic variabilities ¹⁵⁵. However; this perspective of genetic changeover cannot be confirmed or nullified until we have a detailed knowledge of the mentioned genetic changeover processes.

Concluding Remarks: The three major milestones that are expected to occupy the emerging cancer research are (1) Discovery of novel genes that play roles in initiation and termination of tumor process and have a causal role in neoplasia. (2) Identification of gene pathways via which they act. (3) Paving new paths through his knowledge for the welfare and improvement of patients. The first two landmarks are expected to be achieved very recently, keeping in view the advances in cancer research technologies.

These advancing technologies are likely to proceed apace. Sooner genome of human will be in proper, refined shape, and road maps provided by previous studies are sufficient for researchers to follow conditioning that the novel genes are known. There will be a lot of genes, a lot of proteins and a lot of functions to consider. Also, as described above, cancer molecular and cancer biology has not been kept up, and there is a need to separate them. The third challenge listed above is the most difficult to achieve. It is to provide actual benefits to patients. Road maps are hard to found. Excising billions of tumor cells is an intimidating task. Also, each of these cells is capable of speedy evolution and creating variants that resist chemotherapeutic agents ^{156, 157}.

Cancer is no longer an unexplored mystery now. Knowing that a limited number of mutations in a few pathways can cause disasters, targeting those findings in the drug discovery can make wonders. But developing these next-generation drugs would be enough for minimizing cancer mortality in the long term? The western societies enjoying less morbidity rate is due to better prevention not better cure. Preventive measures can help restrain from the disease, such as limiting the exposure to carcinogens such as cigarette smoke, sunlight etc.¹⁵⁸. Early detection of cancer can result in less mortality rate, for example, colon, breast, and prostate cancer.

Moreover, 30 to 40 years are needed to gather all the alterations necessary to progress to metastatic disease ¹⁵⁹. This allows detection of cancers at that stage where cure is possible. In fact, this knowledge will pave a path to the development of new generation drugs, tests and employing target-specific imaging that will make detection of cancers at early stage possible ^{160, 161}. Though less theatrical than cures, early detection and prevention are most feasible means to reduce cancer deaths.

ACKNOWLEDGEMENT: Nil

CONFLICT OF INTEREST: Nil

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     Ul-Hasnain MJ, Anwar T, Afzal B, Malik HMT and Abbas SH: Gene pathways in cancer: beginning, ending and the actors of the story. Int J Life Sci & Rev 2018; 4(3): 35-47. doi: 10.13040/IJPSR.0975-8232.IJLSR.4(3).35-47.

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