Genetic Biomarkers: Potential Roles in Cancer Diagnosis

Crimson Publishers Review Article Wings to the Research

Rozhgar A Khailany1,4, Belan Kanabe2, Amr A Hasan3, Naser Gilani4, Mehmet Ozaslan2, Khandakar ASM Saadat4, Luay T Al-Saleem Agha4, Mohammed O Rahmana5, Ahmet Arslam6, Masa-Aki Ikeda7, Muhammad Safdar6 and Yasmeen Junejo9 1Department of Biology, Iraq ISSN: 2637-7802 2Department of Biology, Turkey 3Department of Medical Laboratory, Iraq 4Department of Medical Biology, Turkey 5Department of Biology, Iraq 6Department of Medical Genetics, Turkey 7Section of Molecular Craniofacial Embryology, Japan 8Department of Breeding and Genetics, Pakistan 9Department of Chemistry, Pakistan *Corresponding author: Rozhgar A Khailany, Department of Biology, College of Science, University of Salahaddin, Erbil, Abstract Iraq Biomarker is an objective rating of abnormal or pathogenic processes, normal biological processes, or pharmacological responses to a curative treatment. It has several potential applications in oncology, in- Submission: May 13, 2019 - Published: June 12, 2019 ment, and monitoring of disease progression. Recently, advances in cancer biomarkers have raised signif- icantcluding; opportunities differential fordiagnosis, improving risk managementassessment, prognosisof cancer identification,patients. Cytogenetic, prediction molecular of response genetics to treat and Volume 4 - Issue 4 epigenetic markers could be utilized for diagnosis and prognosis of cancer and its epidemiologic studies;

How to cite this article: Rozhgar A K, marker may be used to see how well the body reacts to an intervention for a condition or disease. Some Belan K, Amr A H, Naser G, Mehmet O, et reviewsalso, some and biomarkers researches ofnot cancer only reported are specific certain and genetichighly sensitivebiomarkers, for butdetection also coded of cancer. their targetA biological genes al. Genetic Biomarkers: Potential Roles in Cancer Diagnosis. Adv Complement Alt brought about the progress of genetic-based health care services. This review will give a current and Med. 4(4). ACAM.000594.2019. shortand the account underlying on various mechanisms. genetic biomarkersThe finding ofof cancer several with genetic diagnostic targets and and prognostic their relevant values. pathways has DOI: 10.31031/ACAM.2019.04.000594. Keywords: Biomarker; Cancer; Diagnosis; Cytogenetic; Molecular genetics; Epigenetic Copyright@ Rozhgar A Khailany, This article is distributed under the terms of the Creative Commons Attribution 4.0 Introduction International License, which permits unrestricted use and redistribution According to World Health Organization [WHO] delineation of a biological marker, or provided that the original author and biomarker is any substance, structure, or process that can be measured in the body or its source are credited. exams for diagnosis, imaging technologies, and any other subjective measures of an individual products and influence or predict the incidence of outcome or disease [1]. This comprises all health state [1]. Description of biomarker, in the National Cancer Institute [NCI] vocabulary of cancer phrases, is a biomolecule found in tissues, whole blood or other body liquids that is a marker of an abnormal or normal condition, or of a disease [1,2]. A biological marker can also

is a feature that is subjectively deliberated and estimated as an indicator of abnormal, normal be defined as a common component employed as an indicator of a biological situation [1]. It biological activity or pharmacologic responses [3]. Biomarker determination for tumor needs a pathway related to survey which consists of different pathways those are responsible for suitable control of several cell functions [3].

Recently, our knowledge on biomarkers of cancer has evolved significantly for improving effectively [2]. Recent technological advancement has capacitated the investigation of the management of patients with cancer by promoting the detection efficiency and treatment

Advances in Complementary & Alternative medicine 388 ACAM.MS.ID.000594. 4(4).2019 389

several potential biomarkers and renewed interest in developing non-hematological and hematological, include acute lymphoid new cancer biomarkers [2,4]. Personalize medicine hinges on leukemia [AML], acute myeloid leukemia, chronic myeloid/ granulocytic leukemia [CLL], lymphomas, solid tumors and information that is relevant for diagnosis, prognosis, and therapy others [11]. Nowell and Hungerford in the 1960s employing un- biomarkers, which are highly sensitive and specific in showing [5]. Thus, biomarkers discovery and development are one of the banded chromosome preparations, revealed clinical cytogenetic cores of personalized medicine for cancer treatment [5]. National correlativity clearly [12]. A recurrent aberration referred as the comprehensive cancer network [NCCN] suggested and detected Philadelphia chromosome [t[9;22]], was determined in cases with chronic myeloid leukemia [CML] [12]. With the development of test that will help patient care [4]. banding analysis in the 1970s, this correlation was expanded and tumor markers for six major malignancies to define the optimum Various efforts have been made to classify biomarkers of cancer. and cases with the chromosome t[8;21] aberration stand for a General agreements have been constituted. Loosely, a biologically confirmed [12]. AML is a heterogeneous bone marrow malignancy, subset with particular biological and clinical features [13]. The translocation fuses the ETO gene that encodes the CBFA2T1 at the phase of diagnosis or post diagnosis [in treatment course] is developed entity or process which leads to a cancer identification protein on chromosome 8 with the AML1 gene on chromosome potential prospects as biological markers of cancer [6,7]. Different 21 [13]. Acute promyelocytic leukemia [APL] is a subtype of AML categories of cancer biomarkers are employed in early detection, marked by the reciprocal translocation of t[q22;q12] and t[15;17] risk assessment, diagnosis, therapy and cancer management [8,9]. issuing in the fusion gene RARA-PML and an onco-protein that Several past decades, due to the huge knowledge boom, multiple damages myeloid distinction [14]. Fusion of IGH-CCND1, t[11;14], area of the technology development and biological sciences, jointly, have proposed various ways to categorize cancer biomarkers [1]. leukaemia, in splenic lymphoma with villous lymphocytes, in But these categorizations should be viewed contextual as cancer is chiefly found in mantle cell lymphoma, but also in plasma cell B-prolymphocytic leukemia, in multiple myeloma and in chronic lymphocytic leukemia [15]. The TEL [ETV6]-AML1 [RUNX1] aspects of the biomedical science area [1]. Cancer biomarkers can biomarkers identification is one of the major multi-disciplinal chimeric gene fusion, created by the translocation of chromosomes be categorized depending on various parameters such as properties t[12;21] [p13;q22], is the most frequent fusion gene in pediatric and function [5]. Cancer biomarkers that are grouped based on cancer [16]. Burkitt’s lymphoma [BL] is a heterogeneous group their functions include type 0 biomarkers which measure the of extremely increasing mature B-cell malignancies, it is typically natural history of a disease, type I biomarkers are associated with associated with a t[8;14] translocation [17]. BL is featured by a high the effectiveness of pharmacologic agents; and type II biomarkers, turnover rate of malignant cells and the c-myc gene deregulation also known as surrogate endpoint biomarkers, are intended to [17]. Le Beau et al [1983] reported a related chromosome anomaly substitute for clinical endpoints [5]. Current cancer biomarkers association, that of chromosome 16 inversion [inv16] and AML M4; molecular genetics, epigenetic, proteins, glycoproteins, hormones, may be classified into a variety of classes including cytogenetic, antigens, receptors and microorganisms [1]. Prediction and a findingVariation that wasof the soon chromosome confirmed bynumbers others [18].from diploid leading screening biomarker of cancer might also be utilizing for staging to both hypo- and hyper-diploidy as well as aneuploidy have been or grading of cancer [1]. Cancer biomarkers as shown in Figure1 renowned in malignant tumors [11], translocations and exchanges can be grouped according to genomic state and at the disease state. of sister chromatids give raise to structural abnormalities that can be easily marked by employing various banding techniques [19]. Cancer Biomarker Based on Genetics Further, homogeneously stained regions and double minutes are Cytogenetic markers also usually determined in tumor cells that can serve as biomarkers for cancer [19]. Although, alterations of the ploidy complement the Cytogenetic is the survey of chromosomes and the sensing clinico-pathological determinations, a weak association between of chromosomal abnormalities at the level of chromosomal and ploidy, clinical and histological staging has been noted in many sub chromosomal regions of genome that affects dosage balance cancers [2]. Aneuploidy is systematically determined in nearly which may be of clinical importance [10]. In cancer, disorders of all cancers [20]. Somatic mosaicism occurs in most tumor cells, heritage and inbuilt aberrations, alterations of genetic occur, and including trisomy 8 in AML and trisomy 12 in CLL [20]. Complete some cases, these alterations of genetic can be detected at the or partial loss of chromosome 7 [monosomy of chromosome 7] cytogenetic resolution analysis [10]. Chromosomal abnormalities, is associated with a variety of myeloid disorders, including AML numerical and structural aberrations are conventional markers in children [21]. The presence of monosomy of chromosome 17 of cancer as the relationship between neoplastic transmutation among breast carcinoma has been already reported [22]. and chromosomal abnormalities has been well constituted [2,11]. Karyotypic alterations of cancer cells are raggedly distributed After quick improvement of high-throughput technologies and end-to-end the genome, and chromosomes, bands and regions appear to be preferentially involved in the various tumors [2]. A whole genome, genes, RNA, proteins, and metabolites, with high its entrance into biomedical field, we could study chromosomes, steadily increasing number of aberrations is found to be related resolution and more affordable methods. Consequently, numerous datasets of genomic accumulate in international repositories, such abnormality associated with the major kinds of neoplasms, both as GEO from the US National Center for Biotechnology Information with specific diseases or subtypes of cancers [2]. Chromosomal

[NCBI], and about 500,000 clonal chromosomal aberrations 16S and 12S ribosomal RNAs, 22 tRNAs and 13 polypeptides [27]. belonging to more than 60,000 neoplasms of human are reported MtDNA has a higher mutation rate than nuclear DNA because of in the latest catalog of chromosome abnormalities in tumor [10]. the lack of DNA repair mechanisms and histone proteins and due Nevertheless, translational utilization of biomarker discovery still to its exposure to reactive oxygen species, which are generated has to face its ultimate challenge: consolidation into routine clinical during oxidative phosphorylation in the inner mitochondrial practice [10]. membrane [28]. MtDNA mutations have been often determined in all human cancer types and have thus been implicated in the Molecular genetic markers process of carcinogenesis [19]. Mutations have been detected in the DNA marker: Cancer is a genetic disorder accompanied lung, uterine cervix, bladder, breast, neck and head cancers in the by a series of mutations in genes [2], that is typically found in form of single mutations, insertions, deletions and mitochondrial two classes of genes: cancer-promoting oncogenes and cancer- microsatellite instabilities [19,29]. preventing tumor suppressor genes [23,24]. Such mutations mRNA marker: Globally, perspective of the mRNA expression can cause gene to either lost or gained function [25]. Oncogenes forms and deregulated pathways may give a more exact cancer and tumor suppressor genes are crucial regulatory genes which picture including its clinical conduct [30]. Nevertheless, the encode proteins that are checkpoints of the cell cycle and also role and function of most of these genes in cancer progress are have an important role for maintaining in the entryway to terminal unknown, and some may even be by stander genes that show no differentiation and cell death [25]. Defect in oncogene and tumor role in tumorigenesis [31]. However, these signatures may serve suppressor gene result in uncontrolled division of cell, which leads as effectual markers because of their unique differential patterns to cancer initiation [25]. Both alleles must be inactivated before the tumor suppressor function is completely lost, as the mutations suggested the mRNA expression potential as a model to separate of tumor suppressor genes have recessive fashion [25]. Loss of of expression [31]. Lots of expression profiling researches had between histologic subtypes of cancer cells, such as clear cell, function changes in tumor suppressor genes generally result in papillary and chromophobe in renal cell carcinoma [RCC] [30]. dysregulation of the cell cycle and DNA-replication, the inhibition of programmed cell death [apoptosis] or disturbed interaction of Some of the techniques employed to determine tumor tumor cells with protective cells of the immune system [23]. Gain biomarkers at the level of mRNA expression include quantitative of function mutations in oncogenes, which are often involved in reverse transcription polymerase chain reaction, differential signal transduction and execution of mitogenic signals, result in a display, serial analysis of gene expression, micro-array and micro- hyperactive growth and proliferation of cells, mutation in only one of the proto-oncogene alleles is needed for the mutant gene product attempted by laser capture-based microscopy in various stages fluid card analysis [32]. Pure RNA signature procurements are and grades of treatment [33]. RNA expression comparative analysis behave in dominant fashion [25,26]. in refers of heat maps, snapshots and supervised algorithms are to influence downstream events [23,25]. Oncogenes generally Single nucleotide mutations in many genes are major markers of DNA, for example BRCA1, BRCA2, RAD1 and CYP1A1 in breast finallyExpression coupled withof RNA prognosis indicates and the diagnosis condition [33]. of a biological system cancer, XRCC1, p53 and ATM in lung, head and neck cancers, [34]. Expression levels of RNA are integrating and highly dynamic PGS2 in lung cancer [6]. Other major biomarkers of DNA include both epigenetic and genetic mechanisms of gene regulation heterozygosity loss; changes in genes copy number and micro- [34]. Therefore, RNAs serve as an effectual phenotype of the cell satellite instability [MSI] [1,2]. Nucleotide mutations in tumor functional condition [34]. suppressor genes [Rb, p16, p19, p53], tumor promoters [Ras, Protein marker: Proteomics of cancer includes detail on APC], DNA-repair related genes and cell cycles [cyclins] have been perhaps all process of biology that happens in cancer cells, coupled with diagnosis and prognosis of various tumors, although microenvironment of cancer tissue and cancer cell-host interaction their medical implications have still to be constituted [2]. The APC [2,35]. Cancer cells produce some macromolecules and many gene commonly responsible for silencing tumor, is inactivated in many cancers, the changed gene has been found in 92% of cases diagnosed with esophageal adenocarcinoma and in 50% of cases proteins into the extra-cellular fluid through releasing that could the bloodstream and thus serve as potential biomarkers of serum with the esophagus squamous cell carcinoma [2]. APC gene defects also serve as markers [2]. Some of these outputs can finish up in [1]. Few crucial antigens of cancer are served as diagnostic and occur in 60% of cases with colorectal carcinoma and are thought to be the earliest genetic defect in the colorectal cancer progression [PSA], alpha-fetoprotein [AFP] and cancer antigen 125 [1]. The [2]. prognostic cancer biomarkers such as prostate specific antigen main executioner biomolecules of cells are proteins [1,36]. Protein Interestingly, besides nuclear aberrations, mitochondrial DNA molecules affect the molecular pathways in transformed and alterations [mtDNA] have been found in patients with cancer, hence normal cells; thus, biomarkers of proteomic are more relevant and informative mutations in mtDNA could serve as biomarkers for the closer to the condition of disease starting onset and development disease [2,19]. Human mtDNA consists of 16.5kb, which is a circular double stranded molecule, contains 37 genes which encode for based biomarkers [36]. [1]. Protein biomarkers are more significant than RNA- or DNA-

Classically, protein-depend signatures are developed from metastatic determination of cancer or detection recurrent cancer the polyacrylamide gel electrophoresis and two-dimensional patients [45]. For example, p16 promoter`s hypermethylation in the circulating serum DNA correlates well with repeated colorectal throughput techniques such as mass spectroscopy, matrix cancer [2]. Hypermethylation of CpG islands overlapping promoters fluorescence difference gel electrophoresis analysis [1]. High in cancer appears to be much frequent than hypomethylation and reverse phase microarray surface enhanced laser absorption of transcription regulatory regions [46]. However, some of the associated laser absorption desorption ionization time of flight cancer with DNA methylation loss embraces gene region, including and quantum dots are improvers to the technologies usable to transcription control sequences [46]. For example, the gene coding desorption ionization time of flight [1,37]. Recently, nano-particles evaluate the proteins potential as cancer biomarkers [1]. The only for the protease urokinase is hypomethylated and overexpressed FDA-approved biomarkers presently usable for medical employ are in conjunction with development of tumor in breast cancers [47]. protein molecules [1]. Although, epigenetic study has led to patients relieve survival with certain varieties of leukemia and lymphoma through the Epigenetic markers employment of drugs that change histone acetylation and DNA DNA methylation marker: Existence of epigenetic methylation, suggested that methylation markers demand large dysregulation is progressively recognized as a cancer hallmark [26]. Accumulating data in the last 10–15 years suggests that Non-coding RNA markers: A Non-coding RNA [ncRNA] is not only genetic alterations but also changes of epigenetic play scale clinical trial and further optimization for further finding [46]. transcribed from primary DNA sequence however not changed over important roles in cancer progression and development [38,39]. into proteins, that is a functional RNA molecule [47]. Epigenetic Epigenetics mentions of inheritable changes in expression of gene related ncRNAs can be partitioned into two main groups; the short ncRNAs and the long ncRNAs. In general, ncRNAs function primary DNA base sequence [40]. Epigenetic regulation is generally in somatic cells that are dictated by other than modifications in the to regulate gene expression at the transcriptional and post- organized at the level of DNA [post-replicative methylation], protein transcriptional level [47]. Both major groups are shown to play a role in DNA methylation targeting, heterochromatin formation, [histoneThe earliestmodifications] epigenetic and indications RNA [RNA interference]joint to cancer [23,41]. was derived from DNA methylation and gene expression studies [42]. Methylation Short non-coding RNA markers: Three major classes of short of DNA involves a covalent DNA alteration and has been found to histone modification, and gene silencing. non-coding RNAs are microRNAs [miRNAs], short interfering RNAs [siRNAs], and piwi-interacting RNAs [piRNAs]. MiRNAs are short 18- of DNA [43]. It has thus long been expected that methylation of DNA influence a diversity of processes that affect function and integrity might play a role in the cancer onset or course [43]. The largely 1993, that control gene expression via translational regulation [48- descriptive nature of DNA methylation researches and the truth 24 nucleotides, non-coding RNA sequences, it was first discovered in 50]. Through interactions with the mRNA 3’-untranslated region, that both hyper- and hypo-methylation have been investigated at several loci have made it hard to assess whether these alterations are causally involved in the transformation process or whether they miRNAs initiate translational controlling and play a significant role of target gene by corrupting the corresponding mRNA and/or in developmental timing [49]. miRNAs finally regulate expression suppressing its translation [48]. Presently, miRNAs have been [44]. The 5-carbon methylation on cytosine residues [5mC] in CpG reflect the changed physiology of quickly dividing cells of cancer determined to play an important role in several pathological and physiological conditions [50,51]. Especially, miRNA deregulation dinucleotide was the first represented covalent DNA alteration and in difference types of cancer has been extensively researched [50]. [45]. The 5mC methyl group exist in the major groove of the double is perhaps the most widespread propertied chromatin modification For example, deregulations in expression of miRNAs have been helix and can interact with transcription factor binding to shut determined to play a role not only in major cancers like lung, breast and silence expression of gene [45]. In addition, there is a class of and prostate but also in uncommon cancers like waldenstrom macroglobulinemia and cholangiocarcinoma [50]. family of proteins, which attach to methylated cytosines and reduce methylated DNA-binding proteins, specifically MBD and MECP2 gene transcription by stopping transcription factors [45]. Recently, Aberrant expression of miRNAs in cancer is correlated to methylation patterns of many genes are changed in cancer, type different mechanisms, which include chromosomal aberration, genomic mutation, polymorphism, epigenetic alteration in miRNA specific panels for various methylation genes have been proposed, [5]. About 50% of human miRNA genes are often situated at for example; RARβ, H-cadherin, p16, FHIT and RASSF1A for lung biogenesis [5], which can play a significant role in tumorigenesis p16, APC, VHL, p14, Timp3 and RASSF1A for kidney cancer [2]. fragile sites and genomic sequences involved in tumors [2] and cancer, TIG1, RARβ, APC and GSTP1 for prostate carcinoma and high frequency of genomic changes in miRNA loci was observed Hypermethylation is usually investigated in malignant cells, in human melanomas, breast and ovarian cancer employing high- that happen inside CpG islands, which are demonstrate in 70% resolution array-based genomic hybridization [52]. miRNAs of all mammalian promoters [42,45]. Methylation of CpG island can help to unreveal the tissue of origin for cancers of unknown plays an important role in transcriptional regulation, and it is primary origin [52,53]. miRNA expression patterns were analyzed ordinarily changed during malignant transmutation [42,45]. in human to identify some types of human cancers including those Hyper-methylation markers may be employed for the primary and

Adv Complement Alt Med Copyright © Rozhgar A Khailany ACAM.MS.ID.000594. 4(4).2019 392 developing in prostate, colon, ovarian, breast and lung [52]. Various of histone alterations is also searched as potential biomarkers of patients and healthy donors such as miR-145 in breast cancer, and the enzymatic machinery that set them as important regulators studies found statistically significant difference between cancer disease prognosis and progression [58]. Modifications of histones miR-141 in prostate cancer and miR-29a in colorectal cancer [52]. that can control cellular differentiation, plasticity, proliferation and According to their downstream signaling effect on genes and gene malignancy processes. products, miRNAs may be down or upregulated in tumors [45]. The ones which are down regulated in malignancies are suggested to therapies that can reverse silencing in human diseases [58]. having a tumor suppressor potential [4]. while, the miRNAs which The main goal in biomedical cancer research are to find Epigenetic therapy places new drug discovery in a critical role. are upregulated in cancers are suggested to having an oncogenic Here, it is important to remember that epigenetic diseases are effect [4]. developed by abnormal hypermethylation of CpG island containing- PIWI-interacting RNAs [piRNAs] are emerging players in promoters that seem to be particularly frequent in cancer cells, cancer genomics. Originally described in the germline, there are so DNA demethylating agents or histone deacetylating inhibitor over 20,000 piRNA genes in the human genome. In contrast to microRNAs, piRNAs interact with PIWI proteins, another member cancers [58]. compounds specifically targets cancer cells and certain kind of of the Argonaute family, and function primarily in the nucleus. Cancer biomarker based on disease states There, they are involved in the epigenetic silencing of transposable elements in addition to the transcriptional regulation of genes. It Technical progress has largely increased our understanding in has recently been demonstrated that piRNAs are also expressed terms of molecular basics of cancer development and treatment response. Recent years these progressions have led to the manner. An increasing number of studies have shown that aberrant determination of several tumor biomarkers. These biomarkers across a variety of human somatic tissue types in a tissue-specific piRNA expression is a signature feature across multiple tumour into four kinds; predictive markers, prognostic markers, detection according the disease stage which they are used, could be classified markers and diagnostic markers (Table 1) [2]. types;Long however, non-coding their specific RNA marker: tumorigenic In the functions recent remainyears we unclear. have observed a huge stretching knowledge regarding long non-coding Predictive biomarkers or response markers intent to objectively and regulation of several biological conditions [54]. lncRNAs are a or the difference results of two or more treatments, including RNAs [lncRNAs] and their significant roles in disease progress measure the benefit probability from a specific clinical treatment, new class of RNA molecules delineated as transcripts by a length toxicity, it is a speedily getaway study area that is initiating to have greater than 200 nucleotides without any potential of translation, that lack coding protein functions [55]. They represent a major, but a significant impact of clinical research [59]. Predictive markers are medication [1]. These markers let clinical profession to pick out a employed entirely in evaluating the effect of dealing with a specific collection of chemotherapeutic causes which will act topper for a even poorly qualified part of human transcriptome, nevertheless, involved in several cellular conditions [54]. An example of lncRNAs, case patient [1]. K-ras is a little G-protein that has an important role evidence is developing that they are significant regulatory molecules such as MALAT, HOTAIR and H19 were found to be aberrantly in the signaling transduction of epidermal growth factor receptor [EGFR], which is expressed in, and has a pathogenic function in participant touching the hallmark events of tumorigenesis, such as colorectal cancer [60]. Energizing defects in K-ras gene may obtain expressed in some of tumors and extensively qualified as important apoptosis, proliferation and metastasis [54,55]. the path from the demand for EGFR signaling rendition anti-EGFR targeting drugs, such as panitumumab and cetuximab ineffective Histone modification markers: Histones are extremely at the residues of amino acid situated on their C and N -terminal [60]. Many studies have presented that benefit from the anti-EGFR conserved alkaline proteins that are post-translationally modified tails [56]. There are four core histones: histone 2A, histone 2B, drugs, panitumumab and cetuximab, is qualified to colorectal tumors have mutant K-ras [60,61]. histone 3, and histone 4 and histone 1, a linker histone. About cancers with wild-type K-ras and there is no benefit in cases whose 146 bps of DNA are wrapped round each histone octamer, which Prognostic biomarker is a marker that gives knowledge on comprises of two copies of each of the core histones, in lefthanded the likely the cancer courses in an untreated individual [60]. It is super helical turns [56]. Histone 1, which is not included in the depended on the separating characteristics between malignant nucleosome “a bead”, serves as a linker and aids secure DNA that and benign tumors [43]. The absence or presence of a prognostic is wound around the nucleosome. Histone residues can become marker could be utilized for the patient selection for treatment but phosphorylated, ubiquitinated, methylated, acetylated, ADP- does not predict the reply to a treatment [59]. As almost patients ribosylated and sumolyated. with cancer are provided some type of adjuvant treatment [post- surgical treatment], several researches of prognostic markers will Covalent alterations of histones can control all DNA-dependent present include who received systemic anticancer treatment, which processes [57]. Recently, it has become more and more apparent that may affect the natural course of the disorder [60]. For example, histone alterations are key players in the chromatin dynamics and states regulation as well as in expression of gene [57]. Given their BRCA1 gene, is over-expression of BRCA1 confers worse prognosis key involvement in the different stages of tumorigenesis, existence the prognosis for human breast cancer, the clinical significance of in untreated patients.

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