Title: How can understanding molecular cellpathology contribute to better approaches for personalised medicine? (SN:15013778)WordCount: 1930IntroductionPersonalisedmedicine is the general term for the use of individual patient data to betterdiagnose, treat and monitor diseases (Schleidgen et al.
, 2013). Most common personalisedmedicine strategies involve genomic interventions, pharmacogenetics,individualised therapeutic strategies, lifestyle-specific medicine and disease subtypespecific medicine, all of which are tailored to the individual characteristicsof the patient’s disease to achieve maximum therapeutic effect (Titova, Jenner& Chaudhuri, 2017). Onemethod of collecting personalised disease information is through theunderstanding of molecular cell pathology (Drcuker & Krapfenbauer, 2013).Alongside broader level of histopathology and imaging used traditionally withinmedicine, molecular cell pathology is an investigative approach whichunderstands and describes the mechanisms of a disease at the macromolecularlevel using patient samples (Medical Research Council, 2014). Thesemacromolecules include DNA, RNA and proteins, so the techniques of molecularpathology often include those of other fields such as genetics and thesetechniques can be used to distinguish between disease origins at a molecularlevel (Peden & Ironside, 2012).
Recent research has shown that molecularpathology is an extremely important tool in the development and implementationof personalised medicine especially for diseases that often present withsimilar and sometimes intermittent symptomatology but have very differentmolecular bases and require targeted therapy (Mills & Janitz, 2012). This paper seeks to discuss the relevance ofmolecular cell pathology using examples of neurodegenerative disorders andcancer to show its impact on disease diagnosis, monitoring of diseaseprogression and individualistic treatment approach.Molecular cell pathology in diagnosisand preventionNeurodegenerativediseases (NDD), one of the major killers of the modern world, are oftencharacterised by loss of function (ataxia) or sensory dysfunction (dementia)resulting from the degeneration of white nerve cells in the brain and spinalcord (Uttara et al., 2009). According to Gotovac et al. 2014, molecular cell pathology can be usedin the diagnosis, treatment and management of neurodegenerative disorders, andthe developing models of disease origin in NDDs are leading to innovativemethods of diagnosis in these diseases and allowing personalised therapy. InParkinson’s disease (PD), one of the key concerns has been the ability todistinguish the disease from multiple system atrophy (MSA), another disease onthe ND movement disorder spectrum (Vallelunga et al., 2014).
Molecularpathology research has identified MicroRNAs as a biomarker which can be used todistinguish between the two diseases (Marques et al., 2017). MicroRNAs regulateprotein translation and are present in cerebrospinal fluid, and specificmicroRNAs are present at differential levels in PD and MSA, allowing accuratediagnosis using quantitative polymerase chain reaction (qPCR) techniques. TraditionalAlzheimer’s disease (AD) diagnosis using only symptomatology lacks specificity whichis only marginally raised by the use of neuroimaging as an adjunct (Wollman& Prohovinik, 2003). The use of molecular pathology to characterisebiomarkers in the disease has therefore proven a popular approach in research.In particular, proteomic analysis of cerebrospinal fluid has revealed thebiomarkers – amyloid-? (A?42), phosphorylated tau (p-tau) and total tau (t-tau)which can act as diagnostic markers with relatively high levels of sensitivityand specificity (Babic & Simic, 2012). Molecular pathology may also providethe ability to detect AD even before its onset, as several biomarkers arepresent in the preclinical phase of the disease and may provide opportunitiesfor preventative medicine rather than diagnosis (Baird, Westwood , 2015).
For example, higher levels of the inflammatory haem enzyme, myeloperoxidase,in blood plasma correlates with the presence and development of Alzheimer’sdisease (Schreitmülleret al., 2013). Genetic aberrations, whether they aresomatic or hereditary are capable of causing cancer (Erole et al.
, 2012).In cancer pathology, the parading ofspecific gene rearrangements and their mutations are useful to healthpractitioners to confirm the diagnosis of particularcancers, namely sarcomas and lymphomas (Szabó et al., 2011). Moreover, the testing of gene also allowspractitioners to know the risk of cancer development in individuals in their lifetime so that preventive measures can be given to the patients who pose a risk ofcancer (Schiavon et al., 2012). For example, BRCA1 and BRCA2 arecrucial genes that regulate cellular function and mutation testing for cancerare done in patients especially patients with familial ovarian and breast cancerbackground.
(McCarthy and Armstrong, 2014) Dysfunctional BRCA1 and BRCA2 proteinspose risk in genomic instability due to DNA repair, transcription regulation,and protein ubiquitination dysfunction which ultimately leads to cancerdevelopment. Monitoring disease progressionThe pathophysiologicalmechanisms underlying Huntingdon’s disease (HD) have proven more difficult touncover, and so molecular pathology approaches in research are more limited forthe diagnosis of the disease. However, some biomarkers have been identifiedwhich allow the tracking of disease progression in HD and may be promisingtargets for personalised medicine and allow the tailoring of therapiesdepending on disease stage (Ryu et al., 2014). In particular, positron emissiontomography (PET) imaging allows the tracking of biomarkers such asphosphodiesterase 10A (PDE10A), which is currently the earliest knownbiological marker of HD-related change (Wilson et al., 2017). This earlydetection and tracking could allow doctors to tailor dosage of therapies suchas tetrabenzanine and implement early disease counselling (Frank, 2014).
Although there are currently no clinically-useful therapies which alter thecourse of disease, the use of early-detection and tracking markers such as PDE10Acould eventually allow doctors to triage patients before disease onset toimplement preventative medicine. Similar biomarkers have also been identifiedfor Alzheimer’s disease and Parkinson’s (Eskildsen et al., 2015), though noneof these have yet been transferred to clinical use.The usage of molecular cell pathology tomonitor progression of diseases such as cancer are currently little althoughsuccessfully conducted studies are reported.
In a longitudinal study in coloncancer patients, a subgroup of patients developed tumour after surgery. (Papadatos-Pastoset al., 2015) Phosphatidylinositol3-kinase (PI3K) pathway regulates proliferation and cell metabolism and severalmutations in PI3K was evident in patients with tumour recurrence. Therefore, thestudy suggested the use of PI3K as a prognostic marker for stratifying coloncancer patients according to their risk of recurrence, thus indicating apossibility of relapse after treatment. This phenomenon, known as “addiction ofoncogenes” uses molecular cell pathology to identify a specific biomarker whichcould provide an insight on cancer progression in individual patients.
Molecular cell pathology and noveltherapies Aswell as allowing greater discrimination between diseases in diagnosis and personalisedtracking of disease progression, molecular pathology also has a critical roleto play in the development of novel therapeutic strategies addressed to eachpatient independently. Advances in research examining the development ofParkinson’s, Alzheimer’s and prion diseases have shown that these diseases arecharacterised by three common features. First, the loss of neuronal function.
Second, the basis of the disease in protein misfolding and aggregation andthirdly the lack of a therapy which is able to halt or reverse the progressionof symptoms (Rowinska-Zyrek, Salerno & Kozlowski, 2015). Close links havealso been shown between the molecular mechanisms in PD and HD, with processessuch as oxidative stress, mitochondrial dysfunction and protein handlingimplicated in their development. As a result, agents which improvemitochondrial function and targeted therapies which interfere with proteinmisfolding have been suggested as potential therapeutic options (Schapira etal., 2014), although such research is in the early stages.Whilethere are no currently any therapies based on molecular cell pathology in NDDs whichcan be used clinically, the field of pharmacogenomics may provide a way formolecular pathology to be used to personalise existing therapeutic strategiesfor patients with NDD on the basis ofgenotypes (Cacabelos et al.
, 2015; Jalalianet al., 2013). Often involving alteration of drug or its dosage, thisfield attempts to reconcile the observed variations in drug response ofdifferent patients with variations in their genetic makeup, thus, attempting tofind reliable genetic correlation for increased, reduced orfunctionally-different drug action. MultipleSclerosis (MS) is an example of a common NDD where genomics plays an importantrole in disease response (Evande et al., 2017).
More than 100 genetic riskfactors have been identified with the development of MS, and there are avariety of disease-modifying therapies available including interferon beta,tumour necrosis factor inhibitors and glatiramer acetate. Variants in the classII region of the human leukocyte antigen (HLA) genes have been associated withthe efficacy of glatiramer acetate, but not interferon beta (Tsareva et al.,2016).
This makes these variant forms of the HLA class II genes an excellentcandidate for determining through molecular pathology whether a patient islikely to be susceptible to glatiramer acetate therapy before beginning apotentially expensive, time-consuming course of treatment which may have littleeffect.Unlike neurodegenerative disorders, molecularcell pathology is currently used for treatment in various types of cancer. Majorityof breast cancer tend to be epithelial where the intrinsic subtypes encompass HER2+, basal-like cancer, and luminal A & B (Yersal and Barutca, 2014). Previously, tumor types were definedthrough histological classification. Nowadays, depending on the identificationof specific molecular subtypes in breast cancer diagnosis, a more personalizedapproach in the field of medicine are used for targeted therapies. For example,Herceptin is only administered to patients with overexpression of the humanepidermal growth factor receptor type 2 (HER2) receptor and patients withER+/PR+ (oestrogen and progesterone hormone receptors) are treated withTamoxifen. (Dowsett et al., 2008) The clinical benefit obtained fromthis is approach over “one size fits all” is that it takes into accountvarious epigenetic and genetic alterations, which are critical drivers for breast tumour biology and hence affect the wayin which the tumour responds to certain treatment schemes.
Effective treatment of lung cancer iscurrently dependent on the understanding of oncological targets in lung cancerpatients that needs the use of molecularcell pathology. The approach identifies driver mutations like generearrangements for the development of drugs and pathway interventions. The newapproach has changed the consideration of lung cancer as a homogenous disease, which can only be treated through surgical pneumonectomy (Dorman et al., 2015). Conversely,understanding molecular cell pathology helps practitioners to use immuno-histochemicalmarker cells to define distinct histopathological cell subgroups which hashelped in successful chemotherapies often involving a combination of chemotherapeutic agents(Grizzle, Srivastava, and Manne, 2011; Laughney et al.
, 2012). The practice has been adopted in the medical field as the standard care in thetreatment of advanced small cell lungcancer, thus making sure that advanced cancers are treated with effectivechemotherapeutic agents as well. (Morabito et al.
, 2014) ConclusionMolecularcell pathology is an emerging powerful tool to understand diseases and tocharacterise them in an individualistic way that has not been previouslypossible. Traditionally, patients have been placed into a particular ‘diseasegroup’ such as lymphoma, Parkinson’s disease or type 2 diabetes and treatedaccording to a common guideline but molecular pathology allows a much morespecific categorisation of an individual’s disease in terms of their cellularmolecular expression and genomics. Fordiseases, which have resisted attempts to develop drugs which halt or reversethe disease, this could provide a powerful clinical method for tailoringtherapies to the precise molecular defects in these individuals, a personalisedmedicine. Molecular pathology may also allow diagnosis to occur much earlierthan disease onset and allow tailoring of therapy to disease progression. Pharmacogenomicapproaches may allow ineffective therapies to be excluded before beginningexpensive therapy with potential side effects. However, the use of ‘may’ and’could’ in almost all research in this field indicates what an early stage thisresearch is at, and with time, promising research is to be transferred to aclinical setting for useful personalised medicine. ReferencesBabi?,M.
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