BIOMARKERS IN CANCER DIAGNOSIS

Abstract: Since the field of cancer biomarkers has grown so rapidly in recent
years, there have been many chances to improve the management of cancer
patients by increasing the effectiveness of treatment and the efficiency of
detection. The investigation of numerous possible biomarkers and the
resurgence of interest in creating novel biomarkers have been made possible by
recent technical advancements. A wide range of biochemical substances, such as
proteins, sugars, lipids, nucleic acids, small metabolites, cytogenetic and
cytokinetic parameters, and entire tumour cells found in bodily fluid, may be
biomarkers of cancer because of their altered state in cancers and potential use
as diagnostic indicators. Deregulating their activity also presents new
possibilities for treating cancer.
KEYWORDS: Biomarkers; cancer; cancer diagnosis; cancer therapy
INTRODUCTION
The knowledge of cancer and its therapy has advanced significantly over the
previous three decades. Molecular biomarkers are compounds that indicate the
presence of cancer in the body and are used in cancer research. Variations in
messenger RNA (mRNA) and/or protein expression, post-translational
modifications of proteins, metabolite levels, and genes are examples of
biomarkers. Genomic, proteomic, and metabolomic biomarkers have the
potential to be used to diagnose cancer. Prostate tissue secretes PSA, which is
authorised for use in the treatment of prostate cancer. Ovarian tissue secretes a
protein known as CA-125, which is thought to be unique to ovarian cancer.
Finding these biomarkers is very important since early cancer detection may
improve available treatments, improving survival rates and enabling better
disease management. [1] Less than 12 biomarkers for cancer response,
surveillance, or recurrence have been authorized by the US Food and Drug
Administration (FDA) in the last 20 years. This is unexpected given that
thousands of biomarkers have been identified or recognized as possible
indicators for the identification and diagnosis of cancer. None, though, have
shown to be successful thus far The molecules known as biomarkers are those
that change significantly during cancer and have significant therapeutic
implications. Prognostic, predictive, and diagnostic biomarkers can be proteins,
isoenzymes, nucleic acids, metabolites, or hormones. The current focus in
clinical cancer diagnosis is on creating analytical techniques that can detect
biomarkers in a sensitive and parallel manner, making point-of-care diagnostics
useful.[5] The currently available clinically approved cancer biomarkers are
most beneficial However, single biomarkers with satisfactory sensitivity (ability
to detect individuals with the disease) and specificity (ability to distinguish
individuals with the disease from those that are either normal or have some
other condition) have not been identified for the most common cancer.[6]
Global cancer statistics for 2018 predicted 18.1 million new cases and 9.6
million cancer-related deaths. Lung, breast, and prostate cancer are the three
main types of cancer The primary reason for the development of new diagnostic
methods for cancer detection is that the disease is curable if it is discovered
early. A biomarker is a crucial tool for the identification and tracking of cancer.
Examples of biomarkers include changes in gene transcription or translation,
protein product modification, and/or gene mutations.[8] Currently, early illness
detection and recurrent disease identification are the most prominent uses of
tumour biomarkers. In the future, more advanced diagnostics that might
anticipate the course of a tumour and forecast how each tumour would react to
specific treatment medications might be created.[9] Finding stable biomarkers
that can be regularly assessed in readily accessible samples is one of the main
issues in cancer research It has been demonstrated over many years that serum
and other bodily fluids include cell-free DNA and RNA and that these
circulating nucleic acids may serve as potential biomarkers.[10] Clinical
oncologists might benefit from quantifiable characteristics known as diagnostic
and prognostic biomarkers when they initially contact with suspicious patients.
These are especially helpful in determining who is at risk of making an early
diagnosis and choosing the most effective treatment option Tracking therapy
responses These biomarkers come in a variety of forms; conventional
biomarkers are those that may be evaluated using radiological Methods.[11]
Platforms for the Analysis of Biomarkers
Genomic Technologies
Genomic technologies make it possible to determine and keep track of genetic
changes brought on by environmental agents and the genetic elements underlying
carcinogenic transformation. Genomic technologies that are frequently utilised
include fluorescence in situ hybridization (FISH), PCR-based tests, and DNA
microarrays. These genomic approaches have several advantages, such as the
availability of numerous robust high-throughput testing methods and the capacity
to amplify particular DNAs and RNAs that may be present in very low
concentrations in the specimens. Genetic mutations, loss of heterozygosity
(LOH), microsatellite instability (MSA), and DNA methylation are examples of
DNA-based biomarkers. The majority of mRNAs discovered in tissues and
physiological fluids are used as RNA-based biomarkers.[1] SAGE technology is
a relatively new advancement that is sensitive, all-inclusive, and capable of
analysing gene expression in species whose genomes are unknown.[3]
Microarray technology has been used by several scientists to monitor and modify
gene expression. Following BRCA1-induced expression in MDA435 breast
cancer cells, several genes were overexpressed, including the early growth
response 1 (EGRI) gene and the DNA-damage inducible gene (GADD45). Ki67
and the prothymosin A gene, which were predictive indicators of breast cancer in
the past, were two of the repressed genes.[9]

Proteomic Technologies
Although it was first used to refer to large-scale, high-throughput protein
separation and identification processes, the word proteomics has since been
extended to cover protein structure and functional analysis. Information from
proteomics differs from and complements information from genomes.[4] By
marking distinct protein populations with fluorescent dyes, the differential in-gel
electrophoresis technique, which was developed recently, makes it easier to
evaluate protein expression. Recently, this method has been applied to find
proteins that are differently expressed in breast cancer and squamous cell
carcinoma. The primary constraints of the 2D-PAGE technique are its incapacity
to identify proteins with low abundance and the challenges associated with
implementing it in high-throughput assays.[5] Protein-based biomarkers include
variations in the amounts and posttranslational modifications of proteins detected
in tissues and body fluids. One benefit of proteomic approaches is the availability
of well-established and quantitative testing techniques. The majority of cancer
biomarkers that are currently employed in clinical settings are antibody-based
assays for proteins in sera, such as cancer antigen-125 (CA-125) for ovarian
cancer and prostate-specific antigen (PSA) for prostate cancer. Previously, the
main proteomic technique for finding biomarkers was mass spectrometry in
conjunction with two-dimensional polyacrylamide gel electrophoresis (2D-
PAGE).[9]
Metabolomic Technologies
Metabolomic methodologies evaluate populations of low-molecular-weight
metabolites using analytical techniques such as gas-liquid chromatography
(GLC), high-performance liquid chromatography (HPLC), nuclear magnetic
resonance spectroscopy (NMR), and mass spectrometry (MS) [5] Metabolomics
refers to the study of metabolites found in cells, organs, and biological fluids.
Because the identities, concentrations, and fluxes of these molecules represent
the results of interactions between gene expression, protein expression, and the
cellular environment, metabolomics has the potential to be useful for both cancer
detection and monitoring. Changes in cellular metabolites are frequently a part of
carcinogenic transformation, and body fluids can contain metabolites of
environmental poisons that are crucial to this process.[9]
Diagnostic & prognostic biomarkers
Recent discoveries in genomes and proteomics have yielded candidate markers
that may be useful for cancer screening, even though few such markers have made
it to the clinic. One of the novel tumour indicators that could aid in the early
detection of cancer is calcitonin. A patient with thyroid medullary carcinoma has
higher serum levels of calcitonin, which may be helpful in screening for this
cancer after additional clinical assessments.[8] It has been discovered that a
number of identified cancer biomarkers have limited sensitivity since they are
only present in a tiny fraction of individuals with a certain kind of cancer. These
markers can help identify recurring diseases in patients whose tumours generate
that specific marker, even though they are not effective for broad screening. CA-
125 is one such biomarker that is found in a subset of ovarian tumours. It is not
advised to use CA-125 for general screening because it is also increased in
endometriosis and a few other benign disorders, and it is unable to detect over
50% of early malignancies. One marker for colon cancer is CEA. It is helpful for
follow-up but has inadequate specificity and insufficient sensitivity to be utilised
as a screening marker. [2]
 Examples of biomarkers in cancer research
Biomarker Tumour Application Method of detection
Genomic
BRCA-1 Breast Cancer Diagnostic RT-PCR
Her-2 Breast cancer Prognostic FISH, PCR
EGFR Lung cancer Prognostic DNA sequence
PD-L1 Lung Cancer Selection of Patients NGS-TMB determination
MSH2 Hepatocellular polymorphism SNP Genotyping
carcinoma
ERCC1 Prostate Cancer polymorphism SNP Genotyping
Proteomic
PRDX6 Prostate cancer Diagnosis 2D-PAGE
ANX1 Lung cancer Diagnosis 2D-DIGE
SMR Prostate cancer Prognosis Mass spectrometry
CA-19 colon cancer Diagnosis Immunoassay
NCHL1 Breast cancer Diagnosis Mass spectrometry
HSP70 Breast prognostic ELISA
Cells as biomarker
CTCs breast cancer Diagnostic Immunocytometry
CSC brain tumour prognostic Immunocytometry
Metabolic biomarker
Glucose metabolism All cancers Diagnostic FDG-PET scan
Cotinine Lung Cancer Exposure HPLC
Deoxynivalenol Esophagus Exposure Mass spectrometry
Metabolomic
Metabolomic profiling ovary Diagnosis 1H NMR spectroscopy

Cancer research can make use of genetic, epigenomic, proteomic, and metabolic biomarkers. The
methods for biomarker analysis and how they are used in cancer research are described. the
biomarker's significance for a particular form of cancer and the characteristics of the specimen that
allow for its analysis.
Advances in biomarker discovery

Finding and confirming novel biomarkers can be accomplished through the use
of differential expression of proteins For many years, 2D-PAGE and mass
spectrometry have been the main methods utilised in conventional proteomics
investigation to find novel biomarkers.[8] Many new biomarkers have been found
thanks to recent developments in biomarker research that use gene arrays in
addition to proteomic technologies like mass spectrometry and two-dimensional
electrophoresis (2-DE). Nuclear matrix protein-22 and bladder tumour antigen
(BTA) are two recent urine-based biomarkers that the FDA approved as
diagnostic indicators for bladder cancer. Calreticulin (CRT), another potential
diagnostic biomarker for bladder cancer, was recently discovered.[9] Using
nanoLC-MS/MS, Sokolowska et al. found receptors for the tumour differentiation
factor (TDF), which is expressed in human breast and prostate cancer cells.
Notably, the receptors in question were members of the heat shock 70-kDa protein
family (HSP70), indicating a connection between the presence of cancer and this
protein family.[8]
Predictive biomarkers
Increasingly, markers that seek to predict cancer outcomes instead of early
detection have been found in recent years. This advancement results from the
ability of novel genomics and proteomics techniques to identify genes and
proteins linked to certain cancer stages. Furthermore, these markers are
frequently seen in the bloodstream at detectable concentrations, maybe as a result
of tumours that are larger and necessitate a prognosis test. These biomarkers can
differentiate between tumours that are invasive and non-invasive, metastatic and
nonmetastatic, and benign and life-threatening.[9]
Limitations of biomarker development
Proteomics limitations in the creation of biomarkers- By discovering toxicity
biomarkers, proteomics has made it possible to better understand the underlying
mechanisms of toxicity and clinical therapies.[2] It has also been utilised to boost
the sensitivity and speed of toxicological screening (Kennedy, 2002). Proteomics
enhanced the predictability of early drug development, discovered non-invasive
biomarkers of toxicity or efficacy, and shed light on the mechanisms of action of
a wide range of chemicals, including metals and peroxisome proliferators
(Kennedy, 2002).23 Low-detection limit clinical biosensors are very promising
for the early identification of crippling illnesses. The ability to identify target
molecules at the single molecule level has been demonstrated thanks to recent
advancements in sensor development. For such sensors, measurement fidelity is
a critical performance criterion that has not received enough attention. Since we
anticipate that systems with higher sensitivity will also respond more strongly to
interfering molecules, measurement fidelity is defined by the system's false
positive rate.[13]
Future of cancer biomarkers
The field of biomarker discovery has to be advanced by a significant and
coordinated effort. The paucity of effective biomarkers for cancer detection,
screening, and treatment is evident from recent developments. The majority of
biomarkers do not meet the necessary standards for sensitivity and specificity to
be used in clinical studies to measure the impact of drugs and for the identification
of cancer.[2] Prognostic and predictive cancer biomarkers hold the key to the
future of clinical cancer management. The requirement for markers that indicate
which treatment choices are most likely to be beneficial for a given patient with
a given cancer and that predict outcomes has increased due to the development
of new medicines. The need for a range of new biomarkers that are both sensitive
and specific is expected to be met by the recent advancements in genomic and
proteomic technologies, such as gene array technology, enhanced two-
dimensional gel electrophoresis, and novel mass spectrometric techniques, in
conjunction with advances in bioinformatic tools. Determining the cost-
effectiveness of clinical cancer management will be significantly influenced by
biomarkers that identify tumours, forecast cancer outcomes, and affect therapy
selection. When combined, a limited panel of biomarkers will accurately predict
the molecular staging of a disease. A key objective for the future of oncology is
the development of straightforward diagnostic kits that may be used in the clinic
or by prospective patients themselves, and that will reliably and precisely predict
malignancy.[9]
CONCLUSION
Molecular markers are more likely to enhance diagnostic imaging throughout the
screening process than to completely replace it shortly. When used in conjunction
with diagnostic imaging, non-invasive molecular markers can help detect cancer
sooner and streamline the screening process, giving physicians more tools in their
arsenal. All of these, along with the entire genome, can be analysed more quickly
and affordably because of a variety of platforms and high throughput
technological advancements. This is significantly influencing how medicine is
currently practised, resulting in the creation of precision medicine through a
personalised approach. therapeutics grounded in pharmacogenomics.3 Recent
developments in mass spectrometry, two-dimensional gel electrophoresis, gene
array technology, and other proteomic and genomic technologies, along with
improvements in bioinformatic tools, hold great promise for addressing the need
for the identification of a wide range of novel biomarkers that are both specific
and sensitive.18 Future and current genomic and proteomic technologies hold
great promise for discovering new biomarkers. By enabling the customisation of
treatment to target the patient's unique molecular lesions and by offering
instruments for anticipating and tracking therapeutic responses, these biomarkers
can greatly improve the effectiveness of cancer care.
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