Biomarkers for PMODs and OSCC Dr.Preethi

1. Current status of biomarkers for
PMODs and OSCCs with emphasis on
specificity and sensitivity of serum and
salivary biomarkers.
Dr. Preethi.A.
PG Student
Dept. Of Oral Pathology
SRM Dental College

2. CONTENT
• INTRODUCTION
• WHAT ARE PMODs AND OSCCs
• PATHOLOGIC DIAGNOSIS
• BIOMARKERS
• CURRENT STATUS
• RECENT ADVANCES
• CONCLUSION

3. INTRODUCTION
OPMD is a clinical diagnosis for which the histological diagnosis may be hyperplasia,
hyperkeratosis, oral epithelial dysplasia (OED) or oral squamous cell carcinoma (OSCC).
Leukoplakia – 1.49 – 2.60. Erythroplakia – 0.02%
Oral cancer – 11th most common cancer in the world (30 % of all cancers). Most lesions
of Oral cancer (80%)– preceded by clinically observable precursor lesions.
Traditional therapeutics have encountered a bottleneck caused by diagnosis delay and
subjective and unreliable assessment.
Biomarkers can overcome this bottleneck and guide us toward precision medicine.

4. POTENTIALLY MALGINANT ORAL
DISORDERS
WHO
1978
•Pre-malignant lesion is “a
morphologically altered
tissue in which
oral cancer is more likely
to occur than its
apparently normal
counterpart.”
•Pre-malignant condition
is “a generalized state
associated with a
significantly increased
risk of cancer.”
Oral
oncology
Journal,
2012
•OPMD
•It is a group of disorders
of varying etiologies,
usually tobacco
characterized by mutagen
associated, spontaneous
or hereditary alterations
or mutations in the
genetic material of oral
epithelial cells with or
without clinical and histo-
morphological alterations
that may lead to oral
squamous cell carcinoma
transformation.
OOOO
journal
,
June
2018
•Potentially premalignant
oral epithelial lesions.
•These lesions have the
potential to become
malignant and that in
their current status, that
is, before malignant
transformation, they may
represent an actual
premalignant state

6. CLINICAL PRESENTATION OF POTENTIALLY
PREMALIGNANT LESIONS
COMMON LESIONS
• Leukoplakia
• PVL
• Erythroplakia
• Erythroleukoplakia
• OSMF
• OLP
LESS COMMON LESIONS
• Palatal lesions in reverse smokers
• Discoid lupus erythematosus
• Epidermolysis bullosa
• Actinitc chelitis
• Oral lichenoid reactions
• Graft-versus-host disease (GvHD)

7. • About 5-18% of epithelial dysplasias become malignant.
• OSCC -62% high mortality rate.
• PMODs are the first indications of micro- and macroscopic alterations of possible
malignant transformations
• The estimated median time for this progression depends on the histologic severity of
the epithelial dysplasia: 58 months for mild, 38 months for moderate, and 12 months
for severe.

8. HALLMARKS OF CANCER

9. MALIGNANT TRANSFORMATION
Risk
factors
Female
gender
Lesion in
Non-smoker
Long
duration
Floor of the
tongue
Larger area
Non-
homogenous
type
Epithelial
dysplasia

10. PATHOLOGICAL DIAGNOSIS
Histo-
pathological
assessment
Cytological
assessment
Histochemistry
/
cytochemistry
Immuno-
histochemistry
Electron
microscopical
assessment
Tumor
markers
assessment
Mordern Aids:
Flow cytometry
Insitu
hybirdisation
Molecular
diagnostic
techniques
DNA microarray
analysis

11. WHAT ARE BIOMARKERS.??
A characteristic that is objectively measured and
evaluated as an indicator of normal biological processes,
pathogenic processes or pharmacological responses to a
therapeutic intervention.
Any substance, structure or process that can be measured
in the body or its products and influence or predict the
incidence or outcome of disease.
• [Strimbu et al: What are biomarkers?; 2011]
LIQUID BIOPSY

12. TYPES OF BIOMARKER
Biochemical /
serological
markers Histochemical /
tissue markers

13. BASED ON
MOLECULAR BASIS
Gen-
omics
Metabol
-omics
Biomarker
Prote-
omics

14. BASED ON CLINICAL APPLICATION
Diagnostic
marker
Prognostic
marker
Predictive
marker
Therapeutic
marker
To determine if a cancer is likely in
some patients and helps to diagnose
the origin of the cancer in advanced
widespread disease
To assess how aggressive a cancer is
likely to be or even how well it
might respond to certain drugs
To detect cancers that recur
after initial treatment
To monitor patients being
treated for cancer.

15. BASED ON COMPONENTS ASSESSED

16. TUMOR MARKERS
• Specific, novel or structurally altered cellular
macromolecule or temporarily, spatially or
quantitatively altered molecules associated with
malignant or in some benign neoplastic cells.
[Madhav Nagpal et al: Tumor markers: A diagnostic tool; 2016]
Cancer biomarkers are usually proteins
detected in the fluids that are either produced
by the tumor itself or in response to the
presence of cancer.

17. BASIC DIAGNOSTIC TERMINOLOGIES
SPECIFICITY
The ability of the test to correctly
identify those without the
disease (true negative rate)
If 100 with no disease are tested
and 96 return a completely
negative result, then the test has
96% specificity
SENSITIVITY
The ability of a test to correctly
identify those with the disease
(true positive rate)
If 100 patients known to have a
disease were tested, and 43 test
positive, then the test has 43%
sensitivity

18. POSITIVE PREDICITIVE VALUE
• It is the percentage of
patients with a positive test
who actually have the
disease
NEGATIVE PREDICITIVE VALUE
• It is the percentage of
patients with a negative test
who do not have the
disease
Positive and negative predictive values are directly related to the prevalence of
the disease in the population

19. Ideal requisites of tumor marker
It should be highly sensitive and should have low false negatives.
It should be highly specific and should have low false positives.
It should have high positive and negative predictive value.
100% accuracy in differentiating between healthy individuals and tumor patients.
It should be able to differentiate between neoplastic and non-neoplastic disease and show positive correlation with tumor volume and
extent.
It should be clinically sensitive i.e. detectable at early stage of tumor.
It should either be a universal marker for all types of malignancies or specific to one type of malignancy.
It should be easily assayable and be able to indicate all changes in cancer patients receiving treatment.

20. TYPES OF TUMOR MARKERS
Tumor
derived
markers
• Originate from neoplastic cells
Tumor
associated
markers
• Produced by cells of un involved
organs ( plasma, enzymes,
proteins etc).

21. SALIVARY BIOMARKERS
Valuable
body fluid.
Non-
invasive,
Larger
quanitity
Painless
Easily
accessible,
Easy to
repeat the
analysis
Standardised
protocols
Cost
effective
MIRROR OF THE
BODY

22. Role of Salivary biomarkers in
diagnosis of cancer
Markopoulos et al, 2010

23. Salivary biomarkers
• Cytokeratins
• MAGE
• Actin & myosin
• MDA
• MMPs
• CD -59,44
• CYFRA21.1
• TNF-alpha
• CtDNA, cfDNA
•Interleukins
•miR-
125a,200a,31
• Defensins
• Endothelin
Peptides
DNA ,
mRNA &
miRNA
Others
Proteins
Cheng et al, 2014

24. S.NO MARKERS DESCRIPTION TYPE OF SPECIMEN INFERENCE
1. MMPs (3,9) Family of enzymes. Helps in regulating cell growth, angiogenesis, and invasiveness. Saliva Poor sensitivity
2. ILs Sub group of cytokines. Important in stimulating immune responses, such as inflammation. Saliva Lack of specificity and sensitivity
3. CD44 An adhesion/homing molecule. Regulates cell migration, growth and differentiation and cell
adhesion.
Saliva and serum Lacks specificity
4. mRNA Molecule that links genes to proteins. Helps in Efficient and smooth interactions of the molecules. Saliva No clinical validation
5. Melanoma associated
antigen gene
Play important roles during embryogenesis, which later deactivated by a genetic mechanism such as
methylation. In the case of tumor formation, these genes are reactivated and the resultant proteins
may be recognized and attacked by the immune system.
Saliva No clinical validation
6. Actin and myosin Key cytoskeletal proteins that facilitate cell motility and invasion, behaviour central to epithelial
tumorigenesis
Saliva Lack of sensitivity and specificity
7. CKs (8,18, CRP) Intracytoplasmic cytoskeleton of epithelial tissue. They are an important component of intermediate
filaments, which help cells resist mechanical stress and are used clinically to identify the cell of origin
of various human tumors.
Saliva and serum No clinical validation
8. Cytokines (Tissue
polypeptide antigen,
leptin, VEGF)
Signalling molecules that mediate and regulate immunity, inflammation and hematopoiesis. Serum Lacks specificity
9. Adiponectine Produced by adipocytes. Acts as anti-diabetic, anti-atherogenic, anti-inflammatory and anti-
angiogenic hormone.
Serum Lack of sensitivity and specificity
10. CYFRA 21-1 Cytokeratin 19 fragment Saliva and serum Lacks specificity
11. TNF-alpha and DCR3 Tumor necrosis factor Serum Lacks sensitivity
12. Big endothelin-1 Vasoactive peptide associated with the development and spread of tumors Serum Lacks specificity and sensitivity
13. miRNAs Able to target multiple mRNAs and, thereby, potentially affect several important cellular pathways
involved in tumorigenic processes.
Saliva and serum High sensitivity in saliva
14. Vitamin D Anti-neoplastic activity Serum Lacks specificity and sensitivity
15. Melondialdehyde MDA, an end product of lipid peroxidation, is widely used as an index for oxidative stress in different
pathological conditions. Particularly, MDA’s high reactivity and capability to form adducts with
multiple biological molecules such as proteins or DNA shows its physiological relevance in cancerous
lesions. MDA–DNA adducts have been detected in oral mucosal cells as a marker for oral cancer risk.
Serum Significant rise in OMPD & OSCC

25. CONCLUSION
• The evaluation of these cancer biomarkers in liquid
biopsy has the advantage of providing a,
– Real-time picture of primary and metastatic tumors at
different time points,
– Giving information about tumor and tumor burden and
– Early evidence of drug resistance and tumor recurrence.

26. THAN
K YOU