Molecular biology of oral cancer The document discusses the molecular basis of oral cancer through three main points: 1) It describes common genetic alterations in oral cancer such as overexpression of oncogenes like EGFR and mutations in tumor suppressor genes like p53. 2) It explains how alterations in proto-oncogenes and oncogenes lead to uncontrolled cell growth and proliferation through signaling pathways and transcription factors. 3) It discusses how defects in DNA repair genes can cause genomic instability, a hallmark of cancer, through increased mutations that evade cell cycle checkpoints and apoptosis.

1. Molecular biology of oral
cancer
Presented by
Raghda ragab Mohamed Hassan

2. Oral cancer
Risk factor for oral cancer
Hallmarks of cancer
Molecular basis of oral cancer.
 Proto – oncogenes, oncogenes.
 Common gene alteration identified in oral cancer.
 Cell cycle and dysregulation in oral cancer.
 Apoptosis and oral cancer.
 Tumor suppressor genes involved in oral cancer.
DNA repair, defects and genome stability.

3.  Oral cancer refers to a subgroup of head and neck
malignancies
that develop at the lips, tongue, salivary glands, gingiva, floor of
the mouth, oropharynx, buccal surfaces and other intra-oral
locations.
 There are several types of oral cancers.
 The majority (>90%) of oral cancers are oral cancer
squamous cell carcinoma (OSCC).
 The incidence and mortality rates worldwide of OSCC are
approximately 5.9 and 3.3 per 100,000 persons per year.

4. Risk factors
for oral
cancer
Alcohol
consumption
Smoking and
tobacco
consumption
Family history of cancer
Excessive sun
Exposure

5. Figure 1: Hallmarks of cancer

6. Cellular basis of cancer
Cancer charactarized by abnormal
and uncontroled cell growth.
In normal tissues, the rate of new
cell growth and old cell death are kept
in balance.
In cancer cell, this balance is disturbed
This disturbtion in cancer result from
 uncontrolled cell growth.
Loss of a cell ability to
undergo apoptosis.

7. There are many differences between cancer cells and normal
cells.

8. Proto-oncogenes, oncogenes and oncoprotein
 Protoncogenes are genes whose protein products
have been found to be important for normal cell
growth signaling and whose overexpression or
mutation leads to unchecked cell growth and
tumorigenesis.
 Oncogenes represent a gain-of-function mutation
 Oncogenes can effect a cellular change through
mutation of only one of the two gene copies.

9. Activation of oncogenes

10. Table 1. Common gene alterations identified in oral cancer
Gene Frequency (%) Function
Proto-oncogenes
EGFR
c-myc/N-myc
K-ras/N-ras
Cyclin D1
STAT-3
>30%
20–40%
30–40%
30%
80%
Cell proliferation, growth
Cell growth, apoptosis
Signaling, growth
Cell-cycle regulation
Cytokine signaling, cell
proliferation
Tumor-suppressor
genes
Rb
p53
p16
30– 50%
50–60%
80%
Cell cycle regulation
Cell-cycle regulation
Senescence, cell-cycle
progression

11. Classification of oncogenes
1. Growth factors
2. Cell surface receptors (e.g EGFR)
3. Intracellular signal transduction pathways (e.g RAS gene
family).
4. DNA binding nuclear proteins transcription factors (MYC).
5. Cell cycle proteins (cyclins and cyclin dependent protein
kinases).
6. Inhibitors of apoptosis (bcl2).

12. Subcellular localization and functions of major classes of cancer-
associated genes

14.  TGF-a
 Transforming growth factor alpha promotes cell
proliferation in oral tissues as well as in other cell
types in the body.
TGF-a is overexpressed early and late in oral
carcinogenesis.
TGF-a stimulates a target cell by binding to the
epidermal growth factor receptor (EGFR) in an
autocrine or paracrine fashion.
TGF-a likely serves a tumor-promoting role in
epithelial carcinogenesis.

15. 2. Cell surface receptors (EGFR )
Growth factor receptors are activated in human tumors
by several mechanisms. These include mutations, gene
rearrangements, and overexpression.
Mutations of genes encoding cell-surface receptors can
result in an increased number of receptors or production
of a ligand-independent mitogenic signal.
EGFR is frequently found to be overexpressed in
human oral cancers.
.

16. 3. Intracellular signal transduction pathways
Of all the members of the intracellular signaling pathway, only
members of the ras gene family (H-ras, K-ras, N-ras) have been
examined in human oral cancer.
 Ras oncogenes encode for the related protein p21 that has been
localized to the cytoplasmic side of the cellular membrane.
Ras proteins bind guanine nucleotides (GDP and GTP) with high
affinity and specificity.
 Ras proteins transmit mitogenic signals by binding GTP and
hydrolysis of GTP to GDP ends the signal.

19. 4. DNA binding nuclear proteins transcription
factors
Transcription factors are proteins that regulate the
expression of other genes.
E.g: c-myc which helps regulate cell proliferation
and differentiation,
C-myc is frequently overexpressed in oral cancers.
Amplification and over-expression of c-myc has been
observed in 20–40% oral cancers.

20. 1-p53
 p53 gene is the most important TSG and has been called the
‘Guardian of the Genome’.
 p53 has a role in maintaining genome stability, and an
important role in cell cycle progression, cellular differentiation,
DNA repair and apoptosis.
p53 is known to be mutated in approximately 70% of oral
tumors.
The loss of the heterozygosity of the p53 allele has been
reported in 20% of oral cancer cases, as well as in 22% of
premalignant oral leukoplakia lesions.

21. Figure : p53 and cellular and genetic stability

22. p53 gene can be inactivated by several mechanisms,
including point mutations, deletion, and binding
with cellular and viral proteins.
 Point mutations result in a structurally altered
protein.
 Deletions lead to a reduction and loss of p53
expression and protein function.

23. p16 gene and its role

24. 5. Cell cycle proteins
cell cycle phases

25. Figure : Cell cycle checkpoints

26. Retinoblastoma gene (Rb)

27. Cyclins, cyclin dependent kinases (CDKs)
 Cyclins are a group of proteins known as the cyclins (D=
Departure; E= Exit through restriction point; A=Arrival at S Phase;
B= Bi or two chromatids ) promote different phases of the cell
cycle.
The cyclins and cyclin dependent kinases (CDKs) form the core
of cell cycle regulation.
 Expression of cyclins is cell cycle phase dependent .
The cyclin family members interact with CDKs, and these
complexes are required to pass through specific phases of the cell
cycle.

28. Figure :Regulation of cell cycle processes by CDK– cyclin complexes.

29. 6. Inhibitors of apoptosis (bcl2)
Apoptosis
( programmed cell death)
Normal cells are either repaired
or die (undergo apoptosis) when
they are damaged or get old.
A
P
O
P
T
O
S
I
s:
Extracellular:
FAS Ligand acting on FASR,
FAS receptor releasing
Initiating Intracellular Enzyme
Caspases- cell death, thus
called
“executioner”
Intracellular: pores in
mitochondrial inner, outer
membranes releasing
Initiating Intracellular Enzyme
Caspases- cell death, thus
called “executioner”

30. DNA repair, Defects and Genomic instability
 In normal cell, DNA damage can occur from environmental agents and
the DNA of normal dividing cells is susceptible to alterations resulting from
errors that occur during DNA replication.
Defects in three types of DNA repair systems, namely, mismatch repair,
nucleotide excision repair, and recombination repair.
 In oral cancer cells, Such mistakes, if not repaired ,it will push the cells in
to neoplastic transformation.
 Defects in repair mechanisms are present in human oral cancers and cause
genomic instability.
Genomic instability occurs when both copies of these genes are lost as in
tumor suppressor genes.

31. Figure : DNA repair. & genomic stability.

32. Figure : Mechanism of genome preservation and stability.