Four classes of normal regulatory genes are involved in carcinogenesis: proto-oncogenes, tumor suppressor genes, programmed cell death genes, and DNA repair genes. The eight hallmarks of cancer include self-sufficiency in growth signals, evading growth suppression, altered metabolism, evading apoptosis, limitless replication, sustained angiogenesis, metastasis, and evading the immune system. Cancer risk increases with age as multiple genetic changes accumulate over time. Heredity also contributes, as some cancers cluster in families due to inherited cancer syndromes, familial cancers, or recessive DNA repair gene mutations.

1. University of Mosul
College of Medicine
Lecture: Neoplasia , lecture No. 5
Subject/year: Neoplasia / 2022
Lecturer: Prof. Dr. Wahda M.T. Al -Nuaimy
Department: Pathology.
Date: 22-11-2022

2. The AIM of this lecture is
• Molecular basis of cancer.
• The four classes of normal regulatory genes are
involved in carcinogenesis.
• Host defense against tumors.
• Mechanisms developed by tumor cells to
escape or evade immune system.
• Cellular and molecular hallmarks of cancer.

3. Intended learning outcomes:
• To explain the molecular basis of cancer.
• To discuss the four classes of normal regulatory
genes are involved in carcinogenesis.
• To define the host defense against tumors.
• To identify the mechanisms developed by tumor
cells to escape or evade immune system.
• To verify the cellular and molecular hallmarks of
cancer.

4.  Nonlethal genetic damage, the initial damage (or
mutation) may be :
A) Acquired by environmental factors such as:
- Radiation
- Chemical substances
- Viruses
B) Inherited in the germ line cells , e.g. Familial
adenomatous polyps (APC gene) autosomal dominant
disorder.
 A tumor is formed by the clonal expansion of a single
precursor (progenitor) cell that has incurred genetic
damage (i.e., tumors are clonal).
Molecular basis of cancer

5.  Involvement of normal regulatory genes.
 Four classes of normal regulatory genes are
involved in carcinogenesis.
1. Proto-oncogenes.
2. Tumor Suppressor Genes.
3. Programmed cell death genes.
4. DNA repair genes.

7. There are several possible ways of
proto-oncogene activation :
• 1-Point mutation :
e.g. RAS gene in esophageal, colonic and
pancreatic tumors.
• 2- Amplification:
e.g. HER 2 in breast cancer.

9. • 3-Translocation to a transcriptionally active site ;
e.g. Burkitt lymphoma due to translocation of MYS
oncogene into immunoglobulin locus.
• 4- Fusion gene creation due to chromosomal
rearrangement ;
Translocation between chromosome 9 and 22
(BCR_ABL fusion gene in CML) .

10. 2- Tumor Suppressor Genes
These are genes whose products normally stop
a cell growing, or trigger checkpoints that cause
cell cycle arrest if DNA damage occurs.
tumor suppressor genes are cell cycle arrest genes or
DNA repair genes, e.g.:
• Mutant P53 gene (found in more than 50% of
cancers).
• Mutant APC gene →Familial adenomatous polyps
• Mutant Rb gene → Retinoblastoma.

11. P53
• A very important gene; it is the guardian of the genome
or the molecular policeman (P53 prevents replication
of damagedDNA)
• P53 prevents neoplastic transformation by three
interlocking mechanisms:
By activation of temporary cell cycle arrest (quiescence)
Or induction of permanent cell cycle arrest (senescence)
Or triggering of programmed cell death (apoptosis).

15. The role of P53 in maintaining the integrity of genome

16. 3- programmed cell death genes:
(apoptosis)
• Tumor mass may result not only from activation
of growth-promoting oncogenes or
inactivation of growth-suppressing tumor
suppressor genes, but also from mutations in
the genes that regulate apoptosis.
• e.g. overexpression of BCL-2 ( anti-apoptotic gene)
in follicular B cell lymphomas.

17. 4. DNA repair genes
• These genes are code for proteins whose
normal function is correct errors in DNA.
• DNA repair genes are active throughout the cell
cycle , particularly during G2 after DNA
replication and before chromosomal division.

18. • Mutations in DNA repair genes can lead to a
failure in repair, which in turn allow
subsequent mutations to accumulate.
• If the rate of DNA damage exceeds the capacity
of the cell to repair it, the accumulation of
errors can result in cancer.

19. Xeroderma pigmentosum
Changes of the skin include marked
freckly hyperpigmentation, atrophy, and
numerous warty & nodular growths.

21. Host Defense against tumors
(Antitumor Effector Mechanisms)
-Tumor cells can be recognized by the immune system as
non-self and destroyed.
-Cell-mediated immunity is the dominant antitumor
mechanism.
• Cytotoxic T-lymphocytes (CD8+ T-Cells) ,NK cells &
Macrophages.
-Although sera from cancer patients may contain antibodies
that recognize tumors, there is limited evidence that they play
a protective role under physiologic conditions.
-Tumor antigens are presented on the cell surface by
MHC class I molecules and are recognized by CD8+
cytotoxic T-lymphocytes.

22. Mechanisms
by which
tumors
evade the
immune
system.

23. Eight Cellular and Molecular Hallmarks of Cancer
1) Self-sufficiency in growth signals.
2) Insensitivity to growth-inhibitory signals.
3) Altered cellular metabolism.
4) Evasion of apoptosis: Tumors are resistant to
programmed cell death.
5) Limitless replicative potential: Tumors have
unrestricted proliferative capacity, a stem cell–like
property.
6) Sustained angiogenesis.
7) Ability to invade and metastasize.
8) Ability to evade the host immune response

24. AGE
• Cancer is most common in those over 55 years of age,
a fact pointing that cancer evolution requires multiple
independent events, apparently taking place over a
long periods of time.
• Certain tumors are particularly common in children
(under 15 years of age), these include
• Leukemias and lymphomas.
• neuroblastomas .
• Wilms’tumor ( nephroblastoma).
• Ewing’s sarcoma .
• Osteosarcoma.
• Rhabdomyosarcoma .
• Retinoblastoma.

25. HEREDITY
• Heredity plays a role in the development of cancer
even in the presence of clearly defined
environmental factors.
• Hereditary forms of cancer can be divided into
three categories.
1- Inherited cancer syndromes.
The predisposition to tumor is an autosomal
dominant trait, as exemplified by Familial
Retinoblastoma and Familial Adenomatous
Polyposis Coli (FAPC).

26. 2- Familial cancers: These are characterized by
familial clustering of specific forms of cancer,
Familial forms of breast, colon, brain and
ovarian cancer are recorded.
Sometimes tumors are linked to certain genes
such as the linkage of BRCA-1 & BRCA-2 to
familial breast & ovarian cancers.
3- Autosomal recessive syndromes of defective
DNA repair e.g., Xeroderma pigmentosa.

28. To summarize :
Four classes of normal regulatory genes are involved in carcinogenesis.
1. Proto-oncogenes.
2. Tumor Suppressor Genes.
3. Programmed cell death genes.
4. DNA repair genes.
Eight Cellular and Molecular Hallmarks of Cancer
1) Self-sufficiency in growth signals.
2) Insensitivity to growth-inhibitory signals.
3) Altered cellular metabolism.
4) Evasion of apoptosis: Tumors are resistant to programmed cell death.
5) Limitless replicative potential: Tumors have unrestricted proliferative
capacity, a stem cell–like property.
6) Sustained angiogenesis.
7) Ability to invade and metastasize.
8) Ability to evade the host immune response.

29. MCQ:
One of the following is cancer suppressor gene
a. Her- 2
b. RAS gene.
c. BCL-2.
d. mutant Rb gene.
e. Bax gene.
All of the following malignant tumors are common in children
except
•
a. Neuroblastomas .
b. Wilms’tumor.
c. Ewing’s sarcoma.
d. Retinoblastoma.
e. lung cancer.

30. Home work??
Try to make MCQ questions about the information
get it’s from this lecture!!

32. Thank you