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Dr.Nazar Jawhar

Major insights into the causes of cancer can be obtained by epidemiologic studies that relate particular environmental, hereditary, and cultural influences to the occurrence of specified neoplasms. Example the well established concept that cigarette smoking is causally related to lung cancer arose primarily from epidemiologic studies. Also comparison of diet and cancer rates in the Western world and Africa has implicated high dietary fat and low fiber in the development of colon cancer

Dr.Nazar Jawhar

Cancer incidence
It is important to study the national incidence & mortality relate for each cancer & also to see if there are any changes in the incidence & death rate of caners over the years.

Dr.Nazar Jawhar

Example the increase in the mortality rate of lung cancer among women ( due to increase in the incidence of smoking among women). Mortality rate from liver cancer increases among males due to the large number of individuals infected with the hepatitis C virus (HCV). In the other hand, there is a decrease in the mortality rate of cervical carcinoma of the female uterus (Why?). Also decrease in deaths from stomach cancer has been attributed to a decrease in some dietary carcinogens, as a consequence of better food preservation or changes in dietary habits

Dr.Nazar Jawhar

Cancer incidence and mortality by site and sex

Dr.Nazar Jawhar

Geographical & environmental factors:
Although both genetics and environmental factors play a role in the pathogenesis of cancer, environmental factors are thought to be the more significant contributors in most common sporadic cancers. Remarkable differences found in the incidence and death rates of specific forms of cancer around the world suggesting a role for environmental factors



Dr.Nazar Jawhar
Geographical & environmental factors:
Example the incidence of CA stomach among both sexes is 7-8 times higher in Japan than in USA (WHY?). Also the mortality rate of skin cancer (especially melanoma) is 6 times higher in NZ than Island (WHY?). Most of these differences are due to environmental influences (occupational cancers).

Dr.Nazar Jawhar

Geographical & environmental factors:
Although racial predispositions cannot be ruled out, it is generally believed that most of these geographic differences are the consequence of environmental influences. Example study of the immigrants So, it is valuable to study the incidence & death rate for specific cancers among different nations of the world which reflect differences in environmental influences.

Dr.Nazar Jawhar

Geographical & environmental factors:
There is no paucity of carcinogenic environmental factors: they lurk in the ambient environment, in the workplace, in food, and in personal practices. Individuals may be exposed to carcinogenic factors when they go outside (ultraviolet [UV] rays, smog), in their medication (methotrexate), at work (asbestos, vinyl chloride), or at home (high-fat diet, alcohol). It appears that almost everything one does to gain a livelihood or for pleasure is fattening, immoral, illegal, or, even worse, oncogenic.

Dr.Nazar Jawhar

AGE:
Age has an important influence on the likelihood of being afflicted with cancer. Most carcinomas occur in the later years of life (>55 years).

Dr.Nazar Jawhar

Children are not spared; cancer accounts for about 10% of all deaths in children under age 15 in the States, second only to accidents. However, the types of cancers that predominate in children are significantly different from those seen in adults. ((Carcinomas, the most common general category of tumor in adults, are extraordinarily rare among children. Instead, acute leukemia and primitive neoplasms of the central nervous system are responsible for approximately 60% of childhood cancer deaths)).

Dr.Nazar Jawhar

The rising incidence with age may be explained by the accumulation of somatic mutations associated with the emergence of malignant neoplasms. The decline in immune competence that accompanies aging may also be a factor. The correlation between the incidence of a particular cancer & the age is important.

Dr.Nazar Jawhar

Heredity:
Is cancer an inherited disease??? The current evidence now indicates that for a large no. of cancers ( including the most common forms), hereditary predisposition exist beside environmental influences. Example: Lung cancer is related to smoking (environmental), but the mortality rate from lung cancer is 4 times greater among relatives of lung cancer patients than among relatives of controls.

Dr.Nazar Jawhar

Hereditary forms of cancer can be divided into 3 categories:

Dr.Nazar Jawhar

Include several well defined cancers that show an autosomal dominant pattern of inheritance ( due to inheritance of a single mutant gene that greatly increases the risk of developing a tumor.
Inherited cancer syndromes

inherited cancer syndromes (autosomal dominant)

Inherited Predisposition
Gene
Retinoblastoma
RB
Li-Fraumeni syndrome (various tumors)
p53
Melanoma
p16/INK4A
Familial adenomatous polyposis/colon cancer
APC
Neurofibromatosis 1 and 2
NF1, NF2
Breast and ovarian tumors
BRCA1, BRCA2
Multiple endocrine neoplasia 1 and 2
MEN1, RET
Hereditary nonpolyposis colon cancer
MSH2, MLH1, MSH6
Renal cell carcinomas
VHL

Dr.Nazar Jawhar

All common sporadic types of cancer have been reported to occur in familial forms. Example: breast CA, ovarian CA, colonic CA, brain CA,…etc.Characters: Early age of onset, affection of 2 or more relatives, multiple or bilateral tumors. The transmission pattern of familial CA is not clear. Familial cancer syndromes

Dr.Nazar Jawhar

A small group of rare autosomal recessive disorders that characterized by chromosomal or DNA defective repair and DNA instability.
Autosomal recessive syndromes of defective DNA repair
inherited autosomal recessive syndromes of defective DNA repair
Xeroderma pigmentosum
Ataxia-telangiectasia
Bloom syndrome
Fanconi anemia

Dr.Nazar Jawhar

Summary: The incidence of cancer varies with age, race, geographic factors, and genetic backgrounds. Cancers are most common at the two extremes of age. The geographic variation results mostly from different environmental exposures. Most cancers are sporadic, but some are familial. Predisposition to hereditary cancers may be autosomal dominant or autosomal recessive. Familial cancers tend to be bilateral and arise earlier in life than their sporadic counterparts.

Dr.Nazar Jawhar

Acquired preneoplastic disorders:

Dr.Nazar Jawhar

Can benign tumor change into malignant??

Dr.Nazar Jawhar

Carcinogenesis
Molecular Basis of Cancer

Dr.Nazar Jawhar

Genetic damage ( mutation) lies at the heart of carcinogenesis. The development of cancer involves the alteration of genes that regulate the cycle of cell growth. Such damage could be: Acquired through the action of environmental agents ( Chemical, virus, radiation). Inherited in the germ line. Then such mutant cells will undergo uncontrolled proliferation with clonal expansion to form a tumorous mass.

Dr.Nazar Jawhar

The targets of genetic damage are 4 classes of normal regulatory genes, these are:

Dr.Nazar Jawhar

Proto-oncogenes (growth promoting genes): A group of normal cellular genes whose products promote cell growth & proliferation. Oncogenes: mutant versions of proto-oncogenes that function autonomously without a requirement for normal growth-promoting signals, thus stimulate cell growth in an unregulated manner.
Protooncogens


Dr.Nazar Jawhar
Signal transduction Tyrosine kinase


Under physiologic conditions, cell proliferation can be readily resolved into the following steps: The binding of a growth factor to its specific receptor Transient activation of the growth factor receptor, which, in turn, activates several signal-transducing proteins on the inner leaflet of the plasma membrane Transmission of the transduced signal across the cytosol to the nucleus via second messengers or by a cascade of signal transduction molecules Induction and activation of nuclear regulatory factors that initiate DNA transcription Entry and progression of the cell into the cell cycle, ultimately resulting in cell division

GF: Many cancer cells acquire the ability to synthesize the same growth factors to which they are responsive, generating an autocrine loop. For example, many glioblastomas secrete platelet-derived growth factor (PDGF) and express the PDGF receptor, TGF-α

GFR: the mutant receptors deliver continuous mitogenic signals to the cell, even in the absence of growth factor in the environment. As RET receptor, epidermal growth factor (EGF) receptor family. The ERB-B2 gene (also called HER-2/NEU), the second member of the EGF receptor family, is amplified in 25% of breast cancers. Because the molecular alteration in ERBB2 is specific for the cancer cells, new therapeutic agents consisting of monoclonal antibodies specific to ERBB2 have been developed and are currently in use clinically, providing an example of targeted therapy. Also about 90% of gastrointestinal stromal tumors have mutation in the receptor tyrosine kinase c-KIT or PDGFR, which are the receptors for stem cell factor and PDGF, respectively. These mutations are amenable to specific inhibition by the tyrosine kinase inhibitor imatinib mesylate. This is another example of targeted therapy.

Signal-transduction: The most well-studied example of a signal-transducing oncoprotein is the RAS family of guanine triphosphate (GTP)-binding proteins (G proteins). Point mutation of RAS family genes is the single most common abnormality of proto-oncogenes in human tumors. Mutated RAS is trapped in its activated GTP-bound form, and the cell is forced into a continuously proliferating state. Approximately 15% to 20% of all human tumors contain mutated versions of RAS proteins. Other e.g is also seen in chronic myeloid leukemia ( CML) the ABL gene is translocated from chromosome 9 to chromosome 22 where it fuses with the BCR gene. The resultant chimeric gene encodes a constitutively active, oncogenic BCR-ABL tyrosine kinase. Recently, imatinib mesylate, a "designer" drug with low toxicity and high therapeutic efficacy has been used in the treatment of CML. It inhibits the BCR-ABL kinase.


Transcription factor: MYC is most commonly involved in human tumors. it is thought that MYC is involved in carcinogenesis by activating genes (such as cyclin D2), that are involved in proliferation.

Dr.Nazar Jawhar

Signal transduction Tyrosine kinase

Associated Human Tumor

Mode of Activation
Proto-oncogene
Category
growth factors
Astrocytoma
Overexpression
SIS (official name PBGFB)
PDGF-β chain Osteosarcoma


Stomach cancer
Overexpression
HST1
Fibroblast growth factors
Bladder cancer
Amplification
INT2 (official name FGF3)

Breast cancer

Melanoma

Astrocytomas

Overexpression
TGFA
TGF-α Hepatocellular carcinomas

Thyroid cancer

Overexpression
HGF
HGF

growth factor receptors

Squamous cell carcinoma of lung, gliomas
Overexpression
ERBB1 (EGFR), ERRB2
EGF-receptor family
Breast and ovarian cancers
Amplification
FLT3
FMS-like tyrosine kinase 3
Leukemia
Point mutation
RET
Receptor for neurotrophic factors
Multiple endocrine neoplasia 2A and B, familial medullary thyroid carcinomas
Point mutation

Gliomas, leukemias

Overexpression, translocation
PDGFRB
PDGF receptor
Gastrointestinal stromal tumors, seminomas, leukemias
Point mutation
KIT
Receptor for stem cell

Dr.Nazar Jawhar

Mechanisms of oncogene activation include:Point mutation: e.g ras Gene amplification: HSR & double minute.Chromosomal rearrangement (translocation): e.g t8:14 (c-myc-Ig) in Burkitt’s lymphoma, t9:22 (abl-bcr) in CML. Epigenetic changes:Example of oncogens: c-sis (GF), c-erb (G receptor), ras (signal transduction), c-myc (nuclear transcription).

Dr.Nazar Jawhar

Dr.Nazar Jawhar
Growth inhibiting genes. They normally function to suppress cell growth. Examples: p53, Rb, NF, VHL,BRCA Tp53: Guardian of the Genome: The p53 gene ,located on chromosome 17p13.1, is the most common target for genetic alteration in human tumors. Over 50% of human tumors contain mutations in this gene.
Tumor suppressor genes

Dr.Nazar Jawhar

Accumulation of neoplastic cells 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 These genes regulate the normal programmed death of a cell, and alteration of the gene, in a sense, immortalizes cells, allowing their continued growth and accumulation. Example:bcl-2 (Ch18).
Genes that regulate apoptosis.

Dr.Nazar Jawhar

(regulate repair of damaged DNA), they influence the ability of the organism to repair non-lethal damage in other genes. Any disability in the DNA repair genes predispose to mutation in the genome & then to neoplastic transformation. Example: hMLH1, hPMS1, hPMS2.
DNA repair genes

Dr.Nazar Jawhar

It is best therefore to consider cancer-related genes in the context of seven fundamental changes in cell physiology that together dictate the malignant phenotype: Self-sufficiency in growth signals Insensitivity to growth-inhibitory signals Evasion of apoptosis Limitless replicative potential (i.e., overcoming cellular senescence) Development of sustained angiogenesis Ability to invade and metastasize Genomic instability resulting from defects in DNA repair


Dr.Nazar Jawhar
The hallmarks of cancer


Most normal human cells have a capacity of 60 to 70 doublings. After this, the cells lose their ability to divide and become senescent. This phenomenon has been ascribed to progressive shortening of telomeres at the ends of chromosomes. So tumor cells must develop ways to avoid both cellular senescence and mitotic catastrophe. This is achieved by maintenance of telomere which is seen in virtually all types of cancers. In 85% to 95% of cancers, this is due to up-regulation of the enzyme telomerase

Dr.Nazar Jawhar

Multistep carcinogenesis
Carcinogenesis is a multistep process at both the phenotypic & genetic levels, resulting from the accumulation of multiple mutations. CA has several phenotypic characters, as excessive growth, local invasion, ability to form distant metastasis, ability to escape immunosurviellance,…etc.). These characters are acquired in a stepwise fashion ( tumor progression) due to the accumulation of mutations.

Dr.Nazar Jawhar

Mutation in no single gene is sufficient to cause cancer. It involves initiation, the first mutation that initiates the earliest phase of abnormal growth. Subsequently, there is a sequence of mutations (progression) in which the tumor acquires new characteristics as increase growth rate, capacity to invade & metastasize, immune evasion ,..etc. Typically, the phenotypic attributes characteristic of malignancy develop when multiple mutations involving multiple genes accumulate

Dr.Nazar Jawhar

Dr.Nazar Jawhar

Dr.Nazar Jawhar






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