Biokimia Kanker :

Karsinogen, Onkogen & Gen Supresif Tumor

F. Ferdinal

Dept. Biokimia dan Biologi Molekuler

Fakultas Kedokteran
Universitas Tarumanagara
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 Pendahuluan
 Kanker dikenal sudah sejak lama sekali !

 Mesir (-2500 SM): osteosarkoma pada mummi.

 Hipocrates (-400 SM) : imbalans antara black humor

dan 3 body humors - natural (alamiah).

 Sir Percivall Pott (1775): kanker skrotum.

 T. Boveri (1914): lesi pada DNA akibat mutasi somatik.

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 P. Broca (1866): kanker payudara dan kanker hati akibat
kelainan yang sifatnya herediter.
 Peyton Rous (1910): RSV menyebabkan kanker – v-src.
 J. Michael Bishop & Harold E. Varmus (1976): v-src punya
pasangan homolog di dalam sel normal – c-src.
 Henry Harris (1969): Gen supresor tumor, berperan dalam
mengendalikan pertumbuhan sel.
 Kanker : adalah penyakit genetik (transformasi ganas)

Cancer is a genetic disease at celular level

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TIMELINE of CANCER DISCOVERIES

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Perubahan pada transformasi ganas
 Perubahan biokimia : aerobic glycolysis, Warburg effect
 Perubahan bentuk sel
 Hilangnya inhibisi kontak pertumbuhan
 Hilangnya inhibisi kontak pergerakan
 Hilangnya ketergantungan pada penjangkaran
 Perubahan struktur sitoskeleton
 Berkurangnya kebutuhan faktor pertumbuhan

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Molecular Basis of Cancer Phenotypes:

1 Immortality ( Telomereae & GST)

2 Decreased Dependence on Growth Factors to
Support Proliferation,
3. Loss of Anchorage-Dependent Growth and
Altered Cell Adhesion,
4 Cell Cycle and Loss of Cell Cycle Control,
5 Apoptosis and Reduced Sensitivity to Apoptosis
6 Increased Genetic Instability (CIN ,
Chromosomal Instability: Aneuploidy, LOH )
7 Angiogenesis

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Six major features of cancer cells
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Some biochemical and genetic changes occurring in human cancer cells
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The cell cycle showing checkpoints at which DNA is monitored before
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The Ames Test to screen for mutagensJump to first page
Berenblum & Shubik (1947)
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Initiators and Promoters

 Tumor Initiators = Mutagens

X rays
 Ultraviolet Light
 DNA alkylating agents

 Tumor Promoters = Proliferation Inducers

 Phorbol Esters (croton oil)
 Inflammation (hepatitis)
 Estrogens and Androgens
 Epstein-Barr Virus

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 Cancer is a Genetic Disease
 Somatic mutations occur in most cancers.
 Inherited germline mutations occur in rare familial
cancer syndromes.
 Increases in mutation rate or genomic instability
increase frequency of cancer.
 Aneuploidy is a hallmark of cancer cells.
 Genetic selection at the level of single cells.

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Genetic Theory of Cancer

dispermic fertilization in sea urchin

Theodor Boveri, 1914

normal cancerIF by Bill Brinkley

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There are 3 main categories of Tumor Suppressor
Genes: Gatekeepers, Caretakers & Landscapers
In 1997 Kenneth Kinzler & Bergt Vogelstein
• Gatekeepers, control cell proliferation by
regulating the cell cycle. That are responsible for
controlling, or inhibiting cell growth.

• Caretakers. maintain the integrity of cellular

genetic material. The true ‘caretaker’ genes, however,
are generally more directly involved with the repair of the
DNA. Eg: mlh1 and msh2

• Landscaper genes, and they encode products that help

create environments that control cell growth, Eg: PTEN
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Some ways in which proteins encoded by oncogenes work. The Figure shows examples of various
proteins encoded by oncogenes. The proteins are listed below with the corresponding oncogene
given in parentheses along with its OMIM number. A growth factor, FGF 3 (INT2,164950); a growth
factor receptor, [EGFR] (HER1, 131550); a G protein (H-RAS-1, 190020); a signal transducer (BRAF,
164757); a transcription factor (MYC,190080); a tyrosine kinase and involved in cell-cell adhesion
(SRC, 190090); a cell cycle regulator (PRAD, 168461); a regulator of apoptosis (BCL2, 151430).
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Burkitt’s Lymphoma Jump to first page
CML
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Point Mutation
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Guardian of the Genome

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3. Genes involved in DNA repair
• Peroderma pigmentosum,
• Ataxia telangiectasia,
• Fanconi’s anemia and
• Bloom’s syndrome

4. Epigenetic
•Metilasi DNA
•Genomic Imprinting
 The overall progression to malignancy is
therefore a complex event.
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Some Genes Associated with Colorectal Carcinogenesis
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