Tumorigenesis, Genome Instability,

and Mutations

Sumadi Lukman Anwar

Division of Surgical Oncology- Department of Surgery
Faculty of Medicine Public Health and Nursing
 Outline

- Tumorigenesis
- Genome instability
- Mutations
 Tumorigenesis
Tumorigenesis/Carcinogenesis/Oncogenesis
 mechanisms of induction of cancer
 transformation of normal cells into cancer cells

Cell proliferation is a physiologic process – occurs in all organs

Homeostasis: balance between cell proliferation and programmed cell
death
DNA mutations  disrupt programming of regulatory process
 Theories of Carcinogenesis
- Genetic theory
- Epigenetic theory
- Immune surveillance theory
- Monoclonal hypothesis

mutations mutations

Mutated cell transmit their characteristics to the daughter cells

Oncogenes, TSG
Genetic defects: Xeroderma pigmentosum, HBOCS
Carcinogens affect activator and suppressor of the genes
Histone modification, DNA methylation, microRNAs, ncRNAs
Immunocompetent host  attack tumor cells
Cancer arises from a single clone of transformed cells -->
Multiple myeloma, leukemia  CD as surface marker
 Multisteps of Carcinogenesis

INITIATION PROMOTION PROGRESSION

Carcinogens Carcinogens
Mutations Mutations
Epigenetic altr Epigenetic altr
Immune defense Immune defense
Clonal evolution Clonal evolution

Carcinogenesis is a multistep process involving genetic, epigenetic

alterations in combination with host immune response and external
exposure of carcinogens
 INITIATION of Carcinogenesis
INITIATION PROMOTION PROGRESSION METASTASIS

The first step of carcinogenesis

Usually is result from irreversible genetic alteration spontaneously or is induced

by carcinogens
Genetic alterations cause dysregulation of cellular signaling pathways including
cell proliferation, cell survivals, and differentiation as well as DNA repair system
 PROMOTION of Carcinogenesis
INITIATION PROMOTION PROGRESSION METASTASIS

The phase between premalignant lesions and the development of invasive

cancer

Usually take long time and reversible

Accumulation of actively proliferating preneoplastic cells

 PROGRESSION of Carcinogenesis
INITIATION PROMOTION PROGRESSION METASTASIS

The final step of neoplastic transformation

Definitive changes of genetics, phenotypic, and proliferation rates

Significant increase of size and accumulation of genetic changes

 METASTASIS of Carcinogenesis
INITIATION PROMOTION PROGRESSION METASTASIS

Spread of cancer cells from the primary sites to the other body parts
- Lymphogenic
- Haematogenic

Invasion and angiogenesis

 Physical Carcinogenesis
Classification: - Radiation
- Non radiation physical agents
Radiation : UV and ionizing radiation

UV irradiation

Sunburn
ROS
DNA strand breaks DNA damages
Inflammation
Apoptosis
 Physical Carcinogenesis
The most important step of UV exposure in carcinogenesis

Formation of pyrimidine dimers in DNA  DNA breaks

DNA damages is usually repaired except in

- Predisposed individuals
- Excessively exposed

Predisposed individuals
- Xeroderma pigmentosum
- Ataxia-teleangiectasia
- Bloom syndrome
- Fanconi’s Anemia
 Physical Carcinogenesis
Ionizing radiation: X-ray, ⍶, ß-rays, radioisotops, proton, neutron
 Physical Carcinogenesis

Non-radiation physical carcinogens

- Chronic mechanical injuries

- Stones in gallbladder
- Stones in urinary tract

- Implants or prostheses
 Biologic Carcinogenesis

Bacteria

Fungus

Parasites

Aflatoxin B1

Codon 249 p53

HCC
 Viral Carcinogenesis

Virus:
- DNA virus : HPV, HBV, EBV, Kaposi’s sarcoma
- RNA virus : HCV, HTLV-1

Persistence of DNA & RNA viruses  mutations in the host cells

 activation GF, inhabitation of TG

Mode of DNA viral oncogenesis

- Replication
- Integration
 Viral Carcinogenesis

Mode of RNA viral oncogenesis

- Reverse transcriptase
- The single strand DNA  complementary DNA provirus
- Integrated into host cell  induce mutation and cell transformation
- Replication-competent
- Viral replication
 Viral Carcinogenesis

What support the etiologic role of viral carcinogenesis

- Epidemiologic data
- Presence of viral DNA in the host cells
- Demonstration of virus-induced transformed cells
- Specific transforming viral genes in premalignant and malignant cells
- In vitro assays: specific viral gene products  cell proliferation,
survival
Viral Carcinogenesis
 Carcinogenesis
Carcinogenesis
Adenocarcinoma

Hyperplasia Polyps Dysplasia

DNA
damage

Normal Early Advance Adeno-

TGFβ Metastasis
epithelium APC adenoma KRAS adenoma P53 carcinoma
Cancer
is a group of disorders that causes cells to escape normal controls on cell division

is a genetic disease

GAIN of oncogenes
LOSS of TSG

Hanahan D, Weinberg RA, Cell 2011.

Genetic alterations in cancer

Oncogenes : tumor promoting genes

Tumor Suppressor Genes : tumor inhibiting genes

Oncogene

The term of oncogenes  first in 1969 by Huebner-Todaro

Genes having potential to cause cancer  proto-oncogene

First is discovered in viruses  vRsc  oncogenic retrovirus

Other viral oncogenes

- Abl
- ErbB
- Fms
- Kit
- Raf
- Sis
- H-Ras
Oncogene

Many oncogenes are identified in viruses

Most human cancers are NOT viral in origin.

A kinase
Cell motility, growth,
differentiation
Oncogene

Proto-oncogenes are tightly regulated in healthy cells.

Activation of proto-oncogenes:
- Mutation
 H-Ras, K-Ras, N-Ras
 EGFR
- Gene amplification
 Myc
 Erb2/HER2
- Chromosomal translocation
 Bcr-Abl
 Myc-IGH
Oncogene
Oncogene
Oncogene

EGFR

Proliferation
RAS MAP2K Survival
P P
PIK3CA AKT1 Angiogenesis
P P
RAS BRAF MEK Invasion
Metastasis
Oncogenic activation due to chromosomal
rearrangement
Tumor Suppressor Gene
Function as growth suppressor in healthy cells
Defects in TSG cause cancer
Deletions
Mutations

Insertion
Tumor Suppressor Gene
Loss of heterozygosity
Tumor Suppressor Gene
Epigenetic silencing
- DNA methylation
- Histone modification
 Cancer Genetics

Type of mutations according to the cells:

- Germline mutation
- Somatic mutation
 Genetic instability
A range of genetic alterations from point mutations to chr rearrangements
(Aguilera and Gonzales, 2008)

An increased rate of genomic alteration

A variety of DNA alterations from single nucleotide to whole chrm changes

(Pikor, 2013)
Types of genetic instability
Based on the levels of disruption
- Nucleotide instability
- Microsatellite instability
- Chromosomal instability

Nucletide instability
Due to defects in the base/nucleotide excision repair pathway

Subtle sequence changes only one to few nucleotides

- Substitution
- Deletion
- Insertion

Disorders associated with nucleotide instability

- Xeroderma pigmentosum
- MYH-associated polyposis
Microsatelite instability
Microsatelite: repetitive DNA seq 1-6bp located throughout genome

Size is highly variable

Microsatelite instability
Microsatelite: repetitive DNA seq 1-6bp located throughout genome

Size is highly variable

is usually caused by defects in mismatch repair: MLH1, MSH2, MSH6, PMS2

May 2017 the FDA Pembrolizumab (Keytruda®) unresected or metastatic

MSI-H solid tumor
Chromosomal instability
Chromosomal aberrations

-Microsatelite
Most prominent
instability
form

- 90% human cancers show  chrm abnormalities and aneuploidi

- An increase rate of chrm abnormalities during cell division

Disorders associated with CIN

Breast cancer, prostate, NSCLC, leukemia, neuroblastoma, lymphoma, Head and
neck cancer
Cause of genetic instability

- Replication dysfunction
- Low replication initiation density
- Faulty replication fork progression
- S-phase checkpoint dysfunction
- Defective nucleosome assembly
-Microsatelite
Failure of post replicative repair
instability
- Failure of homologous recombination repair
- Ageing
Genomic instability and cancer treatment

What we can do for cancer treatment?

Genetic alterations and targeted cancer therapy
EGFR Tyrosine kinse inhibitors (TKIs)

Proliferation
P P RAS MAP2K Survival
P P PIK3CA AKT1 Angiogenesis
Invasion
Metastasis
EGFR mutations provoke autophosphorylation of tyrosine kinases and constitutive EGFR
activation
EGFR TKIs block Mg-ATP binding pocket of TK domains
TKI treatment in NSCLCs with EGFR mutations give 70% progression free survival
Genetic alterations and targeted cancer therapy

https://www.mycancerge
nome.org/content/page/o
verview-of-targeted-
therapies-for-cancer/

84 drugs have been

accepted by FDA

Last update May 2019

Sawyers, Nature 2004

Genetic alterations and targeted cancer therapy

Sawyers, Nature 2004

 Summary

Carcinogenesis is a multistep process involving various genetic mutations

as well as epigenetic alterations and interaction with host immune response.

Carcinogenesis: physical, ionizing radiation, and biological agents

Genomic instability is a hallmark of cancer

Genomic instability: 3 types

Detection of genomic instability  cancer diagnosis, subclassification, and

treatment
THANK YOU