Summary Cancer Genetics
Table of Contents
LECTURE 1: I. Cancer is a genomic disease ................................................................................................... 2
LECTURE 1: II. Oncogene-activation and overexpression............................................................................. 8
LECTURE 2: Tumor Suppressor Gene (TSG) inactivation ............................................................................ 31
LECTURE 3: Cancer epigenetics .................................................................................................................. 35
LECTURE 6: Mutational signatures, DNA repair & replicative stress .......................................................... 44
LECTURE 7: I. Multistep process of cancer formation ................................................................................ 54
LECTURE 7: II. Intratumoral heterogenity (ITH) and tumor evolution........................................................ 61
LECTURE 4. I. Optical Genome Mapping .................................................................................................... 65
LECTURE 4. II. Molecular Diagnostics of Cancer ......................................................................................... 67
LECTURE 5: Single Cell Omics technology and applications ....................................................................... 69
1
,LECTURE 1: I. Cancer is a genomic disease
1. Explain why cancer is considered a genomic disease + provide experimental evidence.
Cancer is considered a genomic disease because it arises through the accumulation of
genetic and epigenetic alterations that disrupt the normal regulation of cell proliferation,
differentiation, and cell death. These alterations activate oncogenes and inactivate tumor
suppressor genes, ultimately leading to malignant transformation.
Several experimental observations support this concept:
- 1. Familial cancer syndromes demonstrate a genetic basis
One of the earliest indications that cancer has a genetic basis came from the observation
that certain cancers occur more frequently within families.
Examples include:
• BRCA1 and BRCA2 germline mutations in hereditary breast and ovarian cancer.
• APC mutations in familial adenomatous polyposis (FAP), which predispose to
colorectal cancer.
• TP53 mutations in Li-Fraumeni syndrome.
These observations showed that inherited mutations in specific genes can strongly increase
cancer risk. They also led to the distinction between:
• Monogenic diseases, caused by mutations in a single high-impact gene.
• Polygenic diseases, caused by the interaction of multiple low-risk variants and
environmental factors.
- 2. Chromosomal abnormalities are recurrent in cancer
Theodor Boveri was one of the first scientists to propose that chromosomal abnormalities
are responsible for cancer development.
Based on microscopic observations, he noticed that cancer cells often contain abnormal
chromosome numbers and structures and suggested that these abnormalities could drive
tumor formation. This was proposed decades before modern karyotyping techniques
became available.
Later, chromosome analysis led to the discovery of the Philadelphia chromosome in
chronic myeloid leukemia (CML), providing direct evidence that recurrent chromosomal
abnormalities are associated with specific cancers.
- 3. Discovery of oncogenes through tumor viruses
In 1910, Peyton Rous demonstrated that filtered extracts from chicken sarcomas could
induce sarcomas in healthy chickens.
This experiment showed that a transmissible factor was capable of causing cancer and
provided one of the first experimental models for carcinogenesis.
With the development of DNA technology in the 1970s, researchers discovered that
the Rous sarcoma virus contained the viral oncogene v-SRC.
Retroviruses convert their RNA into DNA and integrate it into the host genome. Researchers
subsequently discovered the cellular counterpart c-SRC in normal cells.
2
, This led to the concept of a proto-oncogene, a normal growth-regulating gene that can
become an oncogene after mutation. The v-SRC protein contains activating mutations that
cause constitutive tyrosine kinase activity and continuous growth signaling.
This discovery was followed by the identification of many other proto-oncogenes,
including: MYC, ERBB2, ABL1 and KIT
- 4. Transfection experiments identified human oncogenes
Another crucial experiment involved transfecting DNA from tumor cells into immortalized
fibroblasts.
Results showed that:
• DNA from normal cells had no effect.
• DNA from tumor cells caused transformation, loss of contact inhibition, and
abnormal growth.
These experiments led to the identification of RAS as one of the first human oncogenes.
Importantly, researchers discovered that genes mutated in human cancers were often the
same genes previously identified as viral oncogenes. This provided strong evidence that
specific genetic alterations can directly transform normal cells into cancer cells.
- 5. Discovery of tumor suppressor genes
Evidence for tumor suppressor genes came from cell fusion experiments.
When malignant cells were fused with normal cells, the resulting hybrid cells often lost their
tumorigenic properties, suggesting that normal cells contain genes capable of suppressing
cancer development.
Further support came from Knudson's two-hit hypothesis.
Knudson observed that:
• Hereditary retinoblastoma develops at a young age because patients inherit one
defective copy of the gene.
• Sporadic (non-inherited) retinoblastoma develops later because both mutations
must be acquired during life.
This led to the discovery of RB1, which plays a central role in cell-cycle regulation.
Later, TP53 was identified as a second major tumor suppressor gene. TP53 was initially
thought to be an oncogene, but later studies demonstrated that most cancer-associated
mutations cause loss of tumor suppressor activity (dominant-negative effect). In addition,
some mutant TP53 proteins can acquire novel oncogenic gain-of-function properties.
- 6. Recurrent tumor-specific genetic defects
A landmark example is the Philadelphia chromosome in CML.
Researchers discovered that the t(9;22) translocation creates the BCR-ABL1 fusion gene.
The resulting fusion protein has constitutive tyrosine kinase activity, continuously activating
signaling pathways involved in proliferation and survival.
The development of imatinib (Gleevec), which specifically inhibits the ABL1 kinase
domain, resulted in dramatic clinical responses.
3
, This provided definitive proof that cancer cells can depend on specific genetic alterations
and marked the beginning of precision oncology.
- 7. Genetic association studies (GWAS)
Modern genome-wide association studies (GWAS) have identified many inherited variants
that increase cancer susceptibility.
These studies further demonstrate that genetic variation contributes to cancer risk and
support the concept that cancer development is fundamentally linked to genomic
alterations.
2. What are the cancer hallmarks and which genes contribute to these hallmarks?
1. Self-sufficiency in growth signals
Cancer cells become independent of normal growth signals by activating oncogenes
involved in growth factor signaling pathways.
Important examples include:
• SRC, a tyrosine kinase that becomes constitutively active after mutation and
continuously stimulates cell proliferation.
• BCR-ABL1, generated by the t(9;22) translocation in CML, resulting in constitutive
kinase activity and activation of the RAS-MAPK, JAK-STAT and PI3K-AKT pathways.
• RAS, a key mediator of growth factor signaling.
• EGFR (ERBB1), ERBB2/HER2, and KIT, which can be activated through mutation or
amplification.
• BRAF V600E, which constitutively activates MAPK signaling.
• MDM2 amplification, which indirectly promotes proliferation through inhibition of
p53.
2. Inducing angiogenesis
Tumors stimulate blood vessel formation to obtain oxygen and nutrients.
Examples include:
• Upregulation of VEGF signaling.
• Certain mutant p53 proteins can cooperate with chromatin remodeling complexes
such as SWI/SNF and stimulate expression of angiogenic genes including VEGFR2.
• Loss of p53-mediated suppression of angiogenesis.
3. Evading cell death
Cancer cells acquire mechanisms that prevent apoptosis.
Examples include:
• BCL2 activation through the t(14;18) translocation in follicular lymphoma. BCL2
blocks the intrinsic apoptotic pathway and prolongs cell survival.
• Activation of the PI3K-AKT pathway in solid tumors, which promotes survival
signaling.
• Loss of TP53, reducing the ability of cells to undergo apoptosis after DNA damage.
4
Table of Contents
LECTURE 1: I. Cancer is a genomic disease ................................................................................................... 2
LECTURE 1: II. Oncogene-activation and overexpression............................................................................. 8
LECTURE 2: Tumor Suppressor Gene (TSG) inactivation ............................................................................ 31
LECTURE 3: Cancer epigenetics .................................................................................................................. 35
LECTURE 6: Mutational signatures, DNA repair & replicative stress .......................................................... 44
LECTURE 7: I. Multistep process of cancer formation ................................................................................ 54
LECTURE 7: II. Intratumoral heterogenity (ITH) and tumor evolution........................................................ 61
LECTURE 4. I. Optical Genome Mapping .................................................................................................... 65
LECTURE 4. II. Molecular Diagnostics of Cancer ......................................................................................... 67
LECTURE 5: Single Cell Omics technology and applications ....................................................................... 69
1
,LECTURE 1: I. Cancer is a genomic disease
1. Explain why cancer is considered a genomic disease + provide experimental evidence.
Cancer is considered a genomic disease because it arises through the accumulation of
genetic and epigenetic alterations that disrupt the normal regulation of cell proliferation,
differentiation, and cell death. These alterations activate oncogenes and inactivate tumor
suppressor genes, ultimately leading to malignant transformation.
Several experimental observations support this concept:
- 1. Familial cancer syndromes demonstrate a genetic basis
One of the earliest indications that cancer has a genetic basis came from the observation
that certain cancers occur more frequently within families.
Examples include:
• BRCA1 and BRCA2 germline mutations in hereditary breast and ovarian cancer.
• APC mutations in familial adenomatous polyposis (FAP), which predispose to
colorectal cancer.
• TP53 mutations in Li-Fraumeni syndrome.
These observations showed that inherited mutations in specific genes can strongly increase
cancer risk. They also led to the distinction between:
• Monogenic diseases, caused by mutations in a single high-impact gene.
• Polygenic diseases, caused by the interaction of multiple low-risk variants and
environmental factors.
- 2. Chromosomal abnormalities are recurrent in cancer
Theodor Boveri was one of the first scientists to propose that chromosomal abnormalities
are responsible for cancer development.
Based on microscopic observations, he noticed that cancer cells often contain abnormal
chromosome numbers and structures and suggested that these abnormalities could drive
tumor formation. This was proposed decades before modern karyotyping techniques
became available.
Later, chromosome analysis led to the discovery of the Philadelphia chromosome in
chronic myeloid leukemia (CML), providing direct evidence that recurrent chromosomal
abnormalities are associated with specific cancers.
- 3. Discovery of oncogenes through tumor viruses
In 1910, Peyton Rous demonstrated that filtered extracts from chicken sarcomas could
induce sarcomas in healthy chickens.
This experiment showed that a transmissible factor was capable of causing cancer and
provided one of the first experimental models for carcinogenesis.
With the development of DNA technology in the 1970s, researchers discovered that
the Rous sarcoma virus contained the viral oncogene v-SRC.
Retroviruses convert their RNA into DNA and integrate it into the host genome. Researchers
subsequently discovered the cellular counterpart c-SRC in normal cells.
2
, This led to the concept of a proto-oncogene, a normal growth-regulating gene that can
become an oncogene after mutation. The v-SRC protein contains activating mutations that
cause constitutive tyrosine kinase activity and continuous growth signaling.
This discovery was followed by the identification of many other proto-oncogenes,
including: MYC, ERBB2, ABL1 and KIT
- 4. Transfection experiments identified human oncogenes
Another crucial experiment involved transfecting DNA from tumor cells into immortalized
fibroblasts.
Results showed that:
• DNA from normal cells had no effect.
• DNA from tumor cells caused transformation, loss of contact inhibition, and
abnormal growth.
These experiments led to the identification of RAS as one of the first human oncogenes.
Importantly, researchers discovered that genes mutated in human cancers were often the
same genes previously identified as viral oncogenes. This provided strong evidence that
specific genetic alterations can directly transform normal cells into cancer cells.
- 5. Discovery of tumor suppressor genes
Evidence for tumor suppressor genes came from cell fusion experiments.
When malignant cells were fused with normal cells, the resulting hybrid cells often lost their
tumorigenic properties, suggesting that normal cells contain genes capable of suppressing
cancer development.
Further support came from Knudson's two-hit hypothesis.
Knudson observed that:
• Hereditary retinoblastoma develops at a young age because patients inherit one
defective copy of the gene.
• Sporadic (non-inherited) retinoblastoma develops later because both mutations
must be acquired during life.
This led to the discovery of RB1, which plays a central role in cell-cycle regulation.
Later, TP53 was identified as a second major tumor suppressor gene. TP53 was initially
thought to be an oncogene, but later studies demonstrated that most cancer-associated
mutations cause loss of tumor suppressor activity (dominant-negative effect). In addition,
some mutant TP53 proteins can acquire novel oncogenic gain-of-function properties.
- 6. Recurrent tumor-specific genetic defects
A landmark example is the Philadelphia chromosome in CML.
Researchers discovered that the t(9;22) translocation creates the BCR-ABL1 fusion gene.
The resulting fusion protein has constitutive tyrosine kinase activity, continuously activating
signaling pathways involved in proliferation and survival.
The development of imatinib (Gleevec), which specifically inhibits the ABL1 kinase
domain, resulted in dramatic clinical responses.
3
, This provided definitive proof that cancer cells can depend on specific genetic alterations
and marked the beginning of precision oncology.
- 7. Genetic association studies (GWAS)
Modern genome-wide association studies (GWAS) have identified many inherited variants
that increase cancer susceptibility.
These studies further demonstrate that genetic variation contributes to cancer risk and
support the concept that cancer development is fundamentally linked to genomic
alterations.
2. What are the cancer hallmarks and which genes contribute to these hallmarks?
1. Self-sufficiency in growth signals
Cancer cells become independent of normal growth signals by activating oncogenes
involved in growth factor signaling pathways.
Important examples include:
• SRC, a tyrosine kinase that becomes constitutively active after mutation and
continuously stimulates cell proliferation.
• BCR-ABL1, generated by the t(9;22) translocation in CML, resulting in constitutive
kinase activity and activation of the RAS-MAPK, JAK-STAT and PI3K-AKT pathways.
• RAS, a key mediator of growth factor signaling.
• EGFR (ERBB1), ERBB2/HER2, and KIT, which can be activated through mutation or
amplification.
• BRAF V600E, which constitutively activates MAPK signaling.
• MDM2 amplification, which indirectly promotes proliferation through inhibition of
p53.
2. Inducing angiogenesis
Tumors stimulate blood vessel formation to obtain oxygen and nutrients.
Examples include:
• Upregulation of VEGF signaling.
• Certain mutant p53 proteins can cooperate with chromatin remodeling complexes
such as SWI/SNF and stimulate expression of angiogenic genes including VEGFR2.
• Loss of p53-mediated suppression of angiogenesis.
3. Evading cell death
Cancer cells acquire mechanisms that prevent apoptosis.
Examples include:
• BCL2 activation through the t(14;18) translocation in follicular lymphoma. BCL2
blocks the intrinsic apoptotic pathway and prolongs cell survival.
• Activation of the PI3K-AKT pathway in solid tumors, which promotes survival
signaling.
• Loss of TP53, reducing the ability of cells to undergo apoptosis after DNA damage.
4
