3 - Neoplasia Flashcards
1
Q
Carcinogenesis (a.k.a oncogenesis or
tumorogenesis)
A
- Process by which normal cells are transformed into cancer cells.
- Progression of changes on the genetic level (DNA) that ultimately leads to
uncontrolled cell division - Clonal expansion of these genetically modified cells results in tumor formation
- This process is irreversible
- About 30 divisions before clinical symptoms on average (more for tumors that are
discovered late) – goal of screening is pick up cancers early (before clinical symptoms) - Additional genetic changes along with selective pressure can make cancers more
aggressive and less responsive to therapy over time
2
Q
What results in carcinogenesis?
A
- Environmental factors
- E.g. Chemicals (mutagens), ionizing radiation (generates hydroxyl free radicals),
UV radiation (sunlight), and viruses (Epstein-Barr virus, Human papilloma virus,
Hepatitis C, Hepatitis B, Human Herpes Virus 8, HTLV-1), altered gene expression
through epigenetic mechanisms - Specifics of each of these will be covered in respective organ blocks
- Can result in gene mutations in a subset of cells in the body (somatic mutations)
- Inherited (constitutional) mutations in genes responsible
for maintaining the integrity of the genome (DNA repair
genes) or tumor suppressor genes (Knudson two-hit
hypothesis) - These mutations are found in all cells of the person’s body
- Can be a combination of environmental and hereditable
factors
3
Q
What is the carcinogenesis mechanism behind: Xeroderma pigmentosa
Ataxia-telangectasia
Bloom Syndrome
Fanconi’s Anemia
Li-Fraumeni
Familial retinoblastoma
A
acquired and succesive DNA mutations
4
Q
What are some fundamental changes in cell physiology
that together determine the malignant
(cancer) phenotype
A
- Self-sufficiency in growth signals
- Insensitivity to growth-inhibitory signals
- Evasion of apoptosis
- Limitless replicative potential
* Upregulated telomerase – maintains telomere length and
avoids senescence - Sustained angiogenesis
- Avoid immune surveillance
- Ability to invade and metastasize
- Altered cellular metabolism
5
Q
What are the four classes of regulatory genes involved in carcinogenesis?
A
- Growth-promoting/proto-oncogenes
- Self-sufficiency in growth signals
- Growth-inhibiting/tumor suppressor genes
- Insensitivity to growth inhibitory signals
- Genes that regulate programmed cell death (i.e.
apoptosis) - Evasion of apoptosis
- Genes involved in DNA repair
- Allows for mutations that cause the events above
6
Q
What are oncogenes? facts and characteristics?
A
- Most known oncogenes encode:
- transcription factors
- growth regulating proteins
- proteins involved in cell survival, cell to cell, and cell to matrix interactions
- Improper expression leads to neoplasia
- Most are mutated or overexpressed versions of normal
cellular genes (proto-oncogenes) - Considered “dominant” mutations because mutation of a
single allele can lead to neoplasia - Expression of oncogenes can allow the cell to be self
sufficient of growth signals
7
Q
common oncogenic pathway(s)
A
8
Q
Tumor suppressor genes
A
- Normally prevent uncontrolled growth (suppress tumors)
- “Governors”
- “Guardians”
- Considered “recessive” because both alleles need to be
mutated for tumor development - Many familial cancer syndromes involve tumor suppressor
genes - One mutated allele is inherited, and the “normal” allele is
mutated or deleted during the lifetime of the individual,
resulting in carcinogenesis - Genetic syndromes involving tumor suppressor genes are still
considered dominant since inheritance of two mutated alleles
is not required for expression of the phenotype
9
Q
pathogenesis of retinobastoma (dysregulation of Rb regulation gene)
A
10
Q
oncogenic “governors”
A
“governor” mutation leads to transformation by removing an important brake on cellular proliferation
– RB gene
Mutation of RB also interferes with binding to E2F just like hyperphosphorylation
11
Q
oncogenic “guardians”
A
- Responsible for sensing genomic damage.
- DNA damage is sensed by complexes containing ATM/ATR kinases, which
phosphorylate p53, liberating it from inhibitors such as MDM2. - Active p53 upregulates the expression of proteins
such as the cyclin-dependent kinase inhibitor p21,
causing cell-cycle arrest at the G 1 /S checkpoint. - This response leads to the cessation of proliferation
or, if the damage cannot be repaired, the induction of
apoptosis. - E.g. p53, the so-called “guardian of the genome”
- p53 is one of the most commonly mutated gene in
cancer
12
Q
Regulators of cell death
A
- Genes that regulate apoptosis may act like proto-oncogenes or tumor suppressor genes
– E.g. anti-apoptotic proteins could act as an oncogene if inappropriately overexpressed (BCL-2)
13
Q
DNA repair
A
- Defects in DNA repair genes can allow for
accumulation of mutations that result in: - Increased expression of proto-oncogenes
- Decreased expression of tumor suppressor genes
- Changes in expression of genes related to apoptosis
- Defects in DNA repair can be inherited or acquired
- Examples of hereditary syndromes
- Mismatch repair – Lynch syndrome/a.k.a. Hereditary Non-polyposis
Colorectal Cancer (HNPCC) - Nucleotide excision repair – Xeroderma Pigmentosa
14
Q
Molecular mechanisms of Somatic Mutations in Cancer
A
- Chromosomal changes
- Balanced translocations
- Large deletions
- Gene amplification
- Aneuploidy
- Mutations within single genes
- Point mutations
- Missense mutations
- Nonsense mutations
- Small insertions/deletions
- MicroRNAs
- Epigenetic silencing
15
Q
Balanced Translocations
A
- Most commonly seen in hematopoietic and soft tissue neoplasms,
for example - Burkitt’s lymphoma
- Follicular lymphoma
- Chronic myelogenous leukemia
- Ewing’s sarcoma
- Increasingly identified in carcinomas (epithelial tumors)
- Lung cancer
- Translocations can activate proto-oncogenes in two ways:
- Overexpression of proto-oncogenes by removing them from their
normal regulatory elements - Placing proto-oncogenes under the control of an inappropriate,
highly active promoter
16
Q
Burkitt’s lymphoma
A
- High grade B-cell lymphoma
- “Starry sky” histology
- Very high rate of proliferation
- The “stars” are macrophages which are cleaning up the dying tumor cells
- > 90% of cases have a translocation, usually between
chromosomes 8 and 14: t(8;14) - Alternative translocations include t(8;22) and t(2;8)
- These translocations lead to overexpression of the c-MYC gene
on chromosome 8 by juxtaposition with - Immunoglobulin heavy chain gene regulatory elements: chromosome 14
- Kappa light chain promoter: chromosome 2
- Lambda light chain promoter: chromosome 22
17
Q
Follicular Lymphoma
A
- Most common form of indolent non-Hodgkin
lymphoma in the US - 15,000 to 20,000 cases/year
- Middle-aged males and females
- Malignant cells often have a reciprocal translocation
between chromosomes 14 and 18 - Overexpression of the anti-apoptotic gene BCL-2 (chromosome 18) driven
by the immunoglobulin heavy chain promoter (chromosome 14) - Overexpression of BCL-2 interferes with normal
apoptosis of B-cells in the lymph node
18
Q
Chronic myelogenous leukemia
A
- Disorder of myeloid cells in the
bone marrow resulting in
uncontrolled proliferation - Balanced translocation
between chromosomes 22 and 9
fuses the 3’ end of the ABL
tyrosine kinase (chromosome 9)
with the 5’ end of the BCR
protein (chromosome 22). - This fusion protein drives
uncontrolled proliferation of
myeloid cells
19
Q
Ewing’s sarcoma
A
- Soft tissue sarcoma
- 6% to 10% of primary malignant bone tumors
- Second most common bone sarcoma in children
- Most commonly associated with t(11;22)(q24;q12)
- This translocation fuses the EWS transcription factor with
FLI-1 - FLI-1 is a member of the ETS family of transcription factors
- The fusion gene produced by this translocation produces a
chimeric transcription factor that alters the expression of
a network of target genes, resulting in abnormal cell
proliferation and survival.
20
Q
Lung Cancer
A
- EML4-ALK fusion gene
- Present in ~4% of lung
carcinomas - Inversion in the p-arm of
chromosome 2 - Constitutively active ALK (a
tyrosine kinase) - Up-regulates signaling
through several pro-growth
pathways - Can be targeted by ALK
inhibitors
21
Q
Chromosomal deletions
A
- The second most prevalent karyotypic abnormality in tumor cells
- Deletions large enough to be observed karyotypically are more
common in non-hematopoietic solid tumors - Deletion of specific regions of chromosomes may result in the
loss of particular tumor suppressor genes, for example: - del 13q14 - site of the RB gene (retinoblastoma)
- del 17p – site of TP53 (non-hematopoietic solid tumors)
22
Q
Retinoblastoma
A
23
Q
Gene amplification
A
- Proto-oncogenes may be converted to oncogenes via
gene amplification resulting in protein overexpression - Highly amplified genes can produce chromosomal
changes that can be identified microscopically when
performing a karyotype. - Two mutually exclusive patterns are seen:
- multiple, small, extra-chromosomal structures called
“double minutes” - homogeneously staining regions
24
Q
neuroblastoma
A
Amplification of the NMYC gene in human neuroblastoma. The NMYC gene, present
normally on chromosome 2p, becomes amplified and is seen either as extra-
chromosomal double minutes or as a chromosomally integrated homogeneous-staining
region (HSR). The integration of HSRs can involve other autosomes, such as 4, 9, or 13.
25
Aneuploidy
* A number of chromosomes that is not a multiple of
the haploid state (i.e. 23 in humans)
* Common in cancer, especially carcinoma
* Due to errors in mitosis
26
Single gene changes
* Types of changes
* Point mutations – single nucleotide change
* Small insertions – insertion of a few nucleotides
* Small deletions – deletion of a few nucleotides
* Can be activating or inactivating
* Proto-oncogenes – mutations produce a constitutively activated
protein
E.g. RAS and EGFR
* Tumor suppressors – mutations reduce or eliminate activity of the
protein
E.g. RB and TP53
27
Epidermal growth factor receptor (EGFR)
* Transmembrane growth
factor receptor with tyrosine
kinase activity
* Homodimerization and/or
heterodimerization with
other family members after
ligand binding activates
tyrosine kinase activity
* Activation results in
downstream signaling
related to angiogenesis,
differentiation, motility,
proliferation, and survival
28
EGFR mutations in lung cancer
Mutations in the tyrosine kinase domain of EGFR result
in disruption of the auto-inhibitory domain, resulting in
constitutive activity and activation of downstream
signaling pathways
29
KRAS in colon cancer
* A protein in the EGFR signaling pathway with GTPase activity
* Conversion of GTP to GDP results in inactivation of KRAS
* 30% to 40% of colon cancers have mutations in the KRAS gene
which make the protein constitutively active by affecting its
GTPase activity
* Constitutively active KRAS activates downstream pathways resulting in cell
growth and proliferation
30
Epigenetic silencing
* Epigenetics - reversible, heritable changes in gene
expression that occur without mutation of the target
gene through post-translational modification of
histones and DNA methylation
* In normal, differentiated cells, the majority of the
genome is silenced by DNA methylation and histone
modification
* Cancer cells have global DNA hypomethylation with
selective promoter-localized hypermethylation (tumor
suppressor genes)
* Hypermethylation of the MLH1 promoter (a DNA
mismatch repair gene) is seen in a subset of colon
cancer
31
Familial Cancer Syndromes (5-10% of human cancer)
* Autosomal dominant
* Autosomal Recessive (result in chromosomal or DNA
instability)
* Familial Cancers of Uncertain Inheritance (tumors with
early age at onset, tumors arising in two or more close
relatives of the index case, and sometimes multiple or
bilateral tumors)
* Breast Cancer (non-BRCA)
* Ovarian Cancer
* Pancreatic Cancer
32
Autosomal dominant familial cancer
syndromes
* Inheritance of a single mutant allele results in increased
risk for development of tumors
* The tumors these patients develop are also seen
sporadically in patients without the inherited mutant allele
but at a much lower rate and at a later age.
* Patients with autosomal dominant familial cancer
syndromes tend to develop multiple types of tumors
* Examples
*** RB – Retinoblastoma
* TP53 – Li-Fraumeni syndrome (various tumors)
* APC – Familial Adenomatous Polyposis
*** NF1/NF2 – Neurofibromatosis 1 and 2**
* BRCA1/BRCA2 – Breast and ovarian tumors
*** MEN1, RET – Multiple endocrine neoplasia 1 and 2**
* MSH2, MLH1, MSH6, PMS2 – Lynch Syndrome (Hereditary non-polyposis
colorectal cancer; HNPCC)**
33
Li-Fraumeni
* Due to mutations in the TP53 gene
* 25 fold greater chance of developing a malignancy by
age 50 as compared to the general population
* Multiple tumor types possible
* Most commonly: sarcomas, breast cancer, leukemia,
brain tumors, and carcinomas of the adrenal cortex
* Tumors develop at a much earlier age than in the
general population
34
BRCA1/BRCA2
* Mutations in these genes are responsible for 1-3% of
all breast cancer
* These two genes have been implicated as major
contributors to inherited breast cancer and ovarian
cancer
* 20% of women with breast cancer who also have a positive family history
of the breast cancer, have a mutation in one of these genes
* 60-80% of women with breast cancer who have a positive family history of
breast and ovarian cancer have a mutation in BRCA1 or BRCA2
35
How do mutations in BRCA1 and BRCA2
result in breast cancer?
* The function of these proteins has not been fully
elucidated, but they may be involved in the
homologous recombinant DNA repair pathway
* Cells with mutations in BRCA1/2 develop
chromosomal breaks and aneuploidy
* Both copies of BRCA1 or BRCA2 must be mutated for
tumor formation
* BRCA1/2 are rarely mutated in sporadic breast cancer
36
Lynch Syndrome/a.k.a. Hereditary Non-
polyposis Colorectal Cancer (HNPCC)
* 2 to 4% of colon cancer
* Tumors typically in the cecum and proximal colon
* Due to defective mismatch repair genes
* Check DNA for base pairing errors
* Four genes have been identified that can be affected in this syndrome
* Hypermethylation of MLH1 promotor responsible for ~15% of sporadic
cancers
* Patients usually present with colon cancer in their 40s
as opposed to 60s for sporadic colon cancer
* Other associated tumors include: Endometrial,
ovarian, gastric, small intestine, brain, urinary, biliary
tract, and in some cases, skin tumors (sebaceous
glands and keratoacanthomas)
37
Autosomal recessive familial cancer
syndromes
* Rare autosomal recessive disorders
* Characterized by chromosomal or DNA instability and
high rates of certain cancers
* Examples
* Xeroderma Pigmentosa
* Ataxia-telangectasia
* Bloom syndrome
* Fanconi’s anemia
38
Xeroderma Pigmentosa
* Increased risk of cancers on sun-exposed skin – squamous cell
carcinoma, basal cell carcinoma, melanoma
* Ultraviolet (UV) rays in sunlight cause cross-linking of pyrimidine
residues which prevents normal DNA replication
* Normally repaired by the nucleotide excision repair system
* Patients with XP have a defect in one of several proteins involved in the
excision repair system
39
1. The concept of cancer as a genetic disease
2. The molecular basis of cancer
3. The concepts of oncogenes and tumor suppressor genes
4. The role of balanced translocations, large deletions/insertions, gene
amplifications, aneuploidy, single gene mutations, and epigenetic phenomena
in cancer
5. Examples of familial cancer syndromes
Summary
* Cancer is a genetic disease
* Mutations in tumor suppressors and oncogenes can
result in carcinogenesis
* Disruption of DNA repair pathways and apoptosis are
also important to carcinogenesis
* Mutations in cancer are the result of balanced
translocations, large deletions/insertions, gene
amplifications, aneuploidy, and smaller scale
mutations (point mutations, small deletions, and
small insertions) in single genes
* Epigenetic phenomena can also affect the expression
a genes in cancer
* Examples of familial cancer syndromes
