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
Q
Aneuploidy
A
- 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
Q
Single gene changes
A
- 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
Q
Epidermal growth factor receptor (EGFR)
A
- 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
Q
EGFR mutations in lung cancer
A
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
Q
KRAS in colon cancer
A
- 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
Q
Epigenetic silencing
A
- 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
Q
Familial Cancer Syndromes (5-10% of human cancer)
A
- 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
Q
Autosomal dominant familial cancer
syndromes
A
- 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
Q
Li-Fraumeni
A
- 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
Q
BRCA1/BRCA2
A
- 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
Q
How do mutations in BRCA1 and BRCA2
result in breast cancer?
A
- 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
Q
Lynch Syndrome/a.k.a. Hereditary Non-
polyposis Colorectal Cancer (HNPCC)
A
- 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
Q
Autosomal recessive familial cancer
syndromes
A
- 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
Q
Xeroderma Pigmentosa
A
- 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
Q
- The concept of cancer as a genetic disease
- The molecular basis of cancer
- The concepts of oncogenes and tumor suppressor genes
- The role of balanced translocations, large deletions/insertions, gene
amplifications, aneuploidy, single gene mutations, and epigenetic phenomena
in cancer - Examples of familial cancer syndromes
A
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
