Principles of Cancer Biology Flashcards
1. Understand the concept of oncogene and signal transduction pathway (MKS1b) 2. Understand the concept of tumor suppressor gene (MSK1b) 3. Understand the clinical impact of molecular aberrations in the above mentioned genes (MSK1d)
1
Q
What is the definition of oncogenes?
A
- Oncogenes encode proteins or, in some cases, non-protein coding RNAs, that have the potential to promote the initiation or propagation of cancer
- Oncogenes can be encoded by cancer-causing viruses (e.g. human papillomavirus) or the host cell genome
- Proto-oncogenes are normal cellular genes that are converted into activated or dominant oncogenes either by direct mutation (missense mutation, nonsense mutation, translocation, or gene amplification) or over-expression resulting from a variety of possible mechanisms
- Importantly, the same oncogene may be activated in different tumors by different mechanisms
- For example, genes encoding the cyclin proteins, which are oncoproteins that promote cell division, can be amplified in some tumors
- Importantly, the same oncogene may be activated in different tumors by different mechanisms
- In other tumors, cyclins are overexpressed due to missense mutations that target proteins that normally control their degradation
- The conversion of a proto-oncogene to oncogene through mutation is considered a gain-of-function event
- Typically, activation of only one of two proto-oncogene alleles is required, as the function of the mutant oncogene is dominant over the remaining, wild-type allele
- The first oncogene discovered (from the chicken retrovirus, Rous sarcoma virus) was v-Src, encoding a tyrosine kinase that regulates signal transduction
2
Q
What is the definition of cellular transformation?
A
- The process of conversion of a normal cell to a cancer cell, with greatly increased, disordered proliferation and potentially limitless lifespan, is called transformation
- Robert Weinberg and colleagues first defined the minimal requirements for transformation for cultured cells
- sustained proliferation-promoting cell signaling that occurs in the absence of external mitogens
- an infinite replicative lifespan, which in human cells requires constitutive telomere restorative function
- resistance to oncogene-induced cell death, which is largely dependent on the p53 tumor suppressor
- evasion of normal cellular checkpoints that restrict the initiation of DNA replication, which are governed by p53- and Retinoblastoma-dependent pathways
3
Q
What is the laboratory definition of cellular transformation?
A
- In the research laboratory, the classical definition of cellular transformation consists of several directly observable properties using basic cell culture and animal models
- These are gain-of-function properties, compared to normal cells
- immortalization
- ability to survive and proliferate in the absence of serum or exogenous growth factors
- capacity for anchorage-independent focus formation (in soft agar)
- tumor production in immunosuppressed/nude mice
- During the development of cancer in humans and other animals, malignant cells have acquired the ability to alter their micro-environment in order to grow and spread, through the processes of invasion and metastasis and neoangiogenesis (the recruitment of new blood vessels to the tumor)
4
Q
What are oncogenic signal transduction pathways and what happens when these are mutated?
A
- Oncogenic signal transduction pathways play a critical role in both the pathogenesis of human cancer and in guiding the development of cancer therapies
- Signal transduction pathways are comprised of proteins and second messengers that function to relay extracellular signals, such as growth factors, from cell surface receptors to intracellular target molecules within the cytoplasm or nucleus
- In many cases, signal transduction cascades regulate the function of nuclear transcription factors, which turn on or off the expression of hundreds to thousands of genes
- Therefore, mutations that target components of signal transduction machinery can elicit fundamental changes in cell behavior and identity, such as altering proliferative capacity and differentiation programs
- Furthermore, many of the activators of signal transduction pathways are proto-oncogenes
- Likewise, many inhibitors of signal transduction pathways function as tumor suppressors
5
Q
What is oncogene addiction?
A
- In some cases, tumor cells demonstrate dependence on a particular signal transduction pathway or molecule for their survival or to maintain their phenotype as cancer cells
- This dependence is known as oncogene addiction, based on the experimental and clinical observations of reproducible and, sometimes, reversible tumor regression following selective inhibition of a particular molecular target
- Oncogene addiction is exploited by targeted anti-cancer therapies, including:
- imatinib to treat chronic myeloid leukemia (target oncoprotein: BCR-ABL fusion protein)
- all-trans retinoic acid to treat acute promyelocytic leukemia (target oncoprotein: PML-RARα fusion protein)
- trastuzumab for HER2- positive breast cancer (target oncoprotein: HER2/neu)
- gefitinib for EGFR-mutated lung cancer
- Resistance to targeted therapies occurs when cancer cells acquire mutations that provide a means of escaping oncogene addiction in the setting of the inhibited pathway or molecule
6
Q
What is the definition of a tumor suppressor gene?
A
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Tumor suppressor genes encode proteins or, in some cases, non-protein coding RNAs, that restrain cancer formation by opposing key stages of cellular transformation or tumor progression
- In cancers, tumor suppressors are either mutated directly or have their expression or activity reduced below threshold levels
- In each of these cases, mutations or expression alterations affecting tumor suppressor genes are considered loss-of-function
- Typically, but not always, as discussed below, mutations in tumor suppressors are recessive, because the wild-type allele can provide sufficient compensatory function
7
Q
What is haploinsufficiency?
A
- Tumor suppressors that are haploinsufficient do not follow typical recessive behavior when mutated
- These genes do not require both alleles to be mutated for cancer promotion, because loss-of-function mutation of a single allele is sufficient to promote a particular tumorigenic trait
- This is because a precise gene dosage is required to maintain appropriate repression of their target or targets for regulation
- For example, in studies of tumor induction in immunocompetent mice, the p27Kip1 protein, a cyclin-CDK inhibitor encoded by the CDKN1B gene exhibits haploinsufficiency, such that mice with a single copy of CDKN1B deleted develop irradiation- and chemical carcinogen-induced tumors at equal frequency as homozygous CDKN1B-null mice
- Importantly, tumors that develop p27-heterozygous mice do not lose their wild-type copy of CDKN1B
- For example, in studies of tumor induction in immunocompetent mice, the p27Kip1 protein, a cyclin-CDK inhibitor encoded by the CDKN1B gene exhibits haploinsufficiency, such that mice with a single copy of CDKN1B deleted develop irradiation- and chemical carcinogen-induced tumors at equal frequency as homozygous CDKN1B-null mice
- A related concept is that tumor suppressors often directly oppose the activities of oncogenes
- For example, CDKN1B encodes an enzymatic inhibitor (p27) of cyclin-CDK complexes, some of which serve as oncoproteins by driving increased cellular proliferation when deregulated
- Similarly, NF1 (another haploinsufficient tumor suppressor) encodes a tumor suppressor protein that is a negative regulator of the Ras oncoprotein
- NF1 negatively regulates Ras by stimulating its GTPase activity – in the setting of NF1 inactivation, Ras is constitutively bound to GTP and thus hyperactive
8
Q
What are dominant negative mutations?
A
- Some tumor suppressors acquire mutations that enable their mutant gene products to inhibit their wild-type counterparts
- Thus, these mutations would not be considered recessive
- Rather, they are called dominant negative mutations. Many mutations in TP53 are dominant negative
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TP53 encodes the p53 protein, a critical tumor suppressor that is a transcription factor that prevents cell transformation by activating genes that induce apoptosis or senescence in response to DNA damage or expressed oncogenes
- As a transcription factor, p53 binds to DNA as a tetramer, and because most cancer-associated mutations affect the DNA binding domain of p53, mutant p53 proteins effectively inhibit the activity of normal p53 by sequestering wild-type p53 into inactive transcriptional complexes
- Moreover, because p53 normally induces the expression of MDM2, a gene that encodes the ubiquitin ligase that promotes degradation of p53 as part of an auto-regulatory circuit, mutant p53 is hyper-stable since it is unable to activate MDM2
- This defective autoregulatory mechanism explains why mutant p53 is highly expressed in tumors
9
Q
How do germline tumor suppresor gene mutations affect the risk for developing cancer?
A
- Germline tumor suppressor gene mutations are associated with inherited cancer-susceptibility syndromes
- Many of these mutations follow an autosomal dominant pattern of inheritance, in large part because the tumors that arise in affected individuals acquire inactivating mutations in the remaining, wild-type tumor suppressor gene through a process known as loss-of-heterozygosity (LOH)
- The process of LOH was predicted mathematically by Knudson in 1971, based on observations of patients with retinoblastoma, given the occurrence of bilateral and earlier-age onset of disease in patients with known inherited susceptibility and the absence of bilateral retinoblastoma without this family history
10
Q
How do somatic mutations lead to cancer? What are the three most frequently mutated genes?
A
- Somatic mutations in tumor suppressor genes frequently affect tumor suppressor genes that are known to be involved in inherited cancer susceptibility syndromes
- For example, APC, the gene in which mutations are causative in FAP syndrome, is mutated in the majority of sporadic colorectal cancers
- The three most frequently mutated genes in sporadic human cancers are tumor suppressor genes that are involved in inherited cancer susceptibility syndromes:
- CDKN2A, encoding the p16 cyclin D-CDK4 inhibitor
- TP53
- PTEN
11
Q
Describe the multi-step process of tumorigenesis.
A
- Multi-step tumorigenesis is the process of step-wise acquisition of mutations in oncogenes and tumor suppressors during clonal evolution of a cancer
- This process was first described for colorectal cancers by Bert Vogelstein and colleagues and is now known to apply to most human cancers
- During the process of clonal evolution, some gene mutations that directly cause or maintain the tumor phenotype undergo positive selection and are retained in subsequent sub-clones that appear later during disease progression
- These are called driver mutations and occur at high frequencies in a particular tumor type
- In contrast, passenger mutations are of uncertain significance to the tumor phenotype and may occur randomly as a result of tumor cells’ propensity for genomic instability
- These passenger mutations will be relatively rare in frequency across a population of patients and may not persist in subclones found in the same patient
12
Q
What is the phenotype and major genes involved of Li-Fraumeni syndrome?
A
- Individuals affected by multiple different tumors:
- epithelial cancers
- sarcomas
- leukemias
- Tumors occur at separate times
- Major gene involved - TP53
13
Q
What is the phenotype and major genes involved in Cowden syndrome?
A
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Benign mucosal tumors and increased risk of:
- breast cancer
- endometrial cancer
- thyroid cancer
- Major gene involved - PTEN
14
Q
What is the phenotype and major genes involved in familial adenomatous polyposis syndrome?
A
- Early-onset of numerous intestinal polyps with eventual progression to invasive cancer
- Also increased incidence of osteosarcomas and soft tissue tumors
- Major gene involved - APC
15
Q
What is the phenotype and major genes involved in familial atypical multiple mole-melanoma (FAMMM) syndrome?
A
- Atypical moles, increased risk of melanoma and pancreatic cancers
- Major gene involved - CDK2NA
