Hall Book Ch 18 (Cancer Biology)

Question 1

Cancer is thought to be a ( ) disorder.

The control of cell proliferation is the consequence of signals that may be ( ).

Gain-of-function mutations can activate ( ), which are positive growth regulators; tumor suppressor genes are a negative growth regulator.

Answer 1

clonal, positive or negative, oncogenes

Question 2

Oncogenes are genes found in either a mutant or an abnormally expressed form in many human cancers.

Oncogenes can be activated by ( ).

Answer 2

retroviral integration, point mutation, a chromosomal rearrangement such as a translocation, or gene amplification

Question 3

Some human leukemias and lymphomas appear to be caused by specific chromosomal translocations that lead to oncogene activation in several
different ways.

Knudson postulated that all types of retinoblastoma involve two separate mutations. In sporadic retinoblastoma, both mutations occur somatically in the same retinal cell; therefore, this condition is rare. In the heritable form, one of the two mutations is inherited from a parent and is present in all retinal
cells so that the second mutation would occur somatically in any of these
cells; hence, the incidence is close to 100%.
There are many tumor suppressor genes whose location and function are
known; the two most intensively studied are p53 and Rb.
Because oncogenes are gain-of-function mutations, only one copy needs to be
activated; that is, they act in a dominant fashion. Tumor suppressor genes
involve loss-of-function mutations so that both copies must be lost; that is,
they act in a recessive fashion.
Somatic homozygosity is the process by which one chromosome of a pair is
lost, a deletion occurs in the remaining chromosome, and the chromosome
with the deletion replicates.
Carcinogenesis appears to be a multistep process with multiple genetic
alterations occurring. An attractive model of carcinogenesis includes the idea
that an early step causes a mutation in a gene in one of the families
responsible for the stability of the genome. This leads to a mutator phenotype
so that multiple further changes are likely in the progression of the cancer.
Telomeres cap the ends of chromosomes; they are long arrays of TTAGGG
repeats. Each time a normal somatic cell divides, the terminal end of the
telomere is lost; after 40 to 60 divisions, the cell undergoes senescence. Stem
cells and cancer cells activate telomerase, which maintains telomere length,
so the cell becomes immortal.
AT is an autosomal recessive disorder that is caused by a defect in the ATM
kinase. AT cells fail to activate checkpoints in response to DNA damage,
exhibit increased genomic instability at the chromosome level, and have an
increased risk of lymphomas. AT cells and individuals are hypersensitive to
580
ionizing radiation.
The ATR gene expression (AT and Rad3 related) is decreased in patients with
Seckel syndrome. Although it belongs to the same PIKK family as ATM, it is
an essential gene at the cellular level. It has an important role in responding
to DNA breaks in S phase.
RecQ genes encode helicases that play a critical role in protecting replication
forks. Decreased expression of RecQ genes results in aberrant DNA
replication and genomic instability.
There are at least three human syndromes involved in RecQ deficiency: BLM, WS, and RTS. A common feature of all these syndromes is increased
chromosomal instability. These disorders do not result in hypersensitivity to
ionizing radiation. However, BLM cells are sensitive to alkylating agents and
mitomycin C.
NBS is a rare disorder that results in increased cancer incidence. Cells
defective in NBS lack an S phase checkpoint and are radiosensitive.
Patients with ATLD are clinically similar to patients with AT except that their
defect lies in the MRE11 gene. Cells from these patients are also sensitive to
ionizing radiation.
Patients with FA are characterized by their hypersensitivity to crosslinking
agents. Although fibroblasts derived from these patients are not sensitive to
ionizing radiation, tumors arising in these patients are hypersensitive. The
reasons for this are currently unknown.
T cell checkpoint therapeutics are currently being tested in many different
cancers alone or in combination with other anti-cancer agents. While great
enthusiasm exists for T cell checkpoint therapeutics with radiotherapy,
clinical trial data needs to demonstrate how effective this combination will
be. Some of the mechanisms of resistance to T cell checkpoint therapeutics
are known and one of the most important is T cell exclusion from the tumor.

The p53 tumor suppressor gene is an important modulator of oncogeneinduced apoptosis. Levels of p53 are kept low in unstressed cells through the
binding of a specific E3-like ubiquitin ligase, murine double minute 2 (Mdm2).
Binding of Mdm2 to the N-terminus of p53 results in the complex being shuttled
to the cytoplasm, where it is quickly degraded by the proteosome. However, in
response to various stresses, including ionizing radiation, serum starvation, and
hypoxia, p53 protein levels increase both through protein stabilization and
increased protein synthesis. Stabilization of p53 in response to stress is thought
to occur through several mechanisms, including prevention of Mdm2 binding
and phosphorylation of p53. Once stabilized, p53 is a powerful proapoptotic
molecule capable of transcriptionally activating gene expression by sequencespecific DNA binding to regulatory sequences. Transcriptional targets of p53
that induce apoptosis include bax, puma, noxa, and perp and provide a link
between the tumor suppressor activity of p53 and apoptosis. This list of p53-
regulated apoptotic genes is always growing and very dependent on the cell type
and stress. Many of the mutations in the p53 gene found in human tumors are
found within the DNA-binding domain (DBD), highlighting the importance of
this region to the role of p53 as a tumor suppressor and its ability to induce
apoptosis. However, recent reports in the literature indicate a new role for p53 in
the cytoplasm and specifically at the mitochondria, where it may function
directly to release cytochrome c to initiate the caspase cascade and apoptosis,
bypassing the need for its transcriptional activity.