Genetic Basis of Neoplasms Quiz

Study Notes

Neoplasms are tumors, which arise from genetic and molecular alterations.
Carcinogenesis involves the transformation of normal cells into cancerous cells. This process targets four key classes of normal regulatory genes.
The first class are growth-promoting proto-oncogenes, which when activated, lead to cancer.
The second class are growth-inhibiting tumor suppressor genes. These genes normally act as cell cycle checkpoints. Loss of their function allows unchecked cell growth.
The third class are genes that regulate programmed cell death (apoptosis). Altered function affects apoptosis either promoting cell survival if inhibition mechanisms are increased, or decreasing cell survival if mechanisms which promote apoptosis are decreased.
The fourth class are genes involved in DNA repair. Defects in these genes lead to genomic instability and increased risk of mutations.

Proto-oncogenes are normal cellular genes that promote cell proliferation.
Oncogenes are mutated or overexpressed proto-oncogenes, which function independently of normal growth-promoting signals.
Oncoproteins, the proteins produced by oncogenes, stimulate cell proliferation.
Oncogene functions include secreted growth factors, growth factor receptors, cytoplasmic signal transduction proteins, nuclear proteins, and transcription factors, and cell growth genes.
Examples include HER2/neu, which encodes an epidermal growth factor receptor, frequently amplified in breast cancer.

These are normal cellular genes that inhibit cell growth. They act as cell cycle checkpoints to prevent uncontrolled cell growth.
Loss of function mutations are mechanisms by which mutations can cause cancer in these genes. These include: deletion, inactivation point mutations.
Two mutations in both gene alleles are generally necessary for cancer to arise. This is known as the two-hit theory.
Examples include TP53 (p53), which is often implicated in various cancers and RB gene, often mutated in breast and ovarian cancers.
p53 is dubbed the "guardian of the genome", detecting DNA damage and initiating apoptosis or halting the cell cycle when repair is not possible.

Apoptosis-regulating genes control programmed cell death (apoptosis).
Two key classes are: genes that inhibit apoptosis and those that promote apoptosis.
Mutations can reduce or eliminate apoptosis through increasing inhibition and reducing promotion of programmed cell death.
An example is BCL2, an apoptosis-inhibiting gene. Overexpression of BCL2, often due to translocation, is associated with follicular lymphoma.

DNA repair genes maintain genomic stability.
Mutations in DNA repair genes lead to genomic instability and an increase in the risk of mutations in other gene groups.
Examples include nucleotide excision repair and Xeroderma pigmentosum, where mutations make individuals susceptible to skin cancer due to UV exposure as DNA damage is poorly repaired.

Chromosomal changes are frequently seen in cancer.
Changes include gene mutations, structural abnormalities (insertions, deletions, translocations), whole chromosome gains or losses, and chromosomal number abnormalities (aneuploidy and polyploidy).
An example is Chronic myelogenous leukemia where reciprocal translocation between chromosomes 9 and 22 occurs, creating a Philadelphia chromosome leading to fusion proteins.