Question

A rare form of cancer has been identified in 15 unrelated individuals. This cancer does not seem to be hertiable. You are a medical geneticist and you decide to use whole exome sequencing of both normal and cancer cells in these ten individuals to try to find the driver mutations causing this particular cancer. You identify three possible candidate genes that may cause this cancer, which you call Gene X, Gene Y, and Gene Z.

1. All 15 individuals’ normal cells have heterozygous nonsense or frameshift mutations in Gene X. Their cancer cells are also heterozygous for the same mutations as the normal cells in Gene X. Do you think mutations in Gene X cause this uterine cancer? Why or why not?
2. All 15 individuals’ normal cells have homozygous nonsense or frameshift mutations in Gene Y. Their cancer cells are also homozygous for the same mutations as the normal cells in Gene X. Do you think mutations in Gene X cause this uterine cancer? Why or why not?
3. There were no mutations in Gene Z in any of the 15 individuals’ normal cells, but there were heterozygous missense mutations in all 15 individuals’ cancer cells in Gene Z. Do you think mutations in Gene Z cause this uterine cancer? Why or why not?

Answer 1

Normal cells will be converted to tumor cells in two conditions:

i) The proto-oncogenes are mutated to oncogenes. Proto-oncogenes are genes that when mutated are converted to oncogenes that will turn on cell proliferation.

ii) Tumor suppressor genes are genes involved in DNA repair, apoptosis and inhibit cell division. Both copies of tumor suppressor gene need to be mutated for cancer to occur.

Non-sense mutations are mutation in which a stop codon prematurely terminates the protein. Frameshift mutations are mutations where either insertion/deletion /base substitution result in shift in reading frame for protein synthesis, which may result in non-functional protein. Missense mutations are mutations that cause changes/ replacement amino acids by other amino acids in the protein which may or may not make the protein non-functional.

The gene have to expressed differently in normal cells and

a. The gene X shows heterozygous nonsense or frameshift mutation in normal cells as well as cancer cells. Heterozygous mutation indicates that one copy of the allele is wild type while the other copy is mutated. However, as both normal and cancer cells exhibit these mutation gene X is not responsible for the uterine cancer. Gene X is not a proto-oncogene and not involved in uteriine cancer as the mutation is observed in both normal and cancer cells.

b. Gene Y is mutated in both alleles in both normal and tumor cells. If this gene Y was involved in cancer, then the non-functional gene Y protein should have turned normal cells into tumor cells as well. Further, as the mutations are present in both normal and cancer cell, this gene is not expressed in the uterine cells at all. Hence, gene Y will not be involved in uterine cancer.

c. The gene Z is not mutated in normal cells. Tumor cells show heterozygous mutation in gene Z. Hence, gene Z should be proto-oncogenes. Mutation even in one copy of this gene is resulting in cancer. When both copies of the gene are wild type or normal, there is no increased cell division of normal cells observed. Hence, the gene Z is responsible for the uterine cancer observed in all 15 individuals.