Q: Many mature clinicians find “Mutational Oncology” to be a bit mysterious. Please help them understand. As they pertain to cancer, what are somatic (as opposed to germ line) mutations, transitions, transversions, “point”, “missense”, “nonsense”, insertion, deletion, and copy numbers and why does it matter?
A: With the plethora of molecular alterations that commonly occur in cancer, it can be confusing to understand what causes them and how these alterations affect the proteins that these genes encode. To begin, in cancer a somatic alteration refers to a non-inherited molecular alteration, which can occur spontaneously during replication or may be due to DNA damage or mistakes during DNA damage repair, and is only detectable in the tumor. These mutations are not passed to offspring. In contrast, a germ line mutation is heritable and detectable in nearly all tissues.
Many types of alterations occur in cancer. For example, a point mutation is the modification of a single base in a DNA coding sequence. A point mutation may be a transversion (replacement of a purine base with a pyrimidine and vice versa) or more commonly, a transition (replacement of a purine with a purine or pyrimidine with a pyrimidine). These single-base modifications can have several different effects. One common type of mutation is a missense mutation, in which the resulting base substitution changes the coding sequence for one amino acid to another. Another type of single base substitution may lead to a change from a coding amino acid to a termination codon, resulting in premature truncation of the protein. A point mutation may also result in the insertion or deletion of a base resulting in a change of the reading frame (a frameshift mutation) during protein translation. Finally, a single base substitution may not have an effect and will code for the same amino acid; this effect is known as a silent mutation.
These seemingly simple changes in DNA coding sequences can have profound effects on protein function. If the coding sequence of a protein is altered, this can lead to a number of different altered behaviors including inactivation or activation, mislocalization, or altered transcription (which can affect mRNA and protein expression). For example, the well-known missense mutations BRAF V600E and EGFR T790M mutations change these proteins from their normal functioning state to a hyperactive state. In the case of a truncating or frameshift mutations, this can result in the loss of key portions of the protein that are critical to its function. For example, a truncating mutation that results in the loss of a kinase domain in a tyrosine kinase protein will completely abrogate that function of the protein. It is these functional characterizations that lead to the classification of variants as deleterious/pathogenic or benign.
Knowing the tumor profile of a patient can aid in treatment decisions, aid in the identification of potential targeted therapies that may be beneficial, and identify clinical trials that can be beneficial to the patient. Additionally, genetic testing for certain germline mutations can identify patients that have an increased risk for developing certain cancers, a well-known example being BRCA testing for breast cancer risk. Another perhaps more critical role in personalized medicine that genetic profiling of patient tumors plays is the guidance on treatments that should not be used for a particular patient. In particular, some mutations can render a tumor resistant to certain drugs and others can lead to acquired resistance after an initial response. In the era of personalized medicine, determination of mutation type and the effect of that mutation on protein function can be a critical part of cancer treatment.