What common genomic alterations do biomarker tests look for?
Biomarker tests looks for genomic alterations in tumors, using resected tissue/ tumor biopsy or liquid (blood) biopsies.
COLONTOWN’s Scientific Director, Manju George, explains how these alterations can provide information that can impact your treatment options.
A genomic alteration can be any change in genetic information. There are many types of such alterations, or mutations. For crc patients, the most important type is a mutation in the DNA sequence (a “point” mutation) which results in a change in the amino acid sequence in the encoded protein that affects its function. These mutations may be drug-able and of use to us clinically. There can be other point mutations which don’t change the protein function.
There can also be other genetic alterations which are not limited to a single nucleotide, but involve larger regions of the genome.
The genetic material (genome) is packed inside the nucleus of a cell in a much condensed structure called a chromosome. Human cells have 23 pairs of chromosomes. About 20,000 genes in our genome are distributed on these 23 chromosomes. This distribution is the same between all humans. for e.g.., the BRAF gene in humans is located on Chromosome 7, the KRAS gene is on Chromosome 12. Genetic changes (large scale) can involve parts of a chromosome.
Gene Rearrangement
A gene rearrangement is when parts of a gene gets stuck to another chromosome (chromosomal translocation) and is rearranged. A gene fusion is one kind of a gene rearrangement. This can affect its function and shut the gene off or make it overactive depending on where it is translocated. This can happen due to errors when a cell is dividing.
Deletions
There can be deletions (losses) of large parts of a chromosome, where many genes are lost. If a tumor suppressor gene is in the chromosomal region that is deleted, then that can make cells grow and divide abnormally.
Amplifications
Amplifications (gains or duplications) involve multiple copies of a chromosomal region. All the genes present in this region maybe found in multiple copies, so proteins encoded by this region maybe found in large amounts. If one of these genes encodes an oncogene or a growth factor or its receptor, this could make the cells with such alterations grow and divide abnormally.
For crc patients, what is relevant to treatment options are mutations and amplifications.
Many of the deleterious (bad) mutations cause a protein to become overactive or not be controlled by regulatory mechanisms that work in normal cells. Researchers have developed drugs or antibodies that block the function of such mutant proteins and such drugs are available to us.
Some gene amplifications behave like overactive proteins. In such cases, inhibitors can work.
Some gene rearrangements or translocations are common in some cancers and drugs are available in some cases that target those rearrangements. In such cases, knowing if our cancer has such rearrangements would be useful.
The genomic testing companies look at large numbers of published studies and (their own studies) and come up with a panel of genomic alterations that are associated with certain kinds of cancers. Then they screen patient samples for these genomic alterations. Currently about 300 different mutations in 72 cancer-relevant genes are tested in CRC. Germ-line testing (which looks for inherited genetic changes) examines an array of genetic changes common to many cancers using genomic DNA isolated from blood. Tests like Foundation One and Oncotarget DX isolate genomic DNA from tumor tissue and look at CRC-relevant genetic changes. Liquid biopsies like Guardant 360 look at circulating tumor DNA from blood and looks at CRC-relevant genomic changes.
Some gene rearrangements or translocations are common in some cancers and drugs are available in some cases that target those rearrangements. In such cases, knowing if our cancer has such rearrangements would be useful.