Cancer arises due to the accumulation of alterations in genes that control cell survival, growth, proliferation, and differentiation, which provides a distinct genetic profile of the cancer. This genetic profile is typically assessed using DNA and/or RNA obtained from a biopsy of the primary tumor and aids in providing a therapeutic strategy for dealing with the tumor.
However, genomic instability and the ability to evolve to various interactions with microenvironmental cues, including therapeutic drugs, is a hallmark of cancer. Constant and unchecked mutations destabilize cells and increase the likelihood of moving from one stage of tumor development to the next, which consists of tumorigenisis, progression, and metastasis. Interestingly, as the cells evolve the accumulation of these mutations creates distinct populations of cells at each stage that can differ in their proliferation rate and treatment response.
Identification of these alterations requires serial sampling of the tumor genome, often from multiple metastatic sites. The most routine procedure for obtaining tumor samples is by using solid biopsy methods, which can be invasive, inconveniencing the patient and creating potential surgical complications. For these reasons, monitoring the cancer through solid biopsies can be very challenging. Recently, liquid biopsies have taken the place of solid biopsies to address tumor heterogeneity and possible treatment options.
How can a solid tumor be detected in a liquid biopsy? When a cell undergoes apoptosis or necrosis its DNA enters the bloodstream, referred to as cell-free DNA (cfDNA). Foreign or variant forms of DNA can be separated from normal cell cfDNA by the identification of differences in their genetic and epigenetic characteristics, also known as “specific markers,” found only in the foreign or variant DNA. For tumors, this cfDNA can help identify changes in the heterogeneity of solid tumors. However, this is limited due to the varying yields and tumor cfDNA fractions in the overall cfDNA population.
Whole-exome sequencing (WES) is a widely used targeted sequencing method that targets exomes, the protein-coding region of the human genome, which contains approximately 85% of known disease-related variants. WES has been shown to efficiently identify coding variants across a wide range of applications, including population genetics, genetic disease, and cancer studies. Given the sensitivity of WES, it is plausible that this method may be used to determine types and stages of cancers that are infrequently biopsied.
To capture the genetic diversity of breast and prostate metastatic tumor cfDNA, researchers at the Broad Institute of MIT and Harvard took on two main challenges; the first was to address the low yield of tumor cfDNA for WES analysis and the second was to compare the similarities or differences of WES cfDNA profiling with that of solid tumor biopsies. Using an analytical approach called ichorCNA, the authors were able to determine a sufficient tumor cfDNA content for WES (≥10%) in patients. Of the 520 patients 30-40% had a cfDNA content of ≥10%. For these patients, the authors were also able to show that WES analysis of cfDNA and solid tumor biopsies gave highly similar results (Click HERE to read the article). These results suggest the plausibility of using WES to detect clinically relevant tumor alterations in cfDNA without having to perform a biopsy from the solid tumor.
Blood biopsies to detect tumor cfDNA offer a non-invasive and easily accessible way for diagnosis, prognosis, and guidance for tumor treatments. This technique is a step forward in developing personalized care for treating cancer patients, however, the field still needs more proof that using blood biopsies in treatment helps patients.
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