Abstract
The US National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) created the Cancer Genome Atlas (TCGA) Project in 2006. The TCGA’s goal was to sequence the genomes of 10,000 tumors to identify common genetic changes among different types of tumors for developing genetic-based treatments. TCGA offered great potential for cancer patients, but in reality has little impact on clinical applications. Recent reports place the past TCGA approach of testing a small tumor mass at a single time-point at a crossroads. This crossroads presents us with the conundrum of whether we should sequence more tumors or obtain multiple biopsies from each individual tumor at different time points. Sequencing more tumors with the past TCGA approach of single time-point sampling can neither capture the heterogeneity between different parts of the same tumor nor catch the heterogeneity that occurs as a function of time, error rates, and random drift. Obtaining multiple biopsies from each individual tumor presents multiple logistical and financial challenges. Here, we review current literature and rethink the utility and application of the TCGA approach. We discuss that the TCGA-led catalogue may provide insights into studying the functional significance of oncogenic genes in reference to non-cancer genetic background. Different methods to enhance identifying cancer targets, such as single cell technology, real time imaging of cancer cells with a biological global positioning system, and cross-referencing big data sets, are offered as ways to address sampling discrepancies in the face of tumor heterogeneity. We predict that TCGA landmarks may prove far more useful for cancer prevention than for cancer diagnosis and treatment when considering the effect of non-cancer genes and the normal genetic background on tumor microenvironment. Cancer prevention can be better realized once we understand how therapy affects the genetic makeup of cancer over time in a clinical setting. This may help create novel therapies for gene mutations that arise during a tumor’s evolution from the selection pressure of treatment.
Highlights
The fight against cancer has been long and baffling
The the Cancer Genome Atlas (TCGA) is based on a hypothesis that (1) a unique and reproducible genetic difference exists among patients’ tumors, (2) the signatures can be identified utilizing whole genome sequencing (WGS) for each cancer type, and (3) as WGS technology advances, TCGA will help develop individualized treatment
Recent reports on spatial and temporal intratumoral heterogeneity [5,6] question the clinical value of TCGA sampling of a minute biopsy of tumor at a single timepoint of tumor growth
Summary
The fight against cancer has been long and baffling. Worldwide instances of cancer increase through the years, yet cancer research is still attempting to comprehend its fundamental science and the history of hopeful medical advances is littered with disappointments. By incorporating key markers yielded from TCGA, cytokine profiling of tumors would provide an additional layer of diagnostic and prognostic information in conjunction with gene expression Another forms of soluble biomarkers are those that undergo DNA methylation because this can be detected in blood serum samples of cancer patients [75]. Lack of knowledge on co-evolution dynamics potentially hinders the progress of a team-based, cross-disciplinary approach like TCGA [100] Can these changes of cancer subclones be followed at the single cell level with a “biological global positioning system (bGPS)” [34], with visualization techniques for exploring oncogenomics data, allowing researchers to effectively visualize multidimensional oncogenomics datasets [101]?
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