The Cancer Genome: Paradigm or Paradox?

SIMPLE SUMMARY: The observation that genetic mutations often do not cause cancer or disease in the phenomena of mosaicism, clonal hematopoiesis of indeterminate potential (CHIP), and heteroplasmy provides us with important clues about the origin and nature of cancer. We should be wary that the cancer genome may lead us astray to the wrong destination on a bad expedition unless we adopt the right cancer theory to elucidate it, and adhere to the proper scientific method to investigate it. ABSTRACT: Nowadays, many professionals are sequencing the DNA and studying the cancer genome. However, if the genetic theory of cancer is flawed, our faith in the cancer genome will falter. If gene sequencing is only a tool, we should question what we are making or creating with this tool. When we do not have the right cancer theory at our disposal, we cannot be sure that what we create from the cancer genome is meaningful or useful. In this article, we illustrate that mosaicism, CHIP, and heteroplasmy dispute our traditional perspectives about a genetic origin of cancer and challenge our current narratives about the cancer genome. We caution that when we have the wrong cancer theory, big data can provide poor evidence. Precision medicine may become rather imprecise. Targeted therapy either does not work or work for the wrong reasons. The cancer genome thus becomes a paradox rather than a paradigm.