New insights into the role of intra-tumor genetic heterogeneity in carcinogenesis: identification of complex single gene variance within tumors

Aim: Present cancer hypotheses are almost all based on the concept that accumulation of specific driver gene mutations cause carcinogenesis. The discovery of intra-tumor genetic heterogeneity (ITGH), has resulted in this hypothesis being modified by assuming that most of these ITGH mutations are in passenger genes. In addition, accumulating ITGH data on driver gene mutations have revealed considerable genotype/phenotype disconnects. This study proposes to investigate this disconnect by examining the nature and degree of ITGH in breast tumors.Methods: ITGH was examined in tumors using next generation sequencing of up to 68,000 reads and analysis tools that allowed for identification of distinct minority variants within single genes, i.e., complex single gene variance (CSGV).Results: CSGV was identified in the androgen receptor genes in all breast tumors examined.Conclusion: Evidence of CSGV suggests that a selection - as opposed to a mutation - centric hypothesis could better explain carcinogenesis. Our hypothesis proposes that tumors develop by the selection of preexisting de novo mutations rather than just the accumulation of de novo mutations. Thus, the role of selection pressures, such as changes in tissue microenvironments will likely be critical to our understanding of tumor resistance as well as the development of more effective treatment protocols