An accurate understanding of the clonal origins of
tumors is critical for designing effective strategies to treat or prevent
cancer and for guiding the field of
cancer risk assessment. The intent of this review is to summarize evidence of multiclonal
tumor origin and, thereby, contest the commonly held assumption of monoclonal
tumor origin. This review describes relevant studies of X chromosome inactivation, analyses of
tumor heterogeneity using other markers, single cell sequencing, and lineage tracing studies in aggregation chimeras and engineered rodent models. Methods for investigating
tumor clonality have an inherent bias against detecting multiclonality. Despite this, multiclonality has been observed within all
tumor stages and within 53 different types of
tumors. For myeloid
tumors, monoclonal
tumor origin may be the predominant path to
cancer and a monoclonal
tumor origin cannot be ruled out for a fraction of other
cancer types. Nevertheless, a large body of evidence supports the conclusion that most
cancers are multiclonal in origin. Cooperation between different cell types and between clones of cells carrying different genetic and/or epigenetic lesions is discussed, along with how polyclonal
tumor origin can be integrated with current perspectives on the genesis of
tumors. In order to develop biologically sound and useful approaches to
cancer risk assessment and
precision medicine, mathematical models of
carcinogenesis are needed, which incorporate multiclonal
tumor origin and the contributions of spontaneous mutations in conjunction with the selective advantages conferred by particular mutations and combinations of mutations. Adherence to the idea that a growth must develop from a single progenitor cell to be considered neoplastic has outlived its usefulness. Moving forward, explicit examination of
tumor clonality, using advanced tools, like lineage tracing models, will provide a strong foundation for future advances in clinical oncology and better training for the next generation of oncologists and pathologists.