Somatic Genomic Mosaicism in Multiple Myeloma
Somatic genomic mosaicism occurs when somatic cells of the body display different genotypes (Table 1), it has recently received increased attention because of its implications in disease, including neurodegenerative diseases and Down syndrome (Iourov et al., 2008, 2010, 2019; Biesecker and Spinner, 2013; Hultén et al., 2013; Vijg, 2014; Campbell et al., 2015; Fernández et al., 2016). Genomic mosaicism also contributes to high levels of cellular heterogeneity in pathological conditions, which is a distinguishing feature of cancer (Heng, 2015, 2019). In fact, high heterogeneity in cancer represents an extreme example of genomic mosaicism. The genomic basis of somatic genomic mosaicism, however, remains to be elucidated. Traditional explanations have focused on defective cellular processes, including imperfect DNA replication and repair, abnormal chromosomal machinery, and a faulty stress response to environmental challenges. As illustrated by the evolutionary mechanism of cancer (Ye et al., 2009), nearly all molecular pathways/mechanisms can contribute to variations in cellular systems. The conventional wisdom is that biosystems are not perfect and that error-generating opportunities exist. Thus, the major goals of molecular medicine have been to detect and fix these errors. Nevertheless, bioerrors (or imperfect-biosystems) do not explain the high degree of genomic mosaicism revealed by large-scale -omics technologies (Vattathil and Scheet, 2016), and plausible mechanisms are not yet revealed (Heng et al., 2016). These novel mechanisms should address (a) both the positive and negative contributions of cellular heterogeneity in normal and disease conditions and (b) the survival strategy of cancer cells to drastically elevate the level of heterogeneity in crisis conditions. Using multiple myeloma (MM) as an example, these mechanisms will be examined in the context of bio-information, adaptive systems (Table 1), and emergent behavior during cancer evolution.