Primary Immunodeficiency and Cancer Predisposition Revisited: Embedding Two Closely Related Concepts Into an...

Common understanding suggests that the normal function of a "healthy" immune system safe-guards and protects against the development of malignancies, whereas a genetically impaired one might increase the likelihood of their manifestation. This view is primarily based on and apparently supported by an increased incidence of such diseases in patients with specific forms of immunodeficiencies that are caused by high penetrant gene defects. As I will review and discuss herein, such constellations merely represent the tip of an iceberg. The overall situation is by far more varied and complex, especially if one takes into account the growing difficulties to define what actually constitutes an immunodeficiency and what defines a cancer predisposition. The enormous advances in genome sequencing, in bioinformatic analyses and in the functional in vitro and in vivo assessment of novel findings together with the availability of large databases provide us with a wealth of information that steadily increases the number of sequence variants that concur with clinically more or less recognizable immunological problems and their consequences. Since many of the newly identified hard-core defects are exceedingly rare, their tumor predisposing effect is difficult to ascertain. The analyses of large data sets, on the other hand, continuously supply us with low penetrant variants that, at least in statistical terms, are clearly tumor predisposing, although their specific relevance for the respective carriers still needs to be carefully assessed on an individual basis. Finally, defects and variants that affect the same gene families and pathways in both a constitutional and somatic setting underscore the fact that immunodeficiencies and cancer predisposition can be viewed as two closely related errors of development. Depending on the particular genetic and/or environmental context as well as the respective stage of development, the same changes can have either a neutral, predisposing and, in some instances, even a protective effect. To understand the interaction between the immune system, be it "normal" or "deficient" and tumor predisposition and development on a systemic level, one therefore needs to focus on the structure and dynamic functional organization of the entire immune system rather than on its isolated individual components alone.