Significance: Understanding the risk factors of carcinogenesis is a major goal of biomedical research. Historically, the focus has been on the role of somatic mutations, and the reason for cancer typically occurring late in life is predominantly attributed to a gradual accumulation of such mutations. We challenge that view and propose that the decline of the immune system is the primary reason why cancer is an age-related disease. The immunological model featured here captures risk profiles for many cancer types and infectious diseases, suggesting that therapies reversing T cell exhaustion or restoring T cell production will be promising avenues of treatment.

In order to maintain functional robustness and species integrity, organisms must ensure high fidelity of the genome duplication process. This is particularly true during early development, where cell division is often occurring both rapidly and coherently. By studying the extreme limits of suppressing DNA replication failure due to double fork stall errors, we uncover a fundamental constant that describes a trade-off between genome size and architectural complexity of the developing organism. This constant has the approximate value N _U ≈ 3 × 10¹² basepairs, and depends only on two highly conserved molecular properties of DNA biology. We show that our theory is successful in interpreting a diverse range of data across the Eukaryota.

In our PNAS article (1), we explore the relationship between thymic involution and rising disease incidence with age. In letters from Jiménez-Alonso et al. (2), Schooling and Zhao (3), and Mortazavi (4), the authors point out several topics deserving further discussion. Experimental research has been unable to clearly determine whether the activity of the thymus dictates cancer risk. As Jiménez-Alonso et al. point out (2), there are experiments from the 1970s in which athymic mice are measured to have similar cancer risk to normal mice, while having increased risk of infectious diseases (5, 6). Furthermore, individuals with DiGeorge syndrome (DGS, 22q11.2 deletion syndrome) often have thymus problems and a higher risk of infectious diseases, yet some reports find that they have similar cancer risk (7, 8). On the other hand, there are experiments in which thymectomized mice displayed a higher cancer risk (9⇓⇓–12) and others in which thymus grafts on nude mice induce cancer remission (13, 14). In addition, there is an association between low T cell receptor excision circles (a by-product of T cell production) and certain cancers (15), and a perspective study found that short leukocyte telomeres predict cancer risk (16). We consider our article (1) to provide statistical support for thymic T cell output strongly influencing cancer incidence. In looking at these results, a few important points should be considered and these are discussed in the following paragraphs. First, the examples cited based on analysis of nude (athymic) mice are not ideal for answering questions about human carcinogenesis, which mostly occurs in or after late middle-age. The mice in these experiments (5, 6) had very short lifespans (one experiment … [↵][1]1To whom correspondence may be addressed. Email: s.palmer{at}hw.ac.uk or tjnewman{at}solaravus.com. [1]: #xref-corresp-1-1