Increased somatic mutation burdens in normal human cells due to defective DNA polymerases

Abstract

Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.

Substitution mutational signatures in whole-genome–sequenced cancers in the UK population

“…DBS16 was associated with SBS10d (Fig. 3C), a hypermutator signature recently reported as due to polymerase d (POLD) dysfunction (19). DBS22 is not associated with very prominent peaks (highest probabilities only 7%).…”

“…For this evaluation, the final dataset included a total of 298,694,545 substitu-tions, 2,675,617 double substitutions, 154,675,475 indels, and 1,958,105 rearrangements (Fig. 1, A and B, and tables S1 and S2) of 19 tumor types [skin, lung, stomach, colorectal, bladder, liver, uterus, ovary, biliary, kidney, pancreas, breast, prostate, bone and soft tissue, central nervous system (CNS), lymphoid, oropharyngeal, neuroendocrine tumors (NETs), and myeloid].…”

Increased risk of cancer in dogs and humans: A consequence of recent extension of lifespan beyond evolutionarily determined limitations?

“…68 Similarly, elevated cancer rates can be found in individuals with germline mutations in DNA polymerases (POLE/POLD1). 69 Companion dogs generally do not have the same level of exposures to industrial (occupational) or social (tobacco) mutagens as humans, their hair coat protects them from cancer-causing ultraviolet radiation from the sun, and controlled breeding practices help to significantly reduce the likelihood for true heritable cancer syndromes to become established. In a singular situation where a syndromic cancer (canine renal cystadenoma and nodular dermatofibrosis, associated with a mutation in the folliculin gene) arose in a canine pedigree, it was rapidly identified and characterized, 70,71 providing tools to eliminate it from the breeding population.…”

Why Do We Care More About Disease than Health?

“…In comparison, our maternally and paternally inherited germline variants are set at the time of conception, subsequently layered with the accumulation of somatic nuclear and mitochondrial gene mutations. It is widely believed that de novo mutations may contribute to some cancers (Vaux 2011), but gene mutations may otherwise have limited specific biological effects (Robinson et al 2021;Versteeg 2014) and even have anti-neoplastic effects in some contexts (Colom et al 2021). Therefore, our genes change little over time, and mostly in one direction (accumulating mutations of uncertain significance), yet our health is highly changeable-capable of declining and improving over short and long periods of time.…”