• Alex Kentsis

  • May 18, 2020

Why do young people get cancer? Developmental mutators, mutagens, and inheritance.

Much of human cancer is a product of aging, from errors during DNA replication, environmental exposures, and the inevitable failure of our bodies. What causes cancer in young people and children?

This new article integrates recently discovered mechanisms of developmental mutations, with new and established findings of inherited cancer predisposition and oncogenic pathogens. By relating the findings of recent human genomic studies with the fundamental mechanisms of cancer pathogenesis, this article also explains key concepts for the clinical diagnosis and rational therapy of patients, as part of recent molecular and precision oncology paradigms. Lastly, a discussion of emerging technologies and therapies provides compelling directions for future work to define the basic molecular and genetic mechanisms of early onset cancers, and improved strategies for their treatment, screening and potential prevention.

While inheritance of germ-line mutations in genes causing cancer predisposition syndromes, or exposure to environmental mutagens and oncogenic pathogens is responsible for early onset of cancer, only approximately 10% of individuals are estimated to have such cancer predisposition. This raises the question of what causes early onset cancers in the majority of children and young adults. With Steven Frank, we advance the developmental mutator hypothesis to explain early onset cancer development.

This idea is based on the recently published findings of distinct features of oncogenic mutations observed in childhood and young adult cancers, and their expression of endogenous mutagenic DNA enzymes. This involves the majority of blood and solid tumors affecting children and young adults, including leukemias, medulloblastomas, neuroblastomas, and sarcomas. The developmental mutator model explains recent findings of widespread somatic genetic mosaicism in normal human tissues, and predicts developmental DNA rearrangements in specific tissues which give rise to early onset cancers in children and young adults without inherited cancer predisposition.

Many questions remain, including what controls the activity of developmental mutators? What processes cause developmental mutations in developing sarcomas, kidney tumors, leukemias, and brain tumors that lack PGBD5 and RAG1/2? How do interactions among developmental mutators, their physiologic control processes and exposures, and familial inheritance converge in human development and disease?

We are always looking for colleagues, collaborators, and students to make progress in these questions.