Complex mutation patterns help understand causes of childhood cancer

Typical mutation patterns in the genome can provide information about the cause of cancer and how to combat it. So far, however, such mutation patterns have mainly been identified in adults with cancer and used for therapy decisions. A team of researchers from the Hopp Children's Cancer Center Heidelberg (KiTZ), the German Cancer Research Center (DKFZ), Heidelberg University Hospital (UKHD) and the Moores Cancer Center in San Diego has now published in the journal Nature Cancer the most comprehensive analysis to date of mutation patterns in the genomes of childhood tumors and leukemias. The data provides important information to better understand the biology of childhood tumors and the mutation patterns can be used as biomarkers to predict response to treatment.

© Thatikonda/ KiTZ

The Hopp Children’s Cancer Center Heidelberg (KiTZ) is a joint institution of the German Cancer Research Center (DKFZ), Heidelberg University Hospital (UKHD) and the University of Heidelberg (Uni HD).

Cancer in adults often arises from changes in the genetic material that accumulate in the various body cells during the course of life. These can, for example, be errors during cell division, during which a copy of the genetic material is also always passed on to the daughter cells. Other causes of mutations are environmental influences such as UV light, alcohol and tobacco consumption. Genetic changes of this kind are called somatic mutations. These occur exclusively in the so-called soma cells, the body's cells, i.e. not in the sperm and egg cells of the germ line and are therefore not passed on to the next generation. The older we get, the more errors creep into our genetic code that can contribute to the development of cancer.

Due to the rapid progress in genome coding, more and more typical mutation patterns have become known in recent years, which are caused by certain environmental influences and defects in the cellular machinery. These mutation patterns provide information about the molecular causes of cancer and are therefore also used for therapy decisions.

Which of these typical mutation patterns also already occur in children and adolescents and what role they play in the development and treatment of childhood cancer was not yet known for certain mutation types and cancers. A team of researchers from the Hopp Children's Cancer Center Heidelberg (KiTZ), the German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD), and the Moores Cancer Center in San Diego therefore analyzed the genome data of a total of 785 childhood tumors and a total of 27 different cancers. It is the most comprehensive analysis to date of somatic mutation patterns in the genome of childhood tumors and leukemias. The researchers distinguished between point mutations, in which only one building block of DNA was incorrectly inserted, and genetic changes caused by deletion or insertion of one or more building blocks of DNA.

As expected, the research team found in the genome of childhood tumors overall only a fraction of the mutation patterns that are relatively common in adults, in part because the mutations that occur as a result of tobacco consumption or other environmental influences generally do not play a role in childhood. Instead, most somatic mutations in children and adolescents appear to arise from errors during cell division, that is, during the natural processes of growth and development. However, somatic mutations of this type are present in almost all cells of the human body, occur throughout life, and do not necessarily lead to cancer development. The research team also made discoveries that are likely to affect treatment recommendations for children and adolescents with cancer: Only about two percent of tumors have a defective special form of DNA repair. Tumors with these mutation patterns are typically targeted with DNA-damaging therapeutics because the cancer cells are unable to repair this damage and subsequently die. Previous studies assumed that defects in this particular form of DNA repair are much more common in childhood cancer. In addition, the research team also identified a completely new mutation pattern that occurred in the most common childhood blood cancers.

"Until now, the repertoire of mutation patterns in childhood tumors could only be insufficiently used for prognoses and therapy recommendations," says Natalie Jäger from KiTZ and DKFZ, who led the study as a bioinformatician. "We hope that our comprehensive analysis will help to use mutation profiles as biomarkers in the future and thus improve personalized cancer therapies for children and adolescents."

 

Further information:
International data base for mutation patterns of cancer diseases
 

Original publication:
Thatikonda et al. Comprehensive analysis of mutational signatures reveals distinct patterns and molecular processes across 27 pediatric cancers. (online publication January 26, 2023) In: Nature Cancer DOI: 10.1038/s43018-022-00509-4

 

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