Mutation accumulation and developmental lineages in normal and Down syndrome human fetal haematopoiesis

Scientific Reports, vol. 10, pp. 12991

Abstract

Children show a higher incidence of leukemia compared to young adolescents, yet their cells have less age-related (oncogenic) somatic mutations. Newborns with Down syndrome have an even higher risk of developing leukemia, which is thought to be driven by mutations that accumulate during fetal development. To characterize mutation accumulation in individual stem and progenitor cells of Down syndrome and karyotypically normal fetuses, we clonally expanded single cells and performed whole-genome sequencing. We found a higher mutation rate in haematopoietic stem and progenitor cells during fetal development compared to the post-infant rate. In fetal trisomy 21 cells the number of somatic mutations is even further increased, which was already apparent during the first cell divisions of embryogenesis before gastrulation. The number and types of mutations in fetal trisomy 21 haematopoietic stem and progenitor cells were similar to those in Down syndrome-associated myeloid preleukemia and could be attributed to mutational processes that were active during normal fetal haematopoiesis. Finally, we found that the contribution of early embryonic cells to human fetal tissues can vary considerably between individuals. The increased mutation rates found in this study, may contribute to the increased risk of leukemia early during life and the higher incidence of leukemia in Down syndrome.

Authors 8

1. Karlijn Hasaart

   Oncode Institute · Princess Máxima Center

   Affiliation as printed

   Princess Máxima Center for Pediatric Oncology and Oncode Institute, Heidelberglaan 25, 3584CS, Utrecht, The Netherlands

2. Freek Manders

   Oncode Institute · Princess Máxima Center

   Affiliation as printed

   Princess Máxima Center for Pediatric Oncology and Oncode Institute, Heidelberglaan 25, 3584CS, Utrecht, The Netherlands

3. Marie‐Louise van der Hoorn Aachen

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands

4. Mark Verheul

   Oncode Institute · Princess Máxima Center

   Affiliation as printed

   Princess Máxima Center for Pediatric Oncology and Oncode Institute, Heidelberglaan 25, 3584CS, Utrecht, The Netherlands

5. Tomasz Poplonski

   Princess Máxima Center

   Affiliation as printed

   Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS, Utrecht, The Netherlands

6. Ewart Kuijk

   Utrecht University · University Medical Center Utrecht · Oncode Institute

   Affiliation as printed

   Center for Molecular Medicine, University Medical Center Utrecht and Oncode Institute, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands

7. Susana M. Chuva de Sousa Lopes Aachen Department of Anatomy and Embryology

   Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC, Leiden, The Netherlands

8. Ruben van Boxtel corresponding

   Oncode Institute · Princess Máxima Center

   Affiliation as printed

   Princess Máxima Center for Pediatric Oncology and Oncode Institute, Heidelberglaan 25, 3584CS, Utrecht, The Netherlands. R.vanBoxtel@prinsesmaximacentrum.nl

   Princess Máxima Center for Pediatric Oncology and Oncode Institute, Heidelberglaan 25, 3584CS, Utrecht, The Netherlands