Somatic Genetic Variation in Children: from Mosaicism to Cancer

This thesis concerns various aspects of somatic mosaicism and genetic intratumor heterogeneity in childhood cancer.

In paper I, I show that aneuploidy in itself does not lead to the level of chromosomal instability that is typically seen in malignant cells. This finding strongly argues against the so called autocatalytic theory of carcinogenesis.

Paper II illustrates that, in rare cases, low-level somatic mosaicism can be unmasked by hitchhiking on the clonal expansion seen in carcinogenesis. Paper III demonstrates that the level of somatic mosaicism at the copy number level in fetuses is lower than in adult humans and that fetal hepatocytes are no more aneuploid than other cells from the fetus. Furthermore, we also detect an organ specific genomic profile in the fetal thymus, due to physiological T-cell receptor rearrangement.

Paper IV highlights that intratumor genetic heterogeneity is a common feature in chemotherapy treated pediatric cancers. In this paper, we also demonstrate that the presence of genetic heterogeneity within single biopsies is associated with lower event free survival and cancer specific overall survival, and that it was a better prognostic predictor than the burden of somatic genetic aberrations.

Paper V provides a map of the landscape of intratumor genetic heterogeneity within the primary lesion in Wilms tumor, neuroblastoma and rhabdomyosarcoma. We also discover four different evolutionary trajectories, and show that the presence of some of these evolutionary patterns within the primary tumor predicts inferior survival.

In conclusion, the findings presented in this thesis demonstrate that genetic variation is a rare but significant feature in normal cells of young human tissues. In contrast, such variation is extremely common within childhood solid tumors. Our data suggest that increased knowledge of the evolutionary dynamics within a tumor might lead to improved risk stratification and more personalized treatment.