Childhood sarcomas are a diverse group of rare cancers arising in bone and soft tissue, encompassing biologically distinct diseases such as osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma. While congenital anomalies are a well-established risk factor for childhood cancer as a whole, much less is known about how specific anomalies relate to risk of specific sarcoma subtypes. Researchers from CLIC examined nearly 22 million children born across nine US states, offering the most detailed assessment to date of childhood sarcoma risk associated with congenital anomalies. The analysis focused on major, non-syndromic anomalies, defined as defects not attributable to a known chromosomal or genetic syndrome.
Results showed that children with major, non-syndromic congenital anomalies had an elevated risk of soft tissue sarcoma overall. The association was strongest for embryonal rhabdomyosarcoma in children with central nervous system anomalies, obstructive genitourinary defects, or limb reduction deformities. Children with hypospadias also had a clearly elevated risk of non-rhabdomyosarcoma soft tissue sarcoma. However, the findings for bone sarcomas were less consistent. Major congenital anomalies were broadly not associated with increased bone tumor risk, although specific subgroups, cardiovascular and integumentary anomalies, were linked to higher osteosarcoma risk. Furthermore, sarcoma risk appeared to vary according to the number of major anomalies. Children with multiple anomalies had a higher incidence of sarcoma, particularly soft tissue sarcoma, than those with a single or no anomaly. This pattern was not observed for bone tumors.
These findings challenge the practice of treating sarcomas as a single etiological entity, an approach largely driven by their rarity. The associations observed in this study indicate that disruptions during the formation of particular congenital conditions may contribute to the development of specific sarcomas, potentially through shared genetic pathways. Nevertheless, the study does not propose that congenital anomalies cause cancer, and absolute sarcoma risk remains low even among affected children. Several associations were based on small case numbers and warrant replication in independent populations. Still, the scale of the cohort allowed detection of patterns that smaller studies would likely have missed.
Overall, these results suggest that yet-unrecognized biological pathways might be involved in predisposition to certain childhood sarcomas. Further research into the underlying mechanisms could therefore uncover new clues and provide important insights into how these rare cancers develop.
Citation:
Authors: Russ Wolters, Ji Yun Tark, Tiffany M Chambers, Tania A Desrosiers, Michael E Scheurer, Charles Shumate, Wendy N Nembhard, Mahsa M Yazdy, Eirini Nestoridi, Amanda E Janitz, Jean Paul Tanner, Russell S Kirby, Jason L Salemi, Yao Yu, Chad D Huff, Sharon E Plon, Philip J Lupo, Jeremy M Schraw
Published In: Pediatr Blood Cancer. 2026 Aug;73(8):e70415. doi: 10.1002/1545-5017.70415.