Why some “lower-risk” childhood cancers turn deadly

Scientists at the Wellcome Sanger Institute, the University of Cambridge, Great Ormond Street Hospital, University College London, and collaborating institutions discovered that some childhood rhabdomyosarcomas classified as lower-risk contain hidden populations of highly aggressive cancer cells. The findings appear in Cancer Research.

Rhabdomyosarcoma is an aggressive muscle tissue cancer affecting approximately 55 children per year in the United Kingdom. Doctors traditionally categorize the disease based on whether tumors contain a specific genetic fusion marker. Children with fusion-positive tumors have substantially lower survival rates, but some children with fusion-negative tumors also develop aggressive cancers that prove fatal, a pattern that existing classification methods failed to explain.

The research team examined tumor samples from 16 children using single-cell RNA sequencing and spatial transcriptomics. These techniques measure gene activity in individual cells and map that activity to specific tumor locations, revealing details that conventional methods cannot detect.

The analysis showed that some non-high-risk tumors contained cells with gene activity patterns resembling those in high-risk tumors. Importantly, aggressive cancers did not require the same genetic mutations to produce similar behavior. Different rare genetic changes affected the same cellular pathways involved in dangerous forms of the disease.

Dr. Karin Straathof of UCL Cancer Institute and GOSH stated: "By studying tumors one cell at a time, we uncovered hidden populations of aggressive cancer cells that conventional methods miss. Although these tumors carry different genetic changes, many converge on the same aggressive pathways."

The discovery could enable doctors to identify children at greater risk of relapse or death even when standard genetic tests suggest lower risk. Researchers are expanding the study to include hundreds of additional tumor samples to identify rare genetic changes capable of producing aggressive cancer and to accelerate development of personalized treatments.