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Neuroblastoma Outcomes Linked to Tumor Evolution Features, Timeframe

NEW YORK – A German research team has uncovered an apparent relationship between tumor evolution and survival outcomes in infants with neuroblastoma tumors, using tumor genomic sequence data to link longer neuroblastoma evolution to more aggressive and deadlier forms of the disease.

"[T]he duration of evolution is an accurate predictor of outcome," co-senior and co-corresponding authors Thomas Höfer, a theoretical systems biologist at the German Cancer Research Center, and Frank Westermann, a neuroblastoma researcher affiliated with the Hopp Children's Cancer Center and the German Cancer Research Center, and their colleagues wrote in Nature Genetics on Monday, noting that "insight into neuroblastoma evolution may prospectively guide treatment decisions."

Using deep whole-genome sequencing, molecular clock analyses, and population genetic models, the researchers characterized tumor development and evolutionary features in relation to event-free survival and overall survival for 100 neuroblastoma cases spanning various disease stages and subtypes. The tumor set encompassed 67 samples taken at the time of diagnosis, along with 33 relapsed tumor samples.

The team's molecular clock analyses, based on neutral somatic single-nucleotide variant (SSNV) patterns, provided a look at the most recent common ancestor (MRCA) for clonal populations in a tumor, including chromosomal gains or losses occurring in early tumor clones and the advent of clones found in the resected tumor.

"In contrast to driver mutations, neutral SSNVs and small indels are continuously accumulated and contain information on tumor evolution," the authors explained, noting that "[a]nalysis of mutational signatures assigned the majority of SSNVs to clock-like signatures."

Their results suggested that neuroblastoma development can stretch back as far as the first trimester of pregnancy. But the duration of this development — and the tumor evolution that took place along the way — differed between patients. In particular, longer tumor evolution prior to diagnosis seemed to coincide with more aggressive forms of neuroblastoma and poorer patient outcomes.

The team subsequently confirmed that pattern by analyzing whole-genome sequence data for primary and metastatic tumor samples sequenced to 30-fold average coverage for 86 additional neuroblastoma cases.

"Remarkably, in our cohort, MRCA class is an accurate predictor of clinical outcome," the authors reported. "This is true regardless of whether we could time an early chromosomal gain, and implies that neuroblastomas with a longer evolutionary history are more aggressive."

While altered mitotic cell division appeared to contribute consistently to neuroblastoma development, the team said, survival outcomes appeared to be more favorable for cases involving tumors with relatively early clonal expansions that began relatively quickly after tumor evolution began, based on clonal and cell content patterns estimated from gain and loss patterns.

In contrast, the researchers' analyses suggested that early tumor aneuploidy events and extended neuroblastoma evolution during tumor development both coincided with more aggressive disease and poorer event-free survival and overall survival outcomes — a pattern suspected of stemming from the acquisition of new mutations that enhance tumor voracity, including alterations affecting genes in pathways that boost telomere maintenance.

"Our findings suggest that MRCA timing may be worth considering as a parameter for patient stratification," the authors wrote.

Moreover, their results suggested a child's age at neuroblastoma diagnosis often corresponded with the MRCA of tumor clones in an unexpected way. In particular, children diagnosed with neuroblastoma at a later age tended to have tumors with longer evolutionary times started at around the same fetal developmental stage as children diagnosed younger.

"Paradoxically, this implies that low-risk tumors reach detectable size earlier than high-risk," the authors explained, adding that "we infer that low-risk tumors have a substantially lower fraction of tumor cell loss than high-risk tumors and hence should grow faster."