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Study of Pediatric Cancers Shows Strong Link Between Tumor Microdiversity, Prognosis

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NEW YORK (GenomeWeb) – Measuring the microdiversity in the tumors of children treated with chemotherapy could help predict which kids are more likely to see their cancer progress and could potentially guide more personalized treatment strategies for at least some childhood cancers, new data has shown.

In a study published today in Nature Communications, a group led by researchers from Lund University in Sweden used SNP arrays to find that separate samples from the same tumors and from primary and metastatic tumors in seven children were highly genomically diverse.

The team also found in a follow-up study of 44 children with kidney cancer that the level of microdiversity within these kids' tumors was strongly associated with their prognosis. Children with microdiversity present in their tumors post-chemotherapy had poorer survival, while those with no sign of microdiversity showed 100 percent survival.

According to the study authors, while research on adult cancers has found that cells within the same tumor can have significantly different genomic landscapes, it had been unclear whether this level of diversity was also present in childhood tumors, and whether it might affect treatment response and the risk of progression.

In fact, previous evidence had led to a view of pediatric tumors as relatively stable compared with most adult cancers. The new results paint the opposite picture, suggesting that not only can some pediatric cancers show high levels of change and resulting diversity in their cell populations, but that this may also be an indicator of aggressive disease and thus something that could inform clinical decision-making for such children.

In the study, David Gisselsson, the paper's senior author and a pediatric pathologist at Lund University, along with colleagues from several other institutions, set out to try to determine the impact of tumor microdiversity on disease progression in pediatric cancer patients using a SNP array genotyping strategy.

"We have long wondered what impact this really has on tumor cell evolution in patients and if it has clinical implications. The study was a first attempt to answer that question," Gisselson told GenomeWeb in an email.

First, the researchers compared sets of samples from the same tumor and from metastases of seven children with solid tumors — including hepatoblastoma, neuroblastoma, nephroblastoma, and rhabdoid tumor — using whole-genome high-resolution SNP arrays. Five of the seven cases had their samples taken after chemotherapy and two were sampled before chemo.

"We chose arrays because it is a very robust method, where validated bioinformatic tools exist to precisely estimate exactly how large a fraction of tumor cells in a sample carry a certain genetic aberration. Also, high-[resolution] arrays are already routinely used to analyze pediatric tumors in many centers so translation to the clinic of our findings would be smoother," Gisselsson wrote.

Although resolution using this strategy was not to the single-nucleotide level, he explained that because childhood cancers typically show more large-scale chromosome changes than point mutations, the team still expected to catch most of the mutations present.

Using this approach, the researchers found that microdiversity was evident in the post-chemo patients' samples, but not in the two pre-chemo subjects.

In four cases, the group could also evaluate changes between the children's primary and metastatic samples, which all showed that additional mutations appeared to be acquired in the metastatic lesions relative to their primary tumors.

Overall, the data indicate that childhood tumors can indeed show microdiversity, and that this may predispose them to further genomic evolution in metastases.

The researchers then went on to a second study of 44 children with the kidney cancer nephroblastoma followed in the SIOP2001 Nephroblastoma Trial and Study, in which patients were treated with both pre- and post-operative chemotherapy.

Samples for all 44 subjects were obtained from nephrecotomy specimens collected after chemo.  Again using high-resolution SNP arrays, the group analyzed the level of microdiversity in each patient's specimen.

Overall, the team found that 20 of the 44 tumors had measurable microdiversity. When they compared the presence of microdiversity to data on the tumors' histology and patients' outcome data, the found that microdiversity was more prevalent in tumors with higher risk histology, in patients with high-stage disease, and in those who eventually died, compared to lower-risk and long-term surviving children.

Patients without microdiversity had 100 percent survival, and microdiversity significantly predicted cancer-specific and event-free survival in both the full cohort and in the largest histopathologic subset of patients, in which it was a better predictor of outcome than tumor stage, the authors wrote.

"The link is expected considering that clonal evolution has been proposed for a long time to be the very basis for chemotherapy resistance, [but] the surprise was that the association was as strong as it was," Gisselsson said in his email.

The group's finding, while only a first step, has interesting clinical implications in terms of potentially being able to predict which children with this cancer or potentially others are at greater risk of disease progression or vice versa.

This could allow clinicians to treat patients with different risk using different strategies, either in terms of therapy or monitoring.

The study authors wrote that microdiversity is a "particularly attractive clinical marker as it is a parameter possible to quantify using standard genome arrays and relatively simple bioinformatics operations."

Moreover, nephroblastoma may also be a particularly apt target for developing a microdiversity-based risk measure because no standard molecular prognostic currently exists for these cancers.

According to Gisselsson, whole-genome genotyping arrays could be a perfectly appropriate platform for potentially measuring tumor microdiversity in the clinical setting, but the team's results must first be confirmed and validated.

Currently the group is hoping to conduct a follow-up study using the International Society of Paediatric Oncology Renal Tumor Study Group clinical trial of children with nephroblastoma, to see if their results can be replicated in this larger prospective cohort.

The team is also working on additional data analyses, Gisselsson wrote, including whole exome sequencing and expression analyses of their initial tumors from neuroblastoma, nephroblastoma, and rhabdomyosarcoma patients.

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