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Recurrent Rearrangements Identified in Rare Infant Soft Tissue Tumors

NEW YORK (GenomeWeb) – A new genomic and transcriptomic analysis of rare, soft tissue tumors that develop in infants has detected recurrent EGFR and BRAF rearrangements that may render them vulnerable to targeted treatment.

As they reported in Nature Communications today, researchers from Germany and the UK did whole-genome sequencing and RNA sequencing on samples from 18 infants with cryptogenic congenital mesoblastic nephroma (CMN) or infantile fibrosarcoma (IFS) soft tissue tumors, identifying EGFR internal tandem duplications (EGFR-ITD), intragenic duplications involving BRAF, and other suspicious rearrangements.

Through subsequent PCR-based screening experiments on hundreds more cases of CMN, IFS, and other soft tissue tumors from infants with nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, or clear cell sarcoma of the kidney, the team again saw recurrent EGFR-ITD in a significant proportion of classical or mixed CMN cases, and in a smaller subset of CMNs with cellular histology. On the other hand, within-BRAF duplications turned up in a handful of cellular CMN or IFS cases.

"[W]hile anatomically these cancers appear different, genetically they are very similar," co-first author Grace Collord, a pediatrics researcher affiliated with the Wellcome Trust Sanger Institute and the University of Cambridge, said in a statement. "We found mutations affecting EGFR and BRAF, both of which are targets for existing drugs."

Prior analyses have identified NTRK3 fusions — often in combination with ETV6 translocations — as driver changes in a subset of CMN cases, particularly those with cellular histology. Such tyrosine receptor kinase (TRK) fusions have prompted interest in early stage clinical trials on TRK inhibitors in fusion-containing soft tissue tumors, the team explained.

Even so, the investigators noted that informative or targetable alterations have not been found for many classical CMNs and other soft tissue tumors, prompting interest in more extensive genomic analyses of NTRK3 fusion-free soft tissue tumors.

For their new analysis, the researchers used Illumina HiSeq X instruments to sequence genomic DNA extracted from fresh frozen tumor tissue and matched normal samples representing 10 infants with classical CMN, three infants with CMN of cellular histology, four mixed CMN cases, and one IFS patient. They further profiled tumor samples from these infants with RNA sequencing on the Illumina HiSeq 2000.

The team's analyses of the sequence data suggested the soft tissue tumors had relatively low burdens of somatic point mutation, copy number alteration, or structural variation, although all 10 classical CMN tumors contained the in-frame EGFR-ITD. The EGFR-ITD was also present in two of the mixed cellularity CMN tumors.

One cellular and one mixed histology CMN tumor contained fusions involving the NTRK1 TRK, the researchers reported, and two of the CMN tumors with cellular histology contained intragenic BRAF rearrangements similar to those detected in IFS in the past.

The team used PCR to screen for similar rearrangements in tumors from 89 more CMN or IFS cases, 208 Wilms tumor cases, 20 cases of clear cell sarcoma of the kidney, three malignant rhabdoid tumor cases, and a dozen nephroblastomatosis cases, picking up EGFR-ITDs in 20 of 35 classical CMN cases, two of 17 cellular CMNs, and nine of 11 CMN tumors with mixed histology.

Three of the IFS tumors tested in the follow-up analysis harbored the BRAF rearrangements, the researchers reported, including two tumors with both BRAF rearrangements and ETV6-NTRK3 gene fusions.

"The finding of co-mutation of NTRK3 and BRAF in IFS raises the possibility of intrinsic resistance of some tumors to TRK inhibition, regardless of whether these mutations occur in the same clone or in independent competing clones," the authors wrote, calling such results "pertinent to clinical trials of TRK inhibitors in CMN and IFS."

"These considerations underscore the need for adequate genomic profiling in order to match patients to the most appropriate basket studies," they added, "and to enable meaningful interpretation of treatment responses."

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