CIC Break-Apart Fluorescence In Situ Hybridisation Misses a Subset of CIC-DUX4 Sarcomas: A Clinicopathological and Molecular Study

Abstract

Aims

Approximately 60–70% of high-grade round-cell sarcomas that lack the EWSR1 rearrangement harbour a rearrangement of the CIC gene, most commonly CIC-DUX4. Recent studies have established that CIC-rearranged sarcomas constitute a distinct group characterised by recognisable histology and immunoprofiles, such as positivity for ETV4 and WT1 and negativity for NKX2.2. Although these sarcomas are increasingly diagnosed in practice by fluorescence in situ hybridisation (FISH) with CIC break-apart probes, the optimal modality to diagnose these sarcomas has not been determined. In this study, we describe 4 round cell sarcomas that showed false-negative results by CIC break-apart FISH assays.

Methods and results

These sarcomas showed characteristic histology of CIC-rearranged sarcomas, and all were immunohistochemically positive for ETV4 and WT1 and negative for NKX2.2. Although FISH showed non-atypical negative signals for CIC rearrangement, high-throughput RNA sequencing identified CIC-DUX4 and its fusion breakpoint in all cases. Their clinical and histological findings as well as fusion points determined by RNA sequencing did not significantly differ from those of 9 FISH-positive CIC-DUX4 sarcoma cases. We estimated that the FISH false-negative rate for CIC-rearranged sarcomas was 14%. Although neither histology nor immunoprofiles (e.g., ETV4 and WT1) are entirely sensitive or specific for CIC-rearranged sarcomas, the observation that these 4 cases were successfully identified by such phenotypes suggested their practical utility.

Conclusions

CIC break-apart FISH assays missed a significant minority of CIC-DUX4 sarcomas, and full awareness of typical morphology and judicious immunohistochemical workups, including analyses of ETV4 and WT1, should complement diagnostic assessment.

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