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Comparison of Molecular Testing Methodologies for CIC-Rearranged Sarcomas
Selene C Koo1, Maria Cardenas2, Patricia Stow1
1From the Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (Koo, Stow, Neary, Shi, Furtado).
Archives of Pathology & Laboratory Medicine
|February 22, 2025
Summary
Detecting capicua transcriptional repressor (CIC) rearrangements is crucial for diagnosing CIC-rearranged sarcoma (CIC-RS). Fluorescence in situ hybridization (FISH), RNA-seq, and methylation profiling showed comparable false-negative rates, highlighting the need for careful reevaluation of results.
Area of Science:
- Oncology
- Molecular Pathology
- Genetics
Background:
- Molecular detection of capicua transcriptional repressor (CIC) rearrangement is critical for diagnosing CIC-rearranged sarcoma (CIC-RS).
- Accurate detection of CIC rearrangements is analytically challenging, impacting diagnostic certainty.
Purpose of the Study:
- To compare the technical performance of fluorescence in situ hybridization (FISH), whole-transcriptome sequencing (RNA-seq), and DNA methylation profiling for CIC-rearrangement detection.
- To evaluate these methods in a large cohort, predominantly pediatric, with suspected CIC-rearranged tumors.
Main Methods:
- Retrospective analysis of 44 tumors with suspected CIC rearrangement.
- Testing modalities included FISH (n=40), RNA-seq (n=31), and methylation array analysis (n=34).
- Comparison of results from multiple testing modalities for concordance and accuracy.
Main Results:
- Fusions were detected in 27 cases, with CIC::DUX4 being the most common (n=15).
- Apparent false-negative rates were 20% for FISH, 14% for RNA-seq, and 14% for methylation array analysis.
- Methylation array false-negatives occurred with CIC::LEUTX fusion, underscoring method-specific limitations.
Conclusions:
- Awareness of molecular testing pitfalls is critical for accurate CIC rearrangement detection.
- FISH results may require confirmation with immunohistochemistry or other molecular methods.
- Positive RNA-seq or methylation array results can be sufficient for CIC-RS diagnosis, but equivocal results necessitate reevaluation.
