Isolated signals in BCL2, MYC, BCL6, and DDIT3 FISH: implications for genetic alterations and protein dysregulation

Fluorescence in situ hybridization (FISH) break-apart probes are widely employed to detect gene rearrangements in malignant tumors. Notwithstanding their utility, the complex genetic alterations in tumors frequently give rise to isolated signals, the mechanisms underlying which remain poorly understood. This study aimed to elucidate the genetic causes of isolated FISH signals in lymphoma and myxoid liposarcoma samples, providing a more accurate basis for interpreting FISH results.

Six cases of lymphoma and myxoid liposarcoma, which showed isolated signals for BCL2, MYC, BCL6, or DDIT3 in FISH detection, were carefully screened. Whole genome resequencing (WGR) was employed to analyze the genetic variations present in these samples. In addition, immunohistochemistry was used to assess the expression levels of the corresponding proteins in these samples.

WGR results revealed that all six cases with isolated signals harbored target gene translocations, with 5'and 3'probe-binding region deletions or inversions detected in BCL2, MYC, and BCL6, and in the 5'probe-binding region of DDIT3. Additionally, overexpression of the corresponding proteins was present in samples with isolated BCL2, MYC, and BCL6 signals.

Deletions or inversions in the probe-binding sequence regions may disrupt probe recognition and binding, leading to isolated FISH signals for BCL2, MYC, BCL6, and DDIT3. Notably, in cases with isolated BCL2, MYC, or BCL6 signals, translocations involving these genes were associated with increased expression of their encoded proteins. These findings improve the understanding of FISH signal interpretation in tumor gene rearrangement detection and provide a valuable reference for clinical diagnosis.