Uterine sarcoma with KAT6B/A::KANSL1 fusion: a molecular and clinicopathological study on 9 cases

Abstract

Uterine sarcomas with KAT6B/A::KANSL1 fusion represent a new entity characterized by bland morphology, commonly with hybrid features of low-grade endometrial stromal sarcoma (LG-ESS) and tumors with smooth muscle differentiation. In our study, we performed a detailed morphological, immunohistochemical, and molecular analysis of 9 cases of these tumors. Six of those had been originally diagnosed as LG-ESS, one as leiomyoma, one as leiomyosarcoma, and the remaining case as sarcoma with the KAT6B/A::KANSL1 fusion. Seven cases showed overlapping features between endometrial stromal and smooth muscle tumors, one case resembled cellular leiomyoma, and one case resembled high-grade endometrial stromal sarcoma. Immunohistochemically, the tumors showed a common expression of smooth muscle markers and endometrial stromal markers. Molecular findings showed the KAT6B/A::KANSL1 fusion in all cases (by NGS and FISH). In addition, mutations affecting genes such as TP53, PDGFRB, NF1, RB1, PTEN, ATM, RB1, FANCD2, and TSC1 were present in all 5 cases with aggressive behavior. One patient with no evidence of disease showed no additional mutations, while another harbored a mutation of a single gene (ERCC3). Of the 8 patients with available follow-up, two died of disease, 3 are currently alive with disease, and 3 have no evidence of disease. The correct recognition of tumors with the KAT6B/A::KANSL1 fusion is essential because despite the bland morphological features of most cases, these tumors have a propensity for aggressive behavior.

Keywords: Endometrial stromal sarcoma; KAT6B/A::KANSL1 fusion; Next generation sequencing; Uterine tumor.

Fig. 1

Histological features of KAT6B/A::KANSL1 fused sarcomas. LG-ESS-like features with typical spiral arterioles (A) (case #1; 200x). Tumor with hybrid fibroblastic and smooth-muscle features (B) (case #9; 200x). Nonspecific spindle cell (C) and round cell (D) morphology with overlapping features between smooth muscle and endometrial stromal differentiation (case #4 and #7; 200x). Tumor resembling cellular leiomyoma with regressive changes (E) (case #3; 100x). Tumor with high-grade features (F) (case #6; 400x)

Fig. 2

Comprehensive characterization of nine sarcomas harboring KAT6B/A::KANSL1 fusion. Summary of morphological features observed (A). Results of immunohistochemical staining (B). Molecular landscape depicting genomic alterations and KAT6A/B::KANSL1 fusion characterization across the analysed samples (C, D). Legend: AWD: alive with disease; DOD: died of disease; inf: infiltrative; NA: not available; NED: no evidence of disease; Neg: negative; Pos: positive. Color-coded genetic alterations: orange, truncating variants; blue, missense variants; gray, copy number deletions; green, large insertions/deletions; blue + gray, concurrent missense variants and copy number deletions

Fig. 3

A principal component analysis (PCA) plot depicting the second and third principal components. The plot differentiates the KAT6A and KAT6B fusion partners through distinct color coding. Individual gene aberrations are denoted by their corresponding gene symbols. Disease status at last follow-up control is indicated for each case (AWD: alive with disease, DOD: died of disease, and NED: no evidence of disease)

Fig. 4

Gene set enrichment analyses of genes differentially expressed in KAT6B/A::KANSL1 sarcomas when compared to LG-ESS. Gene set ordinal association test (GOAT) was used to identify enriched categories within the GO database domain biological process (BP) (A). The cellular component (CC) and molecular functions (MF) domains can be found in Supplementary Fig. 5 (A, B). Effect size (ES) score type “ES up” (red circles) indicates that the gene set is enriched in genes with a positive gene effect size, “ES down” (in dark blue) indicates enrichment of negative gene effect sizes. Colored squares indicate hierarchical clustering of the gene sets. GSEA results visualized as a ridgeline plot, with overrepresentation analysis performed against the Gene Ontology (GO) biological process domain (B). Blue and red dots indicate expression change in individual genes. The underlying data accompanying both figures are provided in Supplementary Table 6 and 7